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Kirk, Allan Douglas

Positions:

David C. Sabiston, Jr. Professor of Surgery

Surgery, Abdominal Transplant Surgery
School of Medicine

Professor of Surgery

Surgery, Abdominal Transplant Surgery
School of Medicine

Professor in the Department of Immunology

Immunology
School of Medicine

Professor in Pediatrics

Pediatrics
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Chair of Surgery

Surgery
School of Medicine

Education:

B.S. 1983

B.S. — Old Dominion University

M.D. 1987

M.D. — Duke University School of Medicine

Ph.D. 1992

Ph.D. — Duke University

Intern & Junior Resident, Surgery

Duke University

Research Fellow, Surgery

Duke University

Senior Resident, Surgery

Duke University

Chief Resident, Surgery

Duke University

Fellow, Multi Organ Transplantation

University of Wisconsin at Madison

News:

Grants:

American Journal of Transplantation

Administered By
Surgery, Abdominal Transplant Surgery
AwardedBy
American Society of Transplantation
Role
Principal Investigator
Start Date
January 01, 2016
End Date
December 31, 2020

Neonatal Porcine Islet Xenografts for the Treatment of Type 1 Diabetes

Administered By
Surgery, Abdominal Transplant Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2014
End Date
August 31, 2020

The Lung Transplant Clinical Trials Network (LT-CTN)

Administered By
Duke Clinical Research Institute
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
July 01, 2014
End Date
June 30, 2019

Immunomodulation to Optimize Vascularized Composite Allograft Integration for Limb Loss Therapy

Administered By
Surgery, Plastic, Maxillofacial, and Oral Surgery
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
February 28, 2015
End Date
February 27, 2019

Role of Mitochondrial Injury in the Pathogenesis of Primary Graft Dysfunction Following Cardiac Transplantation

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 2016
End Date
September 29, 2018

Positioning Vascilarized Composite Allotramsplantation within the Spectrum of Transplantation

Administered By
Surgery, Plastic, Maxillofacial, and Oral Surgery
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
December 15, 2014
End Date
September 14, 2018

Transplant Infectious Diseases Interdisciplinary Research Training Grant

Administered By
Medicine, Infectious Diseases
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 01, 2013
End Date
August 31, 2018

Transplant Tolerance in Non Human Primates

Administered By
Surgery, Abdominal Transplant Surgery
AwardedBy
Emory University
Role
Principal Investigator
Start Date
August 01, 2014
End Date
July 31, 2017

The Role of Rapamycin in Altering Graft Endothelial Cell Alloimmunogenicity

Administered By
Surgery
AwardedBy
American Society of Transplant Surgeons
Role
Principal Investigator
Start Date
September 01, 2016
End Date
June 30, 2017

Role of Mitochondrial Injury in the Pathogenesis of Primary Graft Dysfunction Following Cardiac Transplantation

Administered By
Surgery
AwardedBy
American Society of Transplantation
Role
Principal Investigator
Start Date
July 01, 2016
End Date
June 30, 2017

Exercise, Nitric Oxide Bioavailability and Arteriovenous Fistula Maturation

Administered By
Surgery, Vascular Surgery
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
July 15, 2014
End Date
June 30, 2017

Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients

Administered By
Surgery, Abdominal Transplant Surgery
AwardedBy
University of California - San Francisco
Role
Principal Investigator
Start Date
July 01, 2014
End Date
June 30, 2017

Phase 2 Study of Belatacept, Alemtuzumab, and Sirolimus in Renal Transplantation

Administered By
Surgery, Abdominal Transplant Surgery
AwardedBy
Food and Drug Administration
Role
Principal Investigator
Start Date
February 01, 2015
End Date
May 31, 2017

T Cell Maturation and the Nexus of Viral- and Allo-Immunity

Administered By
Surgery, Abdominal Transplant Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2014
End Date
May 31, 2017

CD57+CD4+ T cells in Belatacept-resistant Renal Allograft Rejection

Administered By
Surgery, Abdominal Transplant Surgery
AwardedBy
Bristol-Myers Squibb Company
Role
Principal Investigator
Start Date
August 31, 2016
End Date
April 01, 2017

Immune Tolerance Network - Flow Cytometry

Administered By
Surgery
AwardedBy
Benaroya Research Institute at Virginia Mason
Role
Principal Investigator
Start Date
February 01, 2016
End Date
January 31, 2017

(TEACH) Atemtuzumab, Costimulation Blockade and Sirolimus: A Tolerogenic Canvas for Donor Antigen Delivery via Mesenchymal

Administered By
Surgery, Abdominal Transplant Surgery
AwardedBy
Benaroya Research Institute at Virginia Mason
Role
Principal Investigator
Start Date
October 01, 2014
End Date
January 31, 2017

ITN056ST Optimal Co-Chair Protocol

Administered By
Surgery
AwardedBy
Benaroya Research Institute at Virginia Mason
Role
Principal Investigator
Start Date
October 01, 2014
End Date
January 31, 2017

ASTS-Alexion Presidential Student Mentor Grant

Administered By
Surgery, Abdominal Transplant Surgery
AwardedBy
American Society of Transplant Surgeons
Role
Principal Investigator
Start Date
July 01, 2015
End Date
October 31, 2016

Development of a Composite Tissue Allotransplantation Research Program

Administered By
Surgery, Plastic, Maxillofacial, and Oral Surgery
AwardedBy
Emory University
Role
Collaborator
Start Date
July 01, 2014
End Date
February 14, 2016

CD57+CD4+ T cells in Belatacept-resistant Renal Allograft Rejection

Administered By
Surgery, Abdominal Transplant Surgery
AwardedBy
Bristol-Myers Squibb Company
Role
Principal Investigator
Start Date
October 01, 2014
End Date
December 31, 2015

Transplant Tolerance in Non-Human Primates

Administered By
Surgery, Abdominal Transplant Surgery
AwardedBy
Emory University
Role
Principal Investigator
Start Date
May 01, 2014
End Date
July 31, 2014
Show More

Publications:

The Knife's Edge of Tolerance: Inducing Stable Multilineage Mixed Chimerism but With a Significant Risk of CMV Reactivation and Disease in Rhesus Macaques.

Although stable mixed-hematopoietic chimerism induces robust immune tolerance to solid organ allografts in mice, the translation of this strategy to large animal models and to patients has been challenging. We have previously shown that in MHC-matched nonhuman primates (NHPs), a busulfan plus combined belatacept and anti-CD154-based regimen could induce long-lived myeloid chimerism, but without T cell chimerism. In that setting, donor chimerism was eventually rejected, and tolerance to skin allografts was not achieved. Here, we describe an adaptation of this strategy, with the addition of low-dose total body irradiation to our conditioning regimen. This strategy has successfully induced multilineage hematopoietic chimerism in MHC-matched transplants that was stable for as long as 24 months posttransplant, the entire length of analysis. High-level T cell chimerism was achieved and associated with significant donor-specific prolongation of skin graft acceptance. However, we also observed significant infectious toxicities, prominently including cytomegalovirus (CMV) reactivation and end-organ disease in the setting of functional defects in anti-CMV T cell immunity. These results underscore the significant benefits that multilineage chimerism-induction approaches may represent to transplant patients as well as the inherent risks, and they emphasize the precision with which a clinically successful regimen will need to be formulated and then validated in NHP models.

Authors
Zheng, HB; Watkins, B; Tkachev, V; Yu, S; Tran, D; Furlan, S; Zeleski, K; Singh, K; Hamby, K; Hotchkiss, C; Lane, J; Gumber, S; Adams, AB; Cendales, L; Kirk, AD; Kaur, A; Blazar, BR; Larsen, CP; Kean, LS
MLA Citation
Zheng, HB, Watkins, B, Tkachev, V, Yu, S, Tran, D, Furlan, S, Zeleski, K, Singh, K, Hamby, K, Hotchkiss, C, Lane, J, Gumber, S, Adams, AB, Cendales, L, Kirk, AD, Kaur, A, Blazar, BR, Larsen, CP, and Kean, LS. "The Knife's Edge of Tolerance: Inducing Stable Multilineage Mixed Chimerism but With a Significant Risk of CMV Reactivation and Disease in Rhesus Macaques." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 17.3 (March 2017): 657-670.
PMID
27500470
Source
epmc
Published In
American Journal of Transplantation
Volume
17
Issue
3
Publish Date
2017
Start Page
657
End Page
670
DOI
10.1111/ajt.14006

Nucleic acid scavenging microfiber mesh inhibits trauma-induced inflammation and thrombosis.

Trauma patients produce a host of danger signals and high levels of damage-associated molecular patterns (DAMPs) after cellular injury and tissue damage. These DAMPs are directly and indirectly involved in the pathogenesis of various inflammatory and thrombotic complications in patients with severe injuries. No effective therapeutic agents for the removal of DAMPs from blood or tissue fluid have been developed. Herein, we demonstrated that nucleic acid binding polymers, e.g., polyethylenimine (PEI) and polyamidoamine dendrimers, immobilized onto electrospun microfiber mesh can effectively capture various DAMPs, such as extracellular DNAs and high mobility group box 1 (HMGB1). Furthermore, treatment with PEI-immobilized microfiber mesh abrogated the ability of DAMPs, released from dead and dying cells in culture or found in patients following traumatic injury, to activate innate immune responses and coagulation in vitro and in vivo. Nucleic acid scavenging microfiber meshes represent an effective strategy to combat inflammation and thrombosis in trauma.

Authors
Lee, J; Jackman, JG; Kwun, J; Manook, M; Moreno, A; Elster, EA; Kirk, AD; Leong, KW; Sullenger, BA
MLA Citation
Lee, J, Jackman, JG, Kwun, J, Manook, M, Moreno, A, Elster, EA, Kirk, AD, Leong, KW, and Sullenger, BA. "Nucleic acid scavenging microfiber mesh inhibits trauma-induced inflammation and thrombosis." Biomaterials 120 (March 2017): 94-102.
PMID
28049065
Source
epmc
Published In
Biomaterials
Volume
120
Publish Date
2017
Start Page
94
End Page
102
DOI
10.1016/j.biomaterials.2016.12.024

Premature T Cell Senescence in Pediatric CKD.

An individual's immune function, susceptibility to infection, and response to immunosuppressive therapy are influenced in part by his/her T cell maturation state. Although childhood is the most dynamic period of immune maturation, scant information regarding the variability of T cell maturation in children with renal disease is available. In this study, we compared the T cell phenotype in children with renal failure (n=80) with that in healthy children (n=20) using multiparameter flow cytometry to detect markers of T cell maturation, exhaustion, and senescence known to influence immune function. We correlated data with the degree of renal failure (dialysis or nondialysis), prior immunosuppression use, and markers of inflammation (C-reactive protein and inflammatory cytokines) to assess the influence of these factors on T cell phenotype. Children with renal disease had highly variable and often markedly skewed maturation phenotypes, including CD4/CD8 ratio reversal, increased terminal effector differentiation in CD8+ T cells, reduction in the proportion of naïve T cells, evidence of T cell exhaustion and senescence, and variable loss of T cell CD28 expression. These findings were most significant in patients who had experienced major immune insults, particularly prior immunosuppressive drug exposure. In conclusion, children with renal disease have exceptional heterogeneity in the T cell repertoire. Cognizance of this heterogeneity might inform risk stratification with regard to the balance between infectious risk and response to immunosuppressive therapy, such as that required for autoimmune disease and transplantation.

Authors
George, RP; Mehta, AK; Perez, SD; Winterberg, P; Cheeseman, J; Johnson, B; Kwun, J; Monday, S; Stempora, L; Warshaw, B; Kirk, AD
MLA Citation
George, RP, Mehta, AK, Perez, SD, Winterberg, P, Cheeseman, J, Johnson, B, Kwun, J, Monday, S, Stempora, L, Warshaw, B, and Kirk, AD. "Premature T Cell Senescence in Pediatric CKD." Journal of the American Society of Nephrology : JASN 28.1 (January 2017): 359-367.
PMID
27413076
Source
epmc
Published In
Journal of the American Society of Nephrology : JASN
Volume
28
Issue
1
Publish Date
2017
Start Page
359
End Page
367
DOI
10.1681/asn.2016010053

Relationship Among Viremia/Viral Infection, Alloimmunity, and Nutritional Parameters in the First Year After Pediatric Kidney Transplantation.

The Immune Development in Pediatric Transplantation (IMPACT) study was conducted to evaluate relationships among alloimmunity, protective immunity, immune development, physical parameters, and clinical outcome in children undergoing kidney transplantation. We prospectively evaluated biopsy-proven acute rejection (BPAR), de novo donor-specific antibody (dnDSA) formation, viremia, viral infection, T cell immunophenotyping, and body mass index (BMI)/weight Z scores in the first year posttransplantation in 106 pediatric kidney transplant recipients. Outcomes were excellent with no deaths and 98% graft survival. Rejection and dnDSAs occurred in 24% and 22%, respectively. Pretransplant cytomegalovirus (CMV) and Epstein-Barr virus (EBV) serologies and subsequent viremia were unrelated to BPAR or dnDSA. Viremia occurred in 73% of children (EBV, 34%; CMV, 23%; BMK viremia, 23%; and JC virus, 21%). Memory lymphocyte phenotype at baseline was not predictive of alloimmune complications. Patients who developed viral infection had lower weight (-2.1) (p = 0.028) and BMI (-1.2) (p = 0.048) Z scores at transplantation. The weight difference persisted to 12 months compared with patients without infection (p = 0.038). These data indicate that there is a high prevalence of viral disease after pediatric kidney transplantation, and underweight status at transplantation appears to be a risk factor for subsequent viral infection. The occurrence of viremia/viral infection is not associated with alloimmune events.

Authors
Ettenger, R; Chin, H; Kesler, K; Bridges, N; Grimm, P; Reed, EF; Sarwal, M; Sibley, R; Tsai, E; Warshaw, B; Kirk, AD
MLA Citation
Ettenger, R, Chin, H, Kesler, K, Bridges, N, Grimm, P, Reed, EF, Sarwal, M, Sibley, R, Tsai, E, Warshaw, B, and Kirk, AD. "Relationship Among Viremia/Viral Infection, Alloimmunity, and Nutritional Parameters in the First Year After Pediatric Kidney Transplantation." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (December 18, 2016).
PMID
27989013
Source
epmc
Published In
American Journal of Transplantation
Publish Date
2016
DOI
10.1111/ajt.14169

Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model.

Costimulation blockade (CoB) via belatacept is a lower-morbidity alternative to calcineurin inhibitor (CNI)-based immunosuppression. However, it has higher rates of early acute rejection. These early rejections are mediated in part by memory T cells, which have reduced dependence on the pathway targeted by belatacept and increased adhesion molecule expression. One such molecule is leukocyte function antigen (LFA)-1. LFA-1 exists in two forms: a commonly expressed, low-affinity form and a transient, high-affinity form, expressed only during activation. We have shown that antibodies reactive with LFA-1 regardless of its configuration are effective in eliminating memory T cells but at the cost of impaired protective immunity. Here we test two novel agents, leukotoxin A and AL-579, each of which targets the high-affinity form of LFA-1, to determine whether this more precise targeting prevents belatacept-resistant rejection. Despite evidence of ex vivo and in vivo ligand-specific activity, neither agent when combined with belatacept proved superior to belatacept monotherapy. Leukotoxin A approached a ceiling of toxicity before efficacy, while AL-579 failed to significantly alter the peripheral immune response. These data, and prior studies, suggest that LFA-1 blockade may not be a suitable adjuvant agent for CoB-resistant rejection.

Authors
Samy, KP; Anderson, DJ; Lo, DJ; Mulvihill, MS; Song, M; Farris, AB; Parker, BS; MacDonald, AL; Lu, C; Springer, TA; Kachlany, SC; Reimann, KA; How, T; Leopardi, FV; Franke, KS; Williams, KD; Collins, BH; Kirk, AD
MLA Citation
Samy, KP, Anderson, DJ, Lo, DJ, Mulvihill, MS, Song, M, Farris, AB, Parker, BS, MacDonald, AL, Lu, C, Springer, TA, Kachlany, SC, Reimann, KA, How, T, Leopardi, FV, Franke, KS, Williams, KD, Collins, BH, and Kirk, AD. "Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (November 26, 2016).
PMID
27888551
Source
epmc
Published In
American Journal of Transplantation
Publish Date
2016
DOI
10.1111/ajt.14141

Toll-Like Receptor Signaling as a Prognostic Tool in Trauma Patients

Authors
Darrabie, MD; Lee, J; Cheeseman, J; Limkakeng, AT; Vaslef, SN; Sullenger, BA; Kirk, AD
MLA Citation
Darrabie, MD, Lee, J, Cheeseman, J, Limkakeng, AT, Vaslef, SN, Sullenger, BA, and Kirk, AD. "Toll-Like Receptor Signaling as a Prognostic Tool in Trauma Patients." October 2016.
Source
wos-lite
Published In
Journal of The American College of Surgeons
Volume
223
Issue
4
Publish Date
2016
Start Page
S159
End Page
S160

Changes in Urinary Microbiome Populations Correlate in Kidney Transplants With Interstitial Fibrosis and Tubular Atrophy Documented in Early Surveillance Biopsies.

An unbalanced microbiome may lead to disease by creating aberrant immune responses. A recent association of cellular rejection with the development of interstitial fibrosis and tubular atrophy (IFTA) suggests the role of immune-mediated tissue injury. We hypothesized that developing IFTA correlates with altered urinary tract microbiomes (UMBs). UMBs at two serial time points, 1 and 6-8 months posttransplant, were assessed by 16S microbial ribosomal gene sequencing in 25 patients developing biopsy-proven IFTA compared to 23 transplant patients with normal biopsies and excellent function (TX) and 20 healthy nontransplant controls (HC). Streptococcus, the dominant genera in HC males, was lower in IFTA and TX males at 1 month compared to HCs. At 6-8 months, Streptococcus was further decreased in IFTA males, but normalized in TX. IFTA males and females had increases in number of genera per sample at 6-8 months. UMB composition varied substantially between individuals in all groups. Despite the wide variation in UMBs between individuals, IFTA was associated with a loss in dominant resident urinary microbes in males, and a parallel increase in nonresident, pathogenic bacteria in males and females. UMB changes may contribute to IFTA development by alteration of the host immune response.

Authors
Modena, BD; Milam, R; Harrison, F; Cheeseman, JA; Abecassis, MM; Friedewald, JJ; Kirk, AD; Salomon, DR
MLA Citation
Modena, BD, Milam, R, Harrison, F, Cheeseman, JA, Abecassis, MM, Friedewald, JJ, Kirk, AD, and Salomon, DR. "Changes in Urinary Microbiome Populations Correlate in Kidney Transplants With Interstitial Fibrosis and Tubular Atrophy Documented in Early Surveillance Biopsies." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (September 6, 2016).
PMID
27597148
Source
epmc
Published In
American Journal of Transplantation
Publish Date
2016
DOI
10.1111/ajt.14038

Cryopreserved Mesenchymal Stromal Cells Are Susceptible to T-Cell Mediated Apoptosis Which Is Partly Rescued by IFNγ Licensing.

We have previously demonstrated that cryopreservation and thawing lead to altered Mesenchymal stromal cells (MSC) functionalities. Here, we further analyzed MSC's fitness post freeze-thaw. We have observed that thawed MSC can suppress T-cell proliferation when separated from them by transwell membrane and the effect is lost in a MSC:T-cell coculture system. Unlike actively growing MSCs, thawed MSCs were lysed upon coculture with activated autologous Peripheral Blood Mononuclear Cells (PBMCs) and the lysing effect was further enhanced with allogeneic PBMCs. The use of DMSO-free cryoprotectants or substitution of Human Serum Albumin (HSA) with human platelet lysate in freezing media and use of autophagy or caspase inhibitors did not prevent thaw defects. We tested the hypothesis that IFNγ prelicensing before cryobanking can enhance MSC fitness post thaw. Post thawing, IFNγ licensed MSCs inhibit T cell proliferation as well as fresh MSCs and this effect can be blocked by 1-methyl Tryptophan, an Indoleamine 2,3-dioxygenase (IDO) inhibitor. In addition, IFNγ prelicensed thawed MSCs inhibit the degranulation of cytotoxic T cells while IFNγ unlicensed thawed MSCs failed to do so. However, IFNγ prelicensed thawed MSCs do not deploy lung tropism in vivo following intravenous injection as well as fresh MSCs suggesting that IFNγ prelicensing does not fully rescue thaw-induced lung homing defect. We identified reversible and irreversible cryoinjury mechanisms that result in susceptibility to host T-cell cytolysis and affect MSC's cell survival and tissue distribution. The susceptibility of MSC to negative effects of cryopreservation and the potential to mitigate the effects with IFNγ prelicensing may inform strategies to enhance the therapeutic efficacy of MSC in clinical use. Stem Cells 2016;34:2429-2442.

Authors
Chinnadurai, R; Copland, IB; Garcia, MA; Petersen, CT; Lewis, CN; Waller, EK; Kirk, AD; Galipeau, J
MLA Citation
Chinnadurai, R, Copland, IB, Garcia, MA, Petersen, CT, Lewis, CN, Waller, EK, Kirk, AD, and Galipeau, J. "Cryopreserved Mesenchymal Stromal Cells Are Susceptible to T-Cell Mediated Apoptosis Which Is Partly Rescued by IFNγ Licensing." Stem cells (Dayton, Ohio) 34.9 (September 2016): 2429-2442.
PMID
27299362
Source
epmc
Published In
Stem Cells
Volume
34
Issue
9
Publish Date
2016
Start Page
2429
End Page
2442
DOI
10.1002/stem.2415

Precision Medicine for Critical Illness and Injury.

Authors
Buchman, TG; Billiar, TR; Elster, E; Kirk, AD; Rimawi, RH; Vodovotz, Y; Zehnbauer, BA
MLA Citation
Buchman, TG, Billiar, TR, Elster, E, Kirk, AD, Rimawi, RH, Vodovotz, Y, and Zehnbauer, BA. "Precision Medicine for Critical Illness and Injury." Critical care medicine 44.9 (September 2016): 1635-1638.
PMID
27525993
Source
epmc
Published In
Critical Care Medicine
Volume
44
Issue
9
Publish Date
2016
Start Page
1635
End Page
1638
DOI
10.1097/ccm.0000000000002028

Memory T cells in organ transplantation: progress and challenges.

Antigen-experienced T cells, also known as memory T cells, are functionally and phenotypically distinct from naive T cells. Their enhanced expression of adhesion molecules and reduced requirement for co-stimulation enables them to mount potent and rapid recall responses to subsequent antigen encounters. Memory T cells generated in response to prior antigen exposures can cross-react with other nonidentical, but similar, antigens. This heterologous cross-reactivity not only enhances protective immune responses, but also engenders de novo alloimmunity. This latter characteristic is increasingly recognized as a potential barrier to allograft acceptance that is worthy of immunotherapeutic intervention, and several approaches have been investigated. Calcineurin inhibition effectively controls memory T-cell responses to allografts, but this benefit comes at the expense of increased infectious morbidity. Lymphocyte depletion eliminates allospecific T cells but spares memory T cells to some extent, such that patients do not completely lose protective immunity. Co-stimulation blockade is associated with reduced adverse-effect profiles and improved graft function relative to calcineurin inhibition, but lacks efficacy in controlling memory T-cell responses. Targeting the adhesion molecules that are upregulated on memory T cells might offer additional means to control co-stimulation-blockade-resistant memory T-cell responses.

Authors
Espinosa, JR; Samy, KP; Kirk, AD
MLA Citation
Espinosa, JR, Samy, KP, and Kirk, AD. "Memory T cells in organ transplantation: progress and challenges." Nature reviews. Nephrology 12.6 (June 2016): 339-347. (Review)
PMID
26923209
Source
epmc
Published In
Nature Reviews Nephrology
Volume
12
Issue
6
Publish Date
2016
Start Page
339
End Page
347
DOI
10.1038/nrneph.2016.9

Anti-Leukocyte Function-Associated Antigen 1 Therapy in a Nonhuman Primate Renal Transplant Model of Costimulation Blockade-Resistant Rejection.

Costimulation blockade with the fusion protein belatacept provides a desirable side effect profile and improvement in renal function compared with calcineurin inhibition in renal transplantation. This comes at the cost of increased rates of early acute rejection. Blockade of the integrin molecule leukocyte function-associated antigen 1 (LFA-1) has been shown to be an effective adjuvant to costimulation blockade in a rigorous nonhuman primate (NHP) model of islet transplantation; therefore, we sought to test this combination in an NHP renal transplant model. Rhesus macaques received belatacept maintenance therapy with or without the addition of LFA-1 blockade, which was achieved using a murine-derived LFA-1-specific antibody TS1/22. Additional experiments were performed using chimeric rhesus IgG1 (TS1/22R1) or IgG4 (TS1/22R4) variants, each engineered to limit antibody clearance. Despite evidence of proper binding to the target molecule and impaired cellular egress from the intravascular space indicative of a therapeutic effect similar to prior islet studies, LFA-1 blockade failed to significantly prolong graft survival. Furthermore, evidence of impaired protective immunity against cytomegalovirus was observed. These data highlight the difficulties in translating treatment regimens between organ models and suggest that the primarily vascularized renal model is more robust with regard to belatacept-resistant rejection than the islet model.

Authors
Anderson, DJ; Lo, DJ; Leopardi, F; Song, M; Turgeon, NA; Strobert, EA; Jenkins, JB; Wang, R; Reimann, KA; Larsen, CP; Kirk, AD
MLA Citation
Anderson, DJ, Lo, DJ, Leopardi, F, Song, M, Turgeon, NA, Strobert, EA, Jenkins, JB, Wang, R, Reimann, KA, Larsen, CP, and Kirk, AD. "Anti-Leukocyte Function-Associated Antigen 1 Therapy in a Nonhuman Primate Renal Transplant Model of Costimulation Blockade-Resistant Rejection." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 16.5 (May 2016): 1456-1464.
PMID
26602755
Source
epmc
Published In
American Journal of Transplantation
Volume
16
Issue
5
Publish Date
2016
Start Page
1456
End Page
1464
DOI
10.1111/ajt.13628

CD57(+) CD4 T Cells Underlie Belatacept-Resistant Allograft Rejection.

Belatacept is a B7-specific fusion protein used to prevent allograft rejection by blocking T cell costimulation. Generally efficacious, it fails to prevent acute rejection in a sizable minority of patients. In experimental models, memory T cells mediate costimulation blockade-resistant rejection (CoBRR), but this remains undefined in humans. To explore relationships between individual patients' immune cell phenotypes and CoBRR, we studied patients receiving belatacept or conventional calcineurin inhibitor-based immunosuppression. We identified a population of CD57(+) PD1(-) CD4 T cells present prior to transplantation that correlated with CoBRR. Contrary to data recognizing CD57 as a marker of senescence on CD8 T cells, we discovered a nonsenescent, cytolytic phenotype associated with CD57 on CD4 T cells. Moreover, CD57(+) CD4 T cells expressed high levels of adhesion molecules implicated in experimental CoBRR, were CD28(-) , expressed a transcriptional phenotype broadly defining allograft rejection and were shown to be present in rejecting human kidney allografts. These data implicate CD57(+) CD4 T cells in clinical CoBRR. If prospectively validated, this characteristic could identify patients at higher risk for acute rejection on belatacept-based therapy.

Authors
Espinosa, J; Herr, F; Tharp, G; Bosinger, S; Song, M; Farris, AB; George, R; Cheeseman, J; Stempora, L; Townsend, R; Durrbach, A; Kirk, AD
MLA Citation
Espinosa, J, Herr, F, Tharp, G, Bosinger, S, Song, M, Farris, AB, George, R, Cheeseman, J, Stempora, L, Townsend, R, Durrbach, A, and Kirk, AD. "CD57(+) CD4 T Cells Underlie Belatacept-Resistant Allograft Rejection." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 16.4 (April 2016): 1102-1112.
PMID
26603381
Source
epmc
Published In
American Journal of Transplantation
Volume
16
Issue
4
Publish Date
2016
Start Page
1102
End Page
1112
DOI
10.1111/ajt.13613

Postdepletion Lymphocyte Reconstitution During Belatacept and Rapamycin Treatment in Kidney Transplant Recipients.

Belatacept is used to prevent allograft rejection but fails to do so in a sizable minority of patients due to inadequate control of costimulation-resistant T cells. In this study, we report control of costimulation-resistant rejection when belatacept was combined with perioperative alemtuzumab-mediated lymphocyte depletion and rapamycin. To assess the means by which the alemtuzumab, belatacept and rapamycin (ABR) regimen controls belatacept-resistant rejection, we studied 20 ABR-treated patients and characterized peripheral lymphocyte phenotype and functional responses to donor, third-party and viral antigens using flow cytometry, intracellular cytokine staining and carboxyfluorescein succinimidyl ester-based lymphocyte proliferation. Compared with conventional immunosuppression in 10 patients, lymphocyte depletion evoked substantial homeostatic lymphocyte activation balanced by regulatory T and B cell phenotypes. The reconstituted T cell repertoire was enriched for CD28(+) naïve cells, notably diminished in belatacept-resistant CD28(-) memory subsets and depleted of polyfunctional donor-specific T cells but able to respond to third-party and latent herpes viruses. B cell responses were similarly favorable, without alloantibody development and a reduction in memory subsets-changes not seen in conventionally treated patients. The ABR regimen uniquely altered the immune profile, producing a repertoire enriched for CD28(+) T cells, hyporesponsive to donor alloantigen and competent in its protective immune capabilities. The resulting repertoire was permissive for control of rejection with belatacept monotherapy.

Authors
Xu, H; Samy, KP; Guasch, A; Mead, SI; Ghali, A; Mehta, A; Stempora, L; Kirk, AD
MLA Citation
Xu, H, Samy, KP, Guasch, A, Mead, SI, Ghali, A, Mehta, A, Stempora, L, and Kirk, AD. "Postdepletion Lymphocyte Reconstitution During Belatacept and Rapamycin Treatment in Kidney Transplant Recipients." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 16.2 (February 2016): 550-564.
PMID
26436448
Source
epmc
Published In
American Journal of Transplantation
Volume
16
Issue
2
Publish Date
2016
Start Page
550
End Page
564
DOI
10.1111/ajt.13469

APOL1 Genotype and Kidney Transplantation Outcomes From Deceased African American Donors.

Two apolipoprotein L1 gene (APOL1) renal-risk variants in donors and African American (AA) recipient race are associated with worse allograft survival in deceased-donor kidney transplantation (DDKT) from AA donors. To detect other factors impacting allograft survival from deceased AA kidney donors, APOL1 renal-risk variants were genotyped in additional AA kidney donors.The APOL1 genotypes were linked to outcomes in 478 newly analyzed DDKTs in the Scientific Registry of Transplant Recipients. Multivariate analyses accounting for recipient age, sex, race, panel-reactive antibody level, HLA match, cold ischemia time, donor age, and expanded criteria donation were performed. These 478 transplantations and 675 DDKTs from a prior report were jointly analyzed.Fully adjusted analyses limited to the new 478 DDKTs replicated shorter renal allograft survival in recipients of APOL1 2-renal-risk-variant kidneys (hazard ratio [HR], 2.00; P = 0.03). Combined analysis of 1153 DDKTs from AA donors revealed donor APOL1 high-risk genotype (HR, 2.05; P = 3 × 10), older donor age (HR, 1.18; P = 0.05), and younger recipient age (HR, 0.70; P = 0.001) adversely impacted allograft survival. Although prolonged allograft survival was seen in many recipients of APOL1 2-renal-risk-variant kidneys, follow-up serum creatinine concentrations were higher than that in recipients of 0/1 APOL1 renal-risk-variant kidneys. A competing risk analysis revealed that APOL1 impacted renal allograft survival, but not recipient survival. Interactions between donor age and APOL1 genotype on renal allograft survival were nonsignificant.Shorter renal allograft survival is reproducibly observed after DDKT from APOL1 2-renal-risk-variant donors. Younger recipient age and older donor age have independent adverse effects on renal allograft survival.

Authors
Freedman, BI; Pastan, SO; Israni, AK; Schladt, D; Julian, BA; Gautreaux, MD; Hauptfeld, V; Bray, RA; Gebel, HM; Kirk, AD; Gaston, RS; Rogers, J; Farney, AC; Orlando, G; Stratta, RJ; Mohan, S; Ma, L; Langefeld, CD; Bowden, DW; Hicks, PJ; Palmer, ND; Palanisamy, A; Reeves-Daniel, AM; Brown, WM; Divers, J
MLA Citation
Freedman, BI, Pastan, SO, Israni, AK, Schladt, D, Julian, BA, Gautreaux, MD, Hauptfeld, V, Bray, RA, Gebel, HM, Kirk, AD, Gaston, RS, Rogers, J, Farney, AC, Orlando, G, Stratta, RJ, Mohan, S, Ma, L, Langefeld, CD, Bowden, DW, Hicks, PJ, Palmer, ND, Palanisamy, A, Reeves-Daniel, AM, Brown, WM, and Divers, J. "APOL1 Genotype and Kidney Transplantation Outcomes From Deceased African American Donors." Transplantation 100.1 (January 2016): 194-202.
PMID
26566060
Source
epmc
Published In
Transplantation
Volume
100
Issue
1
Publish Date
2016
Start Page
194
End Page
202
DOI
10.1097/tp.0000000000000969

First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes--Chapter 4: pre-clinical efficacy and complication data required to justify a clinical trial.

In 2009, the International Xenotransplantation Association (IXA) published a consensus document that provided guidelines and "recommendations" (not regulations) for those contemplating clinical trials of porcine islet transplantation. These guidelines included the IXA's opinion on what constituted "rigorous pre-clinical studies using the most relevant animal models" and were based on "non-human primate testing." We now report our discussion following a careful review of the 2009 guidelines as they relate to pre-clinical testing. In summary, we do not believe there is a need to greatly modify the conclusions and recommendations of the original consensus document. Pre-clinical studies should be sufficiently rigorous to provide optimism that a clinical trial is likely to be safe and has a realistic chance of success, but need not be so demanding that success might only be achieved by very prolonged experimentation, as this would not be in the interests of patients whose quality of life might benefit immensely from a successful islet xenotransplant. We believe these guidelines will be of benefit to both investigators planning a clinical trial and to institutions and regulatory authorities considering a proposal for a clinical trial. In addition, we suggest consideration should be given to establishing an IXA Clinical Trial Advisory Committee that would be available to advise (but not regulate) researchers considering initiating a clinical trial of xenotransplantation.

Authors
Cooper, DKC; Bottino, R; Gianello, P; Graham, M; Hawthorne, WJ; Kirk, AD; Korsgren, O; Park, C-G; Weber, C
MLA Citation
Cooper, DKC, Bottino, R, Gianello, P, Graham, M, Hawthorne, WJ, Kirk, AD, Korsgren, O, Park, C-G, and Weber, C. "First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes--Chapter 4: pre-clinical efficacy and complication data required to justify a clinical trial." Xenotransplantation 23.1 (January 2016): 46-52.
PMID
26916706
Source
epmc
Published In
Xenotransplantation
Volume
23
Issue
1
Publish Date
2016
Start Page
46
End Page
52
DOI
10.1111/xen.12226

Deceased-Donor Apolipoprotein L1 Renal-Risk Variants Have Minimal Effects on Liver Transplant Outcomes.

Apolipoprotein L1 gene (APOL1) G1 and G2 renal-risk variants, common in populations with recent African ancestry, are strongly associated with non-diabetic nephropathy, end-stage kidney disease, and shorter allograft survival in deceased-donor kidneys (autosomal recessive inheritance). Circulating APOL1 protein is synthesized primarily in the liver and hydrodynamic gene delivery of APOL1 G1 and G2 risk variants has caused hepatic necrosis in a murine model.To evaluate the impact of these variants in liver transplantation, this multicenter study investigated the association of APOL1 G1 and G2 alleles in deceased African American liver donors with allograft survival. Transplant recipients were followed for liver allograft survival using data from the Scientific Registry of Transplant Recipients.Of the 639 liver donors evaluated, 247 had no APOL1 risk allele, 300 had 1 risk allele, and 92 had 2 risk alleles. Graft failure assessed at 15 days, 6 months, 1 year and total was not significantly associated with donor APOL1 genotype (p-values = 0.25, 0.19, 0.67 and 0.89, respectively).In contrast to kidney transplantation, deceased-donor APOL1 G1 and G2 risk variants do not significantly impact outcomes in liver transplantation.

Authors
Dorr, CR; Freedman, BI; Hicks, PJ; Brown, WM; Russell, GB; Julian, BA; Pastan, SO; Gautreaux, MD; Muthusamy, A; Chinnakotla, S; Hauptfeld, V; Bray, RA; Kirk, AD; Divers, J; Israni, AK
MLA Citation
Dorr, CR, Freedman, BI, Hicks, PJ, Brown, WM, Russell, GB, Julian, BA, Pastan, SO, Gautreaux, MD, Muthusamy, A, Chinnakotla, S, Hauptfeld, V, Bray, RA, Kirk, AD, Divers, J, and Israni, AK. "Deceased-Donor Apolipoprotein L1 Renal-Risk Variants Have Minimal Effects on Liver Transplant Outcomes." PloS one 11.4 (January 2016): e0152775-.
PMID
27054572
Source
epmc
Published In
PloS one
Volume
11
Issue
4
Publish Date
2016
Start Page
e0152775
DOI
10.1371/journal.pone.0152775

Longitudinal Studies of a B Cell-Derived Signature of Tolerance in Renal Transplant Recipients

Authors
Newell, KA; Asare, A; Sanz, I; Wei, C; Rosenberg, A; Gao, Z; Kanaparthi, S; Asare, S; Lim, N; Stahly, M; Howell, M; Knechtle, S; Kirk, A; Marks, WH; Kawai, T; Spitzer, T; Tolkoff-Rubin, N; Sykes, M; Sachs, DH; Cosimi, AB; Burlingham, WJ; Phippard, D; Turka, LA
MLA Citation
Newell, KA, Asare, A, Sanz, I, Wei, C, Rosenberg, A, Gao, Z, Kanaparthi, S, Asare, S, Lim, N, Stahly, M, Howell, M, Knechtle, S, Kirk, A, Marks, WH, Kawai, T, Spitzer, T, Tolkoff-Rubin, N, Sykes, M, Sachs, DH, Cosimi, AB, Burlingham, WJ, Phippard, D, and Turka, LA. "Longitudinal Studies of a B Cell-Derived Signature of Tolerance in Renal Transplant Recipients." American Journal of Transplantation 15.11 (November 2015): 2908-2920.
Source
crossref
Published In
American Journal of Transplantation
Volume
15
Issue
11
Publish Date
2015
Start Page
2908
End Page
2920
DOI
10.1111/ajt.13480

Immunologic Aging in Adults with Congenital Heart Disease: Does Infant Sternotomy Matter?

Thymectomy is performed routinely in infants undergoing cardiothoracic surgery. Children post-sternotomy have decreased numbers of T lymphocytes, although the mechanisms involved and long-term consequences of this have not been defined. We hypothesized that lymphopenia in patients with adult congenital heart disease (ACHD) would be reflective of premature T cell maturation and exhaustion. Adults with ACHD who had sternotomy to repair congenital heart disease as infants (<1 year) and age-matched ACHD patients without prior sternotomy were studied using polychromatic flow cytometry interrogating markers of lymphocyte maturation, exhaustion and senescence. Group differences were analyzed using Mann-Whitney U and Fisher's exact tests. Eighteen ACHD patients aged 21-40 years participated: 10 cases and 8 controls. Median age at sternotomy for cases was 52 days. Cases and controls were matched for age (28.9 vs. 29.1 years; p = 0.83), gender (p = 0.15) and race (p = 0.62) and had similar case complexity. Cases had a lower mean percentage of cytotoxic CD8 lymphocytes compared to controls (26.8 vs. 33.9 %; p = 0.016), with fewer naive, undifferentiated CD8 T cells (31.0 vs. 53.6 %; p = 0.027). CD8 cells expressing PD1, a marker of immune exhaustion, trended higher in cases versus controls (25.6 vs. 19.0 %; p = 0.083). Mean percentage of CD4 cells was higher in cases versus controls (65.6 vs. 59.6 %; p = 0.027), without differences in CD4 T cell maturation subtype. In summary, ACHD patients who undergo sternotomy as infants exhibit differences in T lymphocyte composition compared to ACHD controls, suggesting accelerated immunologic exhaustion. Investigation is warranted to assess the progressive nature and clinical impact of this immune phenotypic change.

Authors
Elder, RW; George, RP; McCabe, NM; Rodriguez Iii, FH; Book, WM; Mahle, WT; Kirk, AD
MLA Citation
Elder, RW, George, RP, McCabe, NM, Rodriguez Iii, FH, Book, WM, Mahle, WT, and Kirk, AD. "Immunologic Aging in Adults with Congenital Heart Disease: Does Infant Sternotomy Matter?." Pediatric cardiology 36.7 (October 2015): 1411-1416.
PMID
25916315
Source
epmc
Published In
Pediatric Cardiology
Volume
36
Issue
7
Publish Date
2015
Start Page
1411
End Page
1416
DOI
10.1007/s00246-015-1174-9

Immune responses to transplants

© 2016 by John Wiley & Sons, Ltd. All rights reserved.Organ transplantation is the accepted and indeed the preferred treatment for most forms of end-stage organ failure. While the function of the immune system may be to protect against infection or "danger", the immune system, if not suppressed, also efficiently recognizes an organ transplant from a genetically disparate individual. This initiates an immune response, or an alloresponse, against the transplant. The alloimmune response involves adaptive and innate immune systems; T and B cells are the principle mediators of cellular and antibody-mediated rejection. Distinct immunologic and histologic differences exist between acute cellular, antibody mediated, and chronic rejection. Tolerance strategies include immunoregulation, costimulation blockade, and mixed chimerism; mechanisms of tolerance induction may differ from those that are needed to sustain it. Memory T cells are a significant barrier to tolerance induction. Identification of biomarkers for rejection and/or tolerance could initiate individualized immune modulation regimens.

Authors
Lo, DJ; Kirk, AD
MLA Citation
Lo, DJ, and Kirk, AD. "Immune responses to transplants." Transplant Immunology. September 12, 2015. 142-163.
Source
scopus
Publish Date
2015
Start Page
142
End Page
163
DOI
10.1002/9781119072997.ch8

Deceased donor multidrug resistance protein 1 and caveolin 1 gene variants may influence allograft survival in kidney transplantation.

Variants in donor multidrug resistance protein 1 (ABCB1) and caveolin 1 (CAV1) genes are associated with renal allograft failure after transplantation in Europeans. Here we assessed transplantation outcomes of kidneys from 368 African American (AA) and 314 European American (EA) deceased donors based on 38 single-nucleotide polymorphisms (SNPs) spanning ABCB1 and 16 SNPs spanning CAV1, including previously associated index and haplotype-tagging SNPs. Tests for association with time to allograft failure were performed for the 1233 resultant kidney transplantations, adjusting for recipient age, sex, ethnicity, cold ischemia time, panel reactive antibody, human leukocyte antigen match, expanded-criteria donation, and APOL1-nephropathy variants in AA donors. Interaction analyses between APOL1 with ABCB1 and CAV1 were performed. In a meta-analysis of all transplantations, ABCB1 index SNP rs1045642 was associated with time to allograft failure and other ABCB1 SNPs were nominally associated, but not CAV1 SNPs. ABCB1 SNP rs1045642 showed consistent effects with the 558 transplantations from EA donors, but not with the 675 transplantations from AA donors. ABCB1 SNP rs956825 and CAV1 SNP rs6466583 interacted with APOL1 in transplants from AA donors. Thus, the T allele at ABCB1 rs1045642 is associated with shorter renal allograft survival for kidneys from American donors. Interactions between ABCB1 and CAV1 with APOL1 may influence allograft failure for transplanted kidneys from AA donors.

Authors
Ma, J; Divers, J; Palmer, ND; Julian, BA; Israni, AK; Schladt, D; Pastan, SO; Chattrabhuti, K; Gautreaux, MD; Hauptfeld, V; Bray, RA; Kirk, AD; Brown, WM; Gaston, RS; Rogers, J; Farney, AC; Orlando, G; Stratta, RJ; Guan, M; Palanisamy, A; Reeves-Daniel, AM; Bowden, DW; Langefeld, CD; Hicks, PJ; Ma, L; Freedman, BI
MLA Citation
Ma, J, Divers, J, Palmer, ND, Julian, BA, Israni, AK, Schladt, D, Pastan, SO, Chattrabhuti, K, Gautreaux, MD, Hauptfeld, V, Bray, RA, Kirk, AD, Brown, WM, Gaston, RS, Rogers, J, Farney, AC, Orlando, G, Stratta, RJ, Guan, M, Palanisamy, A, Reeves-Daniel, AM, Bowden, DW, Langefeld, CD, Hicks, PJ, Ma, L, and Freedman, BI. "Deceased donor multidrug resistance protein 1 and caveolin 1 gene variants may influence allograft survival in kidney transplantation." Kidney international 88.3 (September 2015): 584-592.
PMID
25853335
Source
epmc
Published In
Kidney international
Volume
88
Issue
3
Publish Date
2015
Start Page
584
End Page
592
DOI
10.1038/ki.2015.105

Lessons of War: Turning Data Into Decisions.

Recent conflicts in Afghanistan and Iraq produced a substantial number of critically wounded service-members. We collected biomarker and clinical information from 73 patients who sustained 116 life-threatening combat wounds, and sought to determine if the data could be used to predict the likelihood of wound failure.From each patient, we collected clinical information, serum, wound effluent, and tissue prior to and at each surgical débridement. Inflammatory cytokines were quantified in both the serum and effluent, as were gene expression targets. The primary outcome was successful wound healing. Computer intensive methods were used to derive prognostic models that were internally validated using target shuffling and cross-validation methods. A second cohort of eighteen critically injured civilian patients was evaluated to determine if similar inflammatory responses were observed.The best-performing models enhanced clinical observation with biomarker data from the serum and wound effluent, an indicator that systemic inflammatory conditions contribute to local wound failure. A Random Forest model containing ten variables demonstrated the highest accuracy (AUC 0.79). Decision Curve Analysis indicated that the use of this model would improve clinical outcomes and reduce unnecessary surgical procedures. Civilian trauma patients demonstrated similar inflammatory responses and an equivalent wound failure rate, indicating that the model may be generalizable to civilian settings.Using advanced analytics, we successfully codified clinical and biomarker data from combat patients into a potentially generalizable decision support tool. Analysis of inflammatory data from critically ill patients with acute injury may inform decision-making to improve clinical outcomes and reduce healthcare costs.United States Department of Defense Health Programs.

Authors
Forsberg, JA; Potter, BK; Wagner, MB; Vickers, A; Dente, CJ; Kirk, AD; Elster, EA
MLA Citation
Forsberg, JA, Potter, BK, Wagner, MB, Vickers, A, Dente, CJ, Kirk, AD, and Elster, EA. "Lessons of War: Turning Data Into Decisions." EBioMedicine 2.9 (September 2015): 1235-1242.
PMID
26501123
Source
epmc
Published In
EBioMedicine
Volume
2
Issue
9
Publish Date
2015
Start Page
1235
End Page
1242
DOI
10.1016/j.ebiom.2015.07.022

Tacrolimus to Belatacept Conversion Following Hand Transplantation: A Case Report.

Vascularized composite allotransplantation (VCA) has emerged as a viable limb replacement strategy for selected patients with upper limb amputation. However, allograft rejection has been seen in essentially all reported VCA recipients indicating a requirement for substantial immunosuppressive therapy. Calcineurin inhibitors have served as the centerpiece agent in all reported cases, and CNI-associated complications associated with the broad therapeutic effects and side effects of calcineurin inhibitors have been similarly common. Recently, belatacept has been approved as a calcineurin inhibitor replacement in kidney transplantation, but to date, its use in VCA has not been reported. Herein, we report on the case of a hand transplant recipient who developed recurrent acute rejection with alloantibody formation and concomitant calcineurin inhibitor nephrotoxicity, all of which resolved upon conversion from a maintenance regimen of tacrolimus, mycophenolate mofetil and steroids to belatacept and sirolimus. This case indicates that belatacept may be a reasonable maintenance immunosuppressive alternative for use in VCA, providing sufficient prophylaxis from rejection with a reduced side effect profile, the latter being particularly relevant for nonlife threatening conditions typically treated by VCA.

Authors
Cendales, L; Bray, R; Gebel, H; Brewster, L; Elbein, R; Farthing, D; Song, M; Parker, D; Stillman, A; Pearson, T; Kirk, AD
MLA Citation
Cendales, L, Bray, R, Gebel, H, Brewster, L, Elbein, R, Farthing, D, Song, M, Parker, D, Stillman, A, Pearson, T, and Kirk, AD. "Tacrolimus to Belatacept Conversion Following Hand Transplantation: A Case Report." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 15.8 (August 2015): 2250-2255.
PMID
25773260
Source
epmc
Published In
American Journal of Transplantation
Volume
15
Issue
8
Publish Date
2015
Start Page
2250
End Page
2255
DOI
10.1111/ajt.13217

Studies Introducing Costimulation Blockade for Vascularized Composite Allografts in Nonhuman Primates.

Vascularized composite allografts (VCAs) are technically feasible. Similar to other organ transplants, VCAs are hampered by the toxicity and incomplete efficacy associated with conventional immunosuppression. Complications attributable to calcineurin inhibitors remain prevalent in the clinical cases reported to date, and these loom particularly large given the nonlifesaving nature of VCAs. Additionally, acute rejection remains almost ubiquitous, albeit controllable with current agents. Costimulation blockade offers the potential to provide prophylaxis from rejection without the adverse consequences of calcineurin-based regimens. In this study, we used a nonhuman-primate model of VCA in conjunction with immunosuppressive regimens containing combinations of B7-specific costimulation blockade with and without adhesion blockade with LFA3-Ig to determine what adjunctive role these agents could play in VCA transplantation when combined with more conventional agents. Compared to tacrolimus, the addition of belatacept improved rejection free allograft survival. The combination with LFA3-Ig reduced CD2(hi) memory T cells, however did not provide additional protection against allograft rejection and hindered protective immunity. Histology paralleled clinical histopathology and Banff grading. These data provide the basis for the study of costimulation blockade in VCA in a relevant preclinical model.

Authors
Freitas, AM; Samy, KP; Farris, AB; Leopardi, FV; Song, M; Stempora, L; Strobert, EA; Jenkins, JA; Kirk, AD; Cendales, LC
MLA Citation
Freitas, AM, Samy, KP, Farris, AB, Leopardi, FV, Song, M, Stempora, L, Strobert, EA, Jenkins, JA, Kirk, AD, and Cendales, LC. "Studies Introducing Costimulation Blockade for Vascularized Composite Allografts in Nonhuman Primates." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 15.8 (August 2015): 2240-2249.
PMID
26139552
Source
epmc
Published In
American Journal of Transplantation
Volume
15
Issue
8
Publish Date
2015
Start Page
2240
End Page
2249
DOI
10.1111/ajt.13379

CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCR  repertoire

Authors
Suessmuth, Y; Mukherjee, R; Watkins, B; Koura, DT; Finstermeier, K; Desmarais, C; Stempora, L; Horan, JT; Langston, A; Qayed, M; Khoury, HJ; Grizzle, A; Cheeseman, JA; Conger, JA; Robertson, J; Garrett, A; Kirk, AD; Waller, EK; Blazar, BR; Mehta, AK; Robins, HS; Kean, LS
MLA Citation
Suessmuth, Y, Mukherjee, R, Watkins, B, Koura, DT, Finstermeier, K, Desmarais, C, Stempora, L, Horan, JT, Langston, A, Qayed, M, Khoury, HJ, Grizzle, A, Cheeseman, JA, Conger, JA, Robertson, J, Garrett, A, Kirk, AD, Waller, EK, Blazar, BR, Mehta, AK, Robins, HS, and Kean, LS. "CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCR  repertoire." Blood 125.25 (June 18, 2015): 3835-3850.
Source
crossref
Published In
Blood
Volume
125
Issue
25
Publish Date
2015
Start Page
3835
End Page
3850
DOI
10.1182/blood-2015-03-631853

Procedure Delegation by Attending Surgeons Performing Concurrent Operations in Academic Medical Centers: Balancing Safety and Efficiency.

Authors
Beasley, GM; Pappas, TN; Kirk, AD
MLA Citation
Beasley, GM, Pappas, TN, and Kirk, AD. "Procedure Delegation by Attending Surgeons Performing Concurrent Operations in Academic Medical Centers: Balancing Safety and Efficiency." Annals of surgery 261.6 (June 2015): 1044-1045.
PMID
25775075
Source
epmc
Published In
Annals of Surgery
Volume
261
Issue
6
Publish Date
2015
Start Page
1044
End Page
1045
DOI
10.1097/sla.0000000000001208

Viral-induced CD28 loss evokes costimulation independent alloimmunity.

Belatacept, a B7-specific fusion protein, blocks CD28-B7 costimulation and prevents kidney allograft rejection. However, it is ineffective in a sizable minority of patients. Although T-cell receptor and CD28 engagement are known to initiate T-cell activation, many human antigen-experienced T-cells lose CD28, and can be activated independent of CD28 signals. We posit that these cells are central drivers of costimulation blockade resistant rejection (CoBRR) and propose that CoBRR might relate to an accumulation of CD28(-) T-cells resulting from viral antigen exposure.We infected C57BL/6 mice with polyomavirus (a BK virus analog), murine cytomegalovirus (a human cytomegalovirus analog), and gammaherpesvirus (HV68; an Epstein-Barr virus analog) and assessed for CD28 expression relative to mock infection controls. We then used mixed lymphocyte reaction (MLR) assays to assess the alloreactive response of these mice against major histocompatibility complex-mismatched cells.We demonstrated that infection with polyomavirus, murine CMV, and HV68 can induce CD28 downregulation in mice. We showed that these analogs of clinically relevant human viruses enable lymphocytes from infected mice to launch an anamnestic, costimulation blockade resistant, alloreactive response against major histocompatibility complex-mismatched cells without prior alloantigen exposure. Further analysis revealed that gammherpesvirus-induced oligoclonal T-cell expansion is required for the increased alloreactivity.Virus exposure results in reduced T-cell expression of CD28, the target of costimulation blockade therapy. These viruses also contribute to increased alloreactivity. Thus, CD28 downregulation after viral infection may play a seminal role in driving CoBRR.

Authors
Mou, D; Espinosa, JE; Stempora, L; Iwakoshi, NN; Kirk, AD
MLA Citation
Mou, D, Espinosa, JE, Stempora, L, Iwakoshi, NN, and Kirk, AD. "Viral-induced CD28 loss evokes costimulation independent alloimmunity." The Journal of surgical research 196.2 (June 2015): 241-246.
PMID
25801976
Source
epmc
Published In
Journal of Surgical Research
Volume
196
Issue
2
Publish Date
2015
Start Page
241
End Page
246
DOI
10.1016/j.jss.2015.02.033

Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure.

Apolipoprotein L1 gene (APOL1) nephropathy variants in African American deceased kidney donors were associated with shorter renal allograft survival in a prior single-center report. APOL1 G1 and G2 variants were genotyped in newly accrued DNA samples from African American deceased donors of kidneys recovered and/or transplanted in Alabama and North Carolina. APOL1 genotypes and allograft outcomes in subsequent transplants from 55 U.S. centers were linked, adjusting for age, sex and race/ethnicity of recipients, HLA match, cold ischemia time, panel reactive antibody levels, and donor type. For 221 transplantations from kidneys recovered in Alabama, there was a statistical trend toward shorter allograft survival in recipients of two-APOL1-nephropathy-variant kidneys (hazard ratio [HR] 2.71; p = 0.06). For all 675 kidneys transplanted from donors at both centers, APOL1 genotype (HR 2.26; p = 0.001) and African American recipient race/ethnicity (HR 1.60; p = 0.03) were associated with allograft failure. Kidneys from African American deceased donors with two APOL1 nephropathy variants reproducibly associate with higher risk for allograft failure after transplantation. These findings warrant consideration of rapidly genotyping deceased African American kidney donors for APOL1 risk variants at organ recovery and incorporation of results into allocation and informed-consent processes.

Authors
Freedman, BI; Julian, BA; Pastan, SO; Israni, AK; Schladt, D; Gautreaux, MD; Hauptfeld, V; Bray, RA; Gebel, HM; Kirk, AD; Gaston, RS; Rogers, J; Farney, AC; Orlando, G; Stratta, RJ; Mohan, S; Ma, L; Langefeld, CD; Hicks, PJ; Palmer, ND; Adams, PL; Palanisamy, A; Reeves-Daniel, AM; Divers, J
MLA Citation
Freedman, BI, Julian, BA, Pastan, SO, Israni, AK, Schladt, D, Gautreaux, MD, Hauptfeld, V, Bray, RA, Gebel, HM, Kirk, AD, Gaston, RS, Rogers, J, Farney, AC, Orlando, G, Stratta, RJ, Mohan, S, Ma, L, Langefeld, CD, Hicks, PJ, Palmer, ND, Adams, PL, Palanisamy, A, Reeves-Daniel, AM, and Divers, J. "Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 15.6 (June 2015): 1615-1622.
PMID
25809272
Source
epmc
Published In
American Journal of Transplantation
Volume
15
Issue
6
Publish Date
2015
Start Page
1615
End Page
1622
DOI
10.1111/ajt.13223

Dual islet transplantation modeling of the instant blood-mediated inflammatory reaction.

Islet xenotransplantation is a potential treatment for diabetes without the limitations of tissue availability. Although successful experimentally, early islet loss remains substantial and attributed to an instant blood-mediated inflammatory reaction (IBMIR). This syndrome of islet destruction has been incompletely defined and characterization in pig-to-primate models has been hampered by logistical and statistical limitations of large animal studies. To further investigate IBMIR, we developed a novel in vivo dual islet transplant model to precisely characterize IBMIR as proof-of-concept that this model can serve to properly control experiments comparing modified xenoislet preparations. WT and α1,3-galactosyltransferase knockout (GTKO) neonatal porcine islets were studied in nonimmunosuppressed rhesus macaques. Inert polyethylene microspheres served as a control for the effects of portal embolization. Digital analysis of immunohistochemistry targeting IBMIR mediators was performed at 1 and 24 h after intraportal islet infusion. Early findings observed in transplanted islets include complement and antibody deposition, and infiltration by neutrophils, macrophages and platelets. Insulin, complement, antibody, neutrophils, macrophages and platelets were similar between GTKO and WT islets, with increasing macrophage infiltration at 24 h in both phenotypes. This model provides an objective and internally controlled study of distinct islet preparations and documents the temporal histology of IBMIR.

Authors
Martin, BM; Samy, KP; Lowe, MC; Thompson, PW; Cano, J; Farris, AB; Song, M; Dove, CR; Leopardi, FV; Strobert, EA; Jenkins, JB; Collins, BH; Larsen, CP; Kirk, AD
MLA Citation
Martin, BM, Samy, KP, Lowe, MC, Thompson, PW, Cano, J, Farris, AB, Song, M, Dove, CR, Leopardi, FV, Strobert, EA, Jenkins, JB, Collins, BH, Larsen, CP, and Kirk, AD. "Dual islet transplantation modeling of the instant blood-mediated inflammatory reaction." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 15.5 (May 2015): 1241-1252.
PMID
25702898
Source
epmc
Published In
American Journal of Transplantation
Volume
15
Issue
5
Publish Date
2015
Start Page
1241
End Page
1252
DOI
10.1111/ajt.13098

A pilot trial targeting the ICOS-ICOS-L pathway in nonhuman primate kidney transplantation.

Costimulation blockade with the B7-CD28 pathway-specific agent belatacept is now used in clinical kidney transplantation, but its efficacy remains imperfect. Numerous alternate costimulatory pathways have been proposed as targets to synergize with belatacept, one of which being the inducible costimulator (ICOS)-ICOS ligand (ICOS-L) pathway. Combined ICOS-ICOS-L and CD28-B7 blockade has been shown to prevent rejection in mice, but has not been studied in primates. We therefore tested a novel ICOS-Ig human Fc-fusion protein in a nonhuman primate (NHP) kidney transplant model alone and in combination with belatacept. ICOS-Ig did not prolong rejection-free survival as a monotherapy or in combination with belatacept. In ICOS-Ig alone treated animals, most graft-infiltrating CD4(+) and CD8(+) T cells expressed ICOS, and ICOS(+) T cells were present in peripheral blood to a lesser degree. Adding belatacept reduced the proportion of graft-infiltrating ICOS(+) T cells and virtually eliminated their presence in peripheral blood. Graft-infiltrating T cells in belatacept-resistant rejection were primarily CD8(+) CD28(-) , but importantly, very few CD8(+) CD28(-) T cells expressed ICOS. We conclude that ICOS-Ig, alone or combined with belatacept, does not prolong renal allograft survival in NHPs. This may relate to selective loss of ICOS with CD28 loss.

Authors
Lo, DJ; Anderson, DJ; Song, M; Leopardi, F; Farris, AB; Strobert, E; Chapin, S; Devens, B; Karrer, E; Kirk, AD
MLA Citation
Lo, DJ, Anderson, DJ, Song, M, Leopardi, F, Farris, AB, Strobert, E, Chapin, S, Devens, B, Karrer, E, and Kirk, AD. "A pilot trial targeting the ICOS-ICOS-L pathway in nonhuman primate kidney transplantation." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 15.4 (April 2015): 984-992.
PMID
25703015
Source
epmc
Published In
American Journal of Transplantation
Volume
15
Issue
4
Publish Date
2015
Start Page
984
End Page
992
DOI
10.1111/ajt.13100

Systems biological analyses reveal the hepatitis C virus (HCV)-specific regulation of hematopoietic development.

Chronic liver disease is characterized by the liver enrichment of myeloid dendritic cells (DCs). To assess the role of disease on myelopoiesis, we utilized a systems biology approach to study development in liver-resident cells expressing stem cell marker CD34. In patients with endstage liver disease, liver CD34+ cells were comprised of two subsets, designated CD34+CD146+ and CD34+CD146-, and hematopoietic function was restricted to CD34+CD146- cells. Liver CD34 frequencies were reduced during nonalcoholic steatohepatitis (NASH) and chronic hepatitis C virus (HCV) compared to alcohol liver disease (ALD), and this reduction correlated with viral load in the HCV cohort. To better understand the relationship between liver CD34+CD146+ and CD34+CD146- subsets and any effects of disease on CD34 development, we used gene expression profiling and computational modeling to compare each subset during ALD and HCV. For CD34+CD146+ cells, increased expression of endothelial cell genes including von Willebrand factor, VE-cadherin, and eNOS were observed when compared to CD34+CD146- cells, and minimal effects of ALD and HCV diseases on gene expression were observed. Importantly for CD34+CD146- cells, chronic HCV was associated with a distinct "imprint" of programs related to cell cycle, DNA repair, chemotaxis, development, and activation, with an emphasis on myeloid and B lymphocyte lineages. This HCV signature was further translated in side-by-side analyses, where HCV CD34+CD146- cells demonstrated superior hematopoietic growth, colony formation, and diversification compared to ALD and NASH when cultured identically. Disease-associated effects on hematopoiesis were also evident by phenotypic alterations in the expression of CD14, HLA-DR, and CD16 by myeloid progeny cells.Etiology drives progenitor fate within diseased tissues. The liver may be a useful source of hematopoietic cells for therapy, or as therapeutic targets.

Authors
Velazquez, VM; Uebelhoer, LS; Thapa, M; Ibegbu, CC; Courtney, C; Bosinger, SE; Magliocca, JF; Adams, AB; Kirk, AD; Knechtle, SJ; Kalman, D; Suthar, MS; Grakoui, A
MLA Citation
Velazquez, VM, Uebelhoer, LS, Thapa, M, Ibegbu, CC, Courtney, C, Bosinger, SE, Magliocca, JF, Adams, AB, Kirk, AD, Knechtle, SJ, Kalman, D, Suthar, MS, and Grakoui, A. "Systems biological analyses reveal the hepatitis C virus (HCV)-specific regulation of hematopoietic development." Hepatology (Baltimore, Md.) 61.3 (March 2015): 843-856.
PMID
25331524
Source
epmc
Published In
Hepatology
Volume
61
Issue
3
Publish Date
2015
Start Page
843
End Page
856
DOI
10.1002/hep.27575

Immunosuppressive Biologic Agents

Authors
MacConmara, M; Nwadei, I; Kirk, AD
MLA Citation
MacConmara, M, Nwadei, I, and Kirk, AD. "Immunosuppressive Biologic Agents." Transplantation of the Liver: Third Edition. January 28, 2015. 1343-1353.
Source
scopus
Publish Date
2015
Start Page
1343
End Page
1353
DOI
10.1016/B978-1-4557-0268-8.00096-8

Long-Term Toxicity of Immunosuppressive Therapy

Authors
Ruiz, R; Kirk, AD
MLA Citation
Ruiz, R, and Kirk, AD. "Long-Term Toxicity of Immunosuppressive Therapy." Transplantation of the Liver: Third Edition. January 28, 2015. 1354-1363.
Source
scopus
Publish Date
2015
Start Page
1354
End Page
1363
DOI
10.1016/B978-1-4557-0268-8.00097-X

The new OPTN kidney allocation policy: potential for inequitable access among highly sensitized patients.

Authors
Bray, RA; Brannon, P; Breitenbach, C; Bryan, C; Chen, D-F; Lai, J; McRacken, T; Kirk, A; Kaplan, B; Pearson, T; Gebel, HM
MLA Citation
Bray, RA, Brannon, P, Breitenbach, C, Bryan, C, Chen, D-F, Lai, J, McRacken, T, Kirk, A, Kaplan, B, Pearson, T, and Gebel, HM. "The new OPTN kidney allocation policy: potential for inequitable access among highly sensitized patients." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 15.1 (January 2015): 284-285. (Letter)
PMID
25403877
Source
epmc
Published In
American Journal of Transplantation
Volume
15
Issue
1
Publish Date
2015
Start Page
284
End Page
285
DOI
10.1111/ajt.13061

Mitigation of autophagy ameliorates hepatocellular damage following ischemia-reperfusion injury in murine steatotic liver

Authors
Gupta, NA; Kolachala, VL; Jiang, R; Abramowsky, C; Shenoi, A; Kosters, A; Pavuluri, H; Anania, F; Kirk, AD
MLA Citation
Gupta, NA, Kolachala, VL, Jiang, R, Abramowsky, C, Shenoi, A, Kosters, A, Pavuluri, H, Anania, F, and Kirk, AD. "Mitigation of autophagy ameliorates hepatocellular damage following ischemia-reperfusion injury in murine steatotic liver." AJP: Gastrointestinal and Liver Physiology 307.11 (December 1, 2014): G1088-G1099.
Source
crossref
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
307
Issue
11
Publish Date
2014
Start Page
G1088
End Page
G1099
DOI
10.1152/ajpgi.00210.2014

Superiority of Rapamycin Over Tacrolimus in Preserving Nonhuman Primate Treg Half-Life and Phenotype After Adoptive Transfer

Authors
Singh, K; Stempora, L; Harvey, RD; Kirk, AD; Larsen, CP; Blazar, BR; Kean, LS
MLA Citation
Singh, K, Stempora, L, Harvey, RD, Kirk, AD, Larsen, CP, Blazar, BR, and Kean, LS. "Superiority of Rapamycin Over Tacrolimus in Preserving Nonhuman Primate Treg Half-Life and Phenotype After Adoptive Transfer." American Journal of Transplantation 14.12 (December 2014): 2691-2703.
Source
crossref
Published In
American Journal of Transplantation
Volume
14
Issue
12
Publish Date
2014
Start Page
2691
End Page
2703
DOI
10.1111/ajt.12934

The kSORT Assay to Detect Renal Transplant Patients at High Risk for Acute Rejection: Results of the Multicenter AART Study

Authors
Roedder, S; Sigdel, T; Salomonis, N; Hsieh, S; Dai, H; Bestard, O; Metes, D; Zeevi, A; Gritsch, A; Cheeseman, J; Macedo, C; Peddy, R; Medeiros, M; Vincenti, F; Asher, N; Salvatierra, O; Shapiro, R; Kirk, A; Reed, E; Sarwal, MM
MLA Citation
Roedder, S, Sigdel, T, Salomonis, N, Hsieh, S, Dai, H, Bestard, O, Metes, D, Zeevi, A, Gritsch, A, Cheeseman, J, Macedo, C, Peddy, R, Medeiros, M, Vincenti, F, Asher, N, Salvatierra, O, Shapiro, R, Kirk, A, Reed, E, and Sarwal, MM. "The kSORT Assay to Detect Renal Transplant Patients at High Risk for Acute Rejection: Results of the Multicenter AART Study." Ed. G Remuzzi. PLoS Medicine 11.11 (November 11, 2014): e1001759-e1001759.
Source
crossref
Published In
PLoS medicine
Volume
11
Issue
11
Publish Date
2014
Start Page
e1001759
End Page
e1001759
DOI
10.1371/journal.pmed.1001759

CD28 negative T cells: is their loss our gain?

CD28 is a primary costimulation molecule for T cell activation. However, during the course of activation some T cells lose this molecule and assume a CD28-independent existence. These CD28- T cells are generally antigen-experienced and highly differentiated. CD28- T cells are functionally heterogeneous. Their characteristics vary largely on the context in which they are found and range from having enhanced cytotoxic abilities to promoting immune regulation. Thus, CD28 loss appears to be more of a marker for advanced differentiation regardless of the cytotoxic or regulatory function being conducted by the T cell. CD28- T cells are now being recognized as playing significant roles in several human diseases. Various functional CD28- populations have been characterized in inflammatory conditions, infections and cancers. Of note, the recent introduction of costimulation blockade-based therapies, particularly those that inhibit CD28-B7 interactions, has made CD28 loss particularly relevant for solid organ transplantation. Certain CD28- T cell populations seem to promote allograft tolerance whereas others contribute to alloreactivity and costimulation blockade resistant rejection. Elucidating the interplay between these populations and characterizing the determinants of their ultimate function may have relevance for clinical risk stratification and personal determination of optimal posttransplant immune management.

Authors
Mou, D; Espinosa, J; Lo, DJ; Kirk, AD
MLA Citation
Mou, D, Espinosa, J, Lo, DJ, and Kirk, AD. "CD28 negative T cells: is their loss our gain?." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 14.11 (November 2014): 2460-2466. (Review)
PMID
25323029
Source
epmc
Published In
American Journal of Transplantation
Volume
14
Issue
11
Publish Date
2014
Start Page
2460
End Page
2466
DOI
10.1111/ajt.12937

Actin Cytoskeletal Disruption following Cryopreservation Alters the Biodistribution of Human Mesenchymal Stromal Cells In Vivo

Authors
Chinnadurai, R; Garcia, MA; Sakurai, Y; Lam, WA; Kirk, AD; Galipeau, J; Copland, IB
MLA Citation
Chinnadurai, R, Garcia, MA, Sakurai, Y, Lam, WA, Kirk, AD, Galipeau, J, and Copland, IB. "Actin Cytoskeletal Disruption following Cryopreservation Alters the Biodistribution of Human Mesenchymal Stromal Cells In Vivo." Stem Cell Reports 3.1 (July 2014): 60-72.
Source
crossref
Published In
Stem Cell Reports
Volume
3
Issue
1
Publish Date
2014
Start Page
60
End Page
72
DOI
10.1016/j.stemcr.2014.05.003

Renal Transplantation Using Belatacept Without Maintenance Steroids or Calcineurin Inhibitors

Authors
Kirk, AD; Guasch, A; Xu, H; Cheeseman, J; Mead, SI; Ghali, A; Mehta, AK; Wu, D; Gebel, H; Bray, R; Horan, J; Kean, LS; Larsen, CP; Pearson, TC
MLA Citation
Kirk, AD, Guasch, A, Xu, H, Cheeseman, J, Mead, SI, Ghali, A, Mehta, AK, Wu, D, Gebel, H, Bray, R, Horan, J, Kean, LS, Larsen, CP, and Pearson, TC. "Renal Transplantation Using Belatacept Without Maintenance Steroids or Calcineurin Inhibitors." American Journal of Transplantation 14.5 (May 2014): 1142-1151.
Source
crossref
Published In
American Journal of Transplantation
Volume
14
Issue
5
Publish Date
2014
Start Page
1142
End Page
1151
DOI
10.1111/ajt.12712

Islet cell xenotransplantation: a serious look toward the clinic

Authors
Samy, KP; Martin, BM; Turgeon, NA; Kirk, AD
MLA Citation
Samy, KP, Martin, BM, Turgeon, NA, and Kirk, AD. "Islet cell xenotransplantation: a serious look toward the clinic." Xenotransplantation 21.3 (May 2014): 221-229.
Source
crossref
Published In
Xenotransplantation
Volume
21
Issue
3
Publish Date
2014
Start Page
221
End Page
229
DOI
10.1111/xen.12095

Bile Acid Aspiration Associated With Lung Chemical Profile Linked to Other Biomarkers of Injury After Lung Transplantation

Authors
Neujahr, DC; Uppal, K; Force, SD; Fernandez, F; Lawrence, C; Pickens, A; Bag, R; Lockard, C; Kirk, AD; Tran, V; Lee, K; Jones, DP; Park, Y
MLA Citation
Neujahr, DC, Uppal, K, Force, SD, Fernandez, F, Lawrence, C, Pickens, A, Bag, R, Lockard, C, Kirk, AD, Tran, V, Lee, K, Jones, DP, and Park, Y. "Bile Acid Aspiration Associated With Lung Chemical Profile Linked to Other Biomarkers of Injury After Lung Transplantation." American Journal of Transplantation 14.4 (April 2014): 841-848.
Source
crossref
Published In
American Journal of Transplantation
Volume
14
Issue
4
Publish Date
2014
Start Page
841
End Page
848
DOI
10.1111/ajt.12631

The role of donor-specific HLA alloantibodies in liver transplantation.

The impact of donor-specific HLA alloantibodies (DSA) on short- and long-term liver transplant outcome is not clearly defined. While it is clear that not all levels of allosensitization produce overt clinical injury, and that liver allografts possess some degree of alloantibody resistance, alloantibody-mediated adverse consequences are increasingly being recognized. To better define the current state of this topic, we assembled experts to provide insights, explore controversies and develop recommendations for future research on the consequences of DSA in liver transplantation. This article summarizes the proceedings of this inaugural meeting. Several insights emerged. Acute antibody-mediated rejection (AMR), although rarely diagnosed, is increasingly understood to overlap with T cell-mediated rejection. Isolated liver allograft recipients are at increased risk of early allograft immunologic injury when preformed DSA are high titer and persist posttransplantation. Persons who undergo simultaneous liver-kidney transplantation are at risk of renal AMR when Class II DSA persist posttransplantation. Other under-appreciated DSA associations include ductopenia and fibrosis, plasma cell hepatitis, biliary strictures and accelerated fibrosis associated with recurrent liver disease. Standardized DSA testing and diagnostic criteria for both acute and chronic AMR are needed to distil existing associations into etiological processes in order to develop responsive therapeutic strategies.

Authors
O'Leary, JG; Demetris, AJ; Friedman, LS; Gebel, HM; Halloran, PF; Kirk, AD; Knechtle, SJ; McDiarmid, SV; Shaked, A; Terasaki, PI; Tinckam, KJ; Tomlanovich, SJ; Wood, KJ; Woodle, ES; Zachary, AA; Klintmalm, GB
MLA Citation
O'Leary, JG, Demetris, AJ, Friedman, LS, Gebel, HM, Halloran, PF, Kirk, AD, Knechtle, SJ, McDiarmid, SV, Shaked, A, Terasaki, PI, Tinckam, KJ, Tomlanovich, SJ, Wood, KJ, Woodle, ES, Zachary, AA, and Klintmalm, GB. "The role of donor-specific HLA alloantibodies in liver transplantation." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 14.4 (April 2014): 779-787.
PMID
24580828
Source
epmc
Published In
American Journal of Transplantation
Volume
14
Issue
4
Publish Date
2014
Start Page
779
End Page
787
DOI
10.1111/ajt.12667

High CTLA-4 Expression on Th17 Cells Results in Increased Sensitivity to CTLA-4 Coinhibition and Resistance to Belatacept

Authors
Krummey, SM; Cheeseman, JA; Conger, JA; Jang, PS; Mehta, AK; Kirk, AD; Larsen, CP; Ford, ML
MLA Citation
Krummey, SM, Cheeseman, JA, Conger, JA, Jang, PS, Mehta, AK, Kirk, AD, Larsen, CP, and Ford, ML. "High CTLA-4 Expression on Th17 Cells Results in Increased Sensitivity to CTLA-4 Coinhibition and Resistance to Belatacept." American Journal of Transplantation 14.3 (March 2014): 607-614.
Source
crossref
Published In
American Journal of Transplantation
Volume
14
Issue
3
Publish Date
2014
Start Page
607
End Page
614
DOI
10.1111/ajt.12600

Recollective homeostasis and the immune consequences of peritransplant depletional induction therapy

Authors
Rosenblum, JM; Kirk, AD
MLA Citation
Rosenblum, JM, and Kirk, AD. "Recollective homeostasis and the immune consequences of peritransplant depletional induction therapy." Immunological Reviews 258.1 (March 2014): 167-182.
Source
crossref
Published In
Immunological Reviews
Volume
258
Issue
1
Publish Date
2014
Start Page
167
End Page
182
DOI
10.1111/imr.12155

The Allo- and Viral-Specific Immunosuppressive Effect of Belatacept, but Not Tacrolimus, Attenuates With Progressive T Cell Maturation

Authors
Xu, H; Perez, SD; Cheeseman, J; Mehta, AK; Kirk, AD
MLA Citation
Xu, H, Perez, SD, Cheeseman, J, Mehta, AK, and Kirk, AD. "The Allo- and Viral-Specific Immunosuppressive Effect of Belatacept, but Not Tacrolimus, Attenuates With Progressive T Cell Maturation." American Journal of Transplantation 14.2 (February 2014): 319-332.
Source
crossref
Published In
American Journal of Transplantation
Volume
14
Issue
2
Publish Date
2014
Start Page
319
End Page
332
DOI
10.1111/ajt.12574

Biomarkers for kidney transplant rejection

Authors
Lo, DJ; Kaplan, B; Kirk, AD
MLA Citation
Lo, DJ, Kaplan, B, and Kirk, AD. "Biomarkers for kidney transplant rejection." Nature Reviews Nephrology 10.4 (January 21, 2014): 215-225.
Source
crossref
Published In
Nature Reviews Nephrology
Volume
10
Issue
4
Publish Date
2014
Start Page
215
End Page
225
DOI
10.1038/nrneph.2013.281

Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection.

De novo donor-specific antibody (DSA) after organ transplantation promotes antibody-mediated rejection (AMR) and causes late graft loss. Previously, we demonstrated that depletion using anti-CD3 immunotoxin combined with tacrolimus and alefacept (AMR regimen) reliably induced early DSA production with AMR in a nonhuman primate kidney transplant model. Five animals were assigned as positive AMR controls, four received additional belatacept and four received additional anti-CD40 mAb (2C10R4). Notably, production of early de novo DSA was completely attenuated with additional belatacept or 2C10R4 treatment. In accordance with this, while positive controls experienced a decrease in peripheral IgM(+) B cells, bela- and 2C10R4-added groups maintained a predominant population of IgM(+) B cells, potentially indicating decreased isotype switching. Central memory T cells (CD4(+) CD28(+) CD95(+)) as well as PD-1(hi) CD4(+) T cells were decreased in both bela-added and 2C10R4-added groups. In analyzing germinal center (GC) reactions in situ, lymph nodes further revealed a reduction of B cell clonal expansion, GC-follicular helper T (Tfh) cells, and IL-21 production inside GCs with additional belatacept or 2C10R4 treatment. Here we provide evidence that belatacept and 2C10R4 selectively suppresses the humoral response via regulating Tfh cells and prevents AMR in this nonhuman primate model.

Authors
Kim, EJ; Kwun, J; Gibby, AC; Hong, JJ; Farris, AB; Iwakoshi, NN; Villinger, F; Kirk, AD; Knechtle, SJ
MLA Citation
Kim, EJ, Kwun, J, Gibby, AC, Hong, JJ, Farris, AB, Iwakoshi, NN, Villinger, F, Kirk, AD, and Knechtle, SJ. "Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 14.1 (January 2014): 59-69.
Website
http://hdl.handle.net/10161/10063
PMID
24354871
Source
epmc
Published In
American Journal of Transplantation
Volume
14
Issue
1
Publish Date
2014
Start Page
59
End Page
69
DOI
10.1111/ajt.12526

Inhibition of αvβ6 Promotes Acute Renal Allograft Rejection in Nonhuman Primates

Authors
Lo, DJ; Farris, AB; Song, M; Leopardi, F; Anderson, DJ; Strobert, EA; Ramakrishnan, S; Turgeon, NA; Mehta, AK; Turnbull, B; Maroni, B; Violette, SM; Kirk, AD
MLA Citation
Lo, DJ, Farris, AB, Song, M, Leopardi, F, Anderson, DJ, Strobert, EA, Ramakrishnan, S, Turgeon, NA, Mehta, AK, Turnbull, B, Maroni, B, Violette, SM, and Kirk, AD. "Inhibition of αvβ6 Promotes Acute Renal Allograft Rejection in Nonhuman Primates." American Journal of Transplantation 13.12 (December 2013): 3085-3093.
Source
crossref
Published In
American Journal of Transplantation
Volume
13
Issue
12
Publish Date
2013
Start Page
3085
End Page
3093
DOI
10.1111/ajt.12467

In Vivo T Cell Costimulation Blockade with Abatacept for Acute Graft-versus-Host Disease Prevention: A First-in-Disease Trial

Authors
Koura, DT; Horan, JT; Langston, AA; Qayed, M; Mehta, A; Khoury, HJ; Harvey, RD; Suessmuth, Y; Couture, C; Carr, J; Grizzle, A; Johnson, HR; Cheeseman, JA; Conger, JA; Robertson, J; Stempora, L; Johnson, BE; Garrett, A; Kirk, AD; Larsen, CP; Waller, EK; Kean, LS
MLA Citation
Koura, DT, Horan, JT, Langston, AA, Qayed, M, Mehta, A, Khoury, HJ, Harvey, RD, Suessmuth, Y, Couture, C, Carr, J, Grizzle, A, Johnson, HR, Cheeseman, JA, Conger, JA, Robertson, J, Stempora, L, Johnson, BE, Garrett, A, Kirk, AD, Larsen, CP, Waller, EK, and Kean, LS. "In Vivo T Cell Costimulation Blockade with Abatacept for Acute Graft-versus-Host Disease Prevention: A First-in-Disease Trial." Biology of Blood and Marrow Transplantation 19.11 (November 2013): 1638-1649.
Source
crossref
Published In
Biology of Blood and Marrow Transplantation
Volume
19
Issue
11
Publish Date
2013
Start Page
1638
End Page
1649
DOI
10.1016/j.bbmt.2013.09.003

Heterologous Immunity Triggered by a Single, Latent Virus in Mus musculus: Combined Costimulation- and Adhesion- Blockade Decrease Rejection

Authors
Beus, JM; Hashmi, SS; Selvaraj, SA; Duan, D; Stempora, LL; Monday, SA; Cheeseman, JA; Hamby, KM; Speck, SH; Larsen, CP; Kirk, AD; Kean, LS
MLA Citation
Beus, JM, Hashmi, SS, Selvaraj, SA, Duan, D, Stempora, LL, Monday, SA, Cheeseman, JA, Hamby, KM, Speck, SH, Larsen, CP, Kirk, AD, and Kean, LS. "Heterologous Immunity Triggered by a Single, Latent Virus in Mus musculus: Combined Costimulation- and Adhesion- Blockade Decrease Rejection." Ed. D Unutmaz. PLoS ONE 8.8 (August 5, 2013): e71221-e71221.
Source
crossref
Published In
PloS one
Volume
8
Issue
8
Publish Date
2013
Start Page
e71221
End Page
e71221
DOI
10.1371/journal.pone.0071221

Class II Alloantibody and Mortality in Simultaneous Liver-Kidney Transplantation

Authors
O'Leary, JG; Gebel, HM; Ruiz, R; Bray, RA; Marr, JD; Zhou, XJ; Shiller, SM; Susskind, BM; Kirk, AD; Klintmalm, GB
MLA Citation
O'Leary, JG, Gebel, HM, Ruiz, R, Bray, RA, Marr, JD, Zhou, XJ, Shiller, SM, Susskind, BM, Kirk, AD, and Klintmalm, GB. "Class II Alloantibody and Mortality in Simultaneous Liver-Kidney Transplantation." American Journal of Transplantation 13.4 (April 2013): 954-960.
Source
crossref
Published In
American Journal of Transplantation
Volume
13
Issue
4
Publish Date
2013
Start Page
954
End Page
960
DOI
10.1111/ajt.12147

Belatacept and Sirolimus Prolong Nonhuman Primate Islet Allograft Survival: Adverse Consequences of Concomitant Alefacept Therapy

Authors
Lowe, MC; Badell, IR; Turner, AP; Thompson, PW; Leopardi, FV; Strobert, EA; Larsen, CP; Kirk, AD
MLA Citation
Lowe, MC, Badell, IR, Turner, AP, Thompson, PW, Leopardi, FV, Strobert, EA, Larsen, CP, and Kirk, AD. "Belatacept and Sirolimus Prolong Nonhuman Primate Islet Allograft Survival: Adverse Consequences of Concomitant Alefacept Therapy." American Journal of Transplantation 13.2 (February 2013): 312-319.
Source
crossref
Published In
American Journal of Transplantation
Volume
13
Issue
2
Publish Date
2013
Start Page
312
End Page
319
DOI
10.1111/j.1600-6143.2012.04341.x

Belatacept and Sirolimus Prolong Nonhuman Primate Renal Allograft Survival Without a Requirement for Memory T Cell Depletion

Authors
Lo, DJ; Anderson, DJ; Weaver, TA; Leopardi, F; Song, M; Farris, AB; Strobert, EA; Jenkins, J; Turgeon, NA; Mehta, AK; Larsen, CP; Kirk, AD
MLA Citation
Lo, DJ, Anderson, DJ, Weaver, TA, Leopardi, F, Song, M, Farris, AB, Strobert, EA, Jenkins, J, Turgeon, NA, Mehta, AK, Larsen, CP, and Kirk, AD. "Belatacept and Sirolimus Prolong Nonhuman Primate Renal Allograft Survival Without a Requirement for Memory T Cell Depletion." American Journal of Transplantation 13.2 (February 2013): 320-328.
Source
crossref
Published In
American Journal of Transplantation
Volume
13
Issue
2
Publish Date
2013
Start Page
320
End Page
328
DOI
10.1111/j.1600-6143.2012.04342.x

The Cam-Path Forward

Authors
Kirk, AD
MLA Citation
Kirk, AD. "The Cam-Path Forward." American Journal of Transplantation 13.1 (January 2013): 9-10.
Source
crossref
Published In
American Journal of Transplantation
Volume
13
Issue
1
Publish Date
2013
Start Page
9
End Page
10
DOI
10.1111/j.1600-6143.2012.04324.x

Belatacept

Authors
Sayed, BA; Kirk, AD; Pearson, TC; Larsen, CP
MLA Citation
Sayed, BA, Kirk, AD, Pearson, TC, and Larsen, CP. "Belatacept." 2013. 314-319.
Source
scival
Publish Date
2013
Start Page
314
End Page
319
DOI
10.1016/B978-1-4557-4096-3.00021-0

Antilymphocyte Globulin, Monoclonal Antibodies, and Fusion Proteins

Authors
Kirk, AD
MLA Citation
Kirk, AD. "Antilymphocyte Globulin, Monoclonal Antibodies, and Fusion Proteins." 2013. 287-313.
Source
scival
Publish Date
2013
Start Page
287
End Page
313
DOI
10.1016/B978-1-4557-4096-3.00020-9

Differential regulation of calcineurin isoforms in transplant patients: A new look at an old problem

Background: Calcineurin is a ubiquitously expressed calcium-dependent phosphatase that is inhibited by the immunosuppressant drugs cyclosporine and tacrolimus. Measuring calcineurin activity in transplant patients has been complicated by a lack of consistent correlation between drug level and enzyme activity, particularly with chronic use. Data from mice lacking the CnAα or CnAβ isoform of the catalytic subunit of calcineurin demonstrate that loss of CnAβ results in immunosuppression, whereas loss of CnAα does not. As such, methods to examine activity of the CnAβ isoform may be more clinically relevant than nonspecific assays. Methods: Because the current enzyme assays are nonisoform specific, we examined association of the CnAα or CnAβ isoform with calmodulin (CaM), a shared binding protein that is only associated with the catalytic subunit in the presence of calcium. We then compared semiquantitated data with total calcineurin activity and immune status in a cohort of pretransplantation controls and postrenal transplantation patients. Results: We found no difference in calcineurin activity between the groups and no difference in the amount of non-isoform-specific catalytic subunit bound to CaM. However, association of CnAα-CaM is increased in transplant patients, whereas CnAβ-CaM is decreased. In addition, the amount of CnAβ-CaM corresponds positively with T-cell activity and negatively with tacrolimus level. Finally, CnAβ-CaM is lower in stable transplant patients compared with those with acute rejection. Conclusions: These data suggest that monitoring specifically the β isoform may be more informative than non-isoform-specific assay methods. © 2013 Lippincott Williams & Wilkins.

Authors
Pena, JA; Titus, L; Jackson, J; Kirk, AD; Gooch, JL
MLA Citation
Pena, JA, Titus, L, Jackson, J, Kirk, AD, and Gooch, JL. "Differential regulation of calcineurin isoforms in transplant patients: A new look at an old problem." Transplantation 96.3 (2013): 239-244.
Source
scival
Published In
Transplantation
Volume
96
Issue
3
Publish Date
2013
Start Page
239
End Page
244
DOI
10.1097/TP.0b013e31829acb64

Primate models in organ transplantation.

Large animal models have long served as the proving grounds for advances in transplantation, bridging the gap between inbred mouse experimentation and human clinical trials. Although a variety of species have been and continue to be used, the emergence of highly targeted biologic- and antibody-based therapies has required models to have a high degree of homology with humans. Thus, the nonhuman primate has become the model of choice in many settings. This article will provide an overview of nonhuman primate models of transplantation. Issues of primate genetics and care will be introduced, and a brief overview of technical aspects for various transplant models will be discussed. Finally, several prominent immunosuppressive and tolerance strategies used in primates will be reviewed.

Authors
Anderson, DJ; Kirk, AD
MLA Citation
Anderson, DJ, and Kirk, AD. "Primate models in organ transplantation." Cold Spring Harbor perspectives in medicine 3.9 (2013): a015503-.
Source
scival
Published In
Cold Spring Harbor perspectives in medicine
Volume
3
Issue
9
Publish Date
2013
Start Page
a015503
DOI
10.1101/cshperspect.a015503

Hepatic enrichment and activation of myeloid dendritic cells during chronic hepatitis C virus infection.

Chronic hepatitis C virus (HCV) infection is a serious disease that can result in numerous long-term complications leading to liver failure or death. Approximately 80% of people fail to clear their infection, largely as the result of weak, narrowly targeting or waning antiviral T-cell responses. Although professional antigen presenting cells (APCs) like dendritic cells (DCs) might serve as targets for modulation of T-cell immunity, the particular role of DCs in immunity to HCV is not known. Moreover the identity, phenotype, and functional characteristics of such populations in the liver, the site of HCV replication, have proven difficult to elucidate. Using a multicolor flow-based approach, we identified six distinct populations of professional APCs among liver interstitial leukocytes isolated from uninfected and HCV-infected patients. Although a generalized enrichment of DCs in the liver compared to blood was observed for all patients, HCV infection was characterized by a significant increase in the frequency of intrahepatic myeloid DCs (both CD1c+ and CD141+). Phenotypic analyses of liver plasmacytoid (pDC) and myeloid DCs (mDC) further revealed the HCV-induced expression of maturation molecules CD80, CD83, CD40, and programmed death ligand-1. Importantly, pDC and mDCs from HCV-infected liver were capable of secreting effector cytokines, interferon-alpha and interleukin-12, respectively, in response to Toll-like receptor stimulation in vitro.Chronic HCV infection facilitates the "customized" recruitment of liver DC subsets with established functional roles in antigen presentation. These DCs are characterized by a mature, activated phenotype and are functionally responsive to antigenic stimulation in vitro. Such findings highlight an important paradox surrounding liver DC recruitment during HCV infection, where despite their activation these cells do not provide adequate protection from the virus.

Authors
Velazquez, VM; Hon, H; Ibegbu, C; Knechtle, SJ; Kirk, AD; Grakoui, A
MLA Citation
Velazquez, VM, Hon, H, Ibegbu, C, Knechtle, SJ, Kirk, AD, and Grakoui, A. "Hepatic enrichment and activation of myeloid dendritic cells during chronic hepatitis C virus infection." Hepatology (Baltimore, Md.) 56.6 (December 2012): 2071-2081.
PMID
22711645
Source
epmc
Published In
Hepatology
Volume
56
Issue
6
Publish Date
2012
Start Page
2071
End Page
2081
DOI
10.1002/hep.25904

The glucagon-like peptide-1 receptor agonist Exendin 4 has a protective role in ischemic injury of lean and steatotic liver by inhibiting cell death and stimulating lipolysis.

Nonalcoholic fatty liver disease is an increasingly prevalent spectrum of conditions characterized by excess fat deposition within hepatocytes. Affected hepatocytes are known to be highly susceptible to ischemic insults, responding to injury with increased cell death, and commensurate liver dysfunction. Numerous clinical circumstances lead to hepatic ischemia. Mechanistically, specific means of reducing hepatic vulnerability to ischemia are of increasing clinical importance. In this study, we demonstrate that the glucagon-like peptide-1 receptor agonist Exendin 4 (Ex4) protects hepatocytes from ischemia reperfusion injury by mitigating necrosis and apoptosis. Importantly, this effect is more pronounced in steatotic livers, with significantly reducing cell death and facilitating the initiation of lipolysis. Ex4 treatment leads to increased lipid droplet fission, and phosphorylation of perilipin and hormone sensitive lipase - all hallmarks of lipolysis. Importantly, the protective effects of Ex4 are seen after a short course of perioperative treatment, potentially making this clinically relevant. Thus, we conclude that Ex4 has a role in protecting lean and fatty livers from ischemic injury. The rapidity of the effect and the clinical availability of Ex4 make this an attractive new therapeutic approach for treating fatty livers at the time of an ischemic insult.

Authors
Gupta, NA; Kolachala, VL; Jiang, R; Abramowsky, C; Romero, R; Fifadara, N; Anania, F; Knechtle, S; Kirk, A
MLA Citation
Gupta, NA, Kolachala, VL, Jiang, R, Abramowsky, C, Romero, R, Fifadara, N, Anania, F, Knechtle, S, and Kirk, A. "The glucagon-like peptide-1 receptor agonist Exendin 4 has a protective role in ischemic injury of lean and steatotic liver by inhibiting cell death and stimulating lipolysis." The American journal of pathology 181.5 (November 2012): 1693-1701.
PMID
22960075
Source
epmc
Published In
The American journal of pathology
Volume
181
Issue
5
Publish Date
2012
Start Page
1693
End Page
1701
DOI
10.1016/j.ajpath.2012.07.015

Platelet-Derived CD154: Ultrastructural Localization and Clinical Correlation in Organ Transplantation

Authors
Charafeddine, AH; Kim, EJ; Maynard, DM; Yi, H; Weaver, TA; Gunay-Aygun, M; Russell, M; Gahl, WA; Kirk, AD
MLA Citation
Charafeddine, AH, Kim, EJ, Maynard, DM, Yi, H, Weaver, TA, Gunay-Aygun, M, Russell, M, Gahl, WA, and Kirk, AD. "Platelet-Derived CD154: Ultrastructural Localization and Clinical Correlation in Organ Transplantation." American Journal of Transplantation 12.11 (November 2012): 3143-3151.
Source
crossref
Published In
American Journal of Transplantation
Volume
12
Issue
11
Publish Date
2012
Start Page
3143
End Page
3151
DOI
10.1111/j.1600-6143.2012.04241.x

Associations of ABCB1 and IL-10 Genetic Polymorphisms With Sirolimus-Induced Dyslipidemia in Renal Transplant Recipients

Authors
Sam, W-J; Chamberlain, CE; Lee, S-J; Goldstein, JA; Hale, DA; Mannon, RB; Kirk, AD; Hon, YY
MLA Citation
Sam, W-J, Chamberlain, CE, Lee, S-J, Goldstein, JA, Hale, DA, Mannon, RB, Kirk, AD, and Hon, YY. "Associations of ABCB1 and IL-10 Genetic Polymorphisms With Sirolimus-Induced Dyslipidemia in Renal Transplant Recipients." Transplantation Journal 94.9 (November 2012): 971-977.
Source
crossref
Published In
Transplantation
Volume
94
Issue
9
Publish Date
2012
Start Page
971
End Page
977
DOI
10.1097/TP.0b013e31826b55e2

Patterns of de novo allo B cells and antibody formation in chronic cardiac allograft rejection after alemtuzumab treatment.

Even though the etiology of chronic rejection (CR) is multifactorial, donor specific antibody (DSA) is considered to have a causal effect on CR development. Currently the antibody-mediated mechanisms during CR are poorly understood due to lack of proper animal models and tools. In a clinical setting, we previously demonstrated that induction therapy by lymphocyte depletion, using alemtuzumab (anti-human CD52), is associated with an increased incidence of serum alloantibody, C4d deposition and antibody-mediated rejection in human patients. In this study, the effects of T cell depletion in the development of antibody-mediated rejection were examined using human CD52 transgenic (CD52Tg) mice treated with alemtuzumab. Fully mismatched cardiac allografts were transplanted into alemtuzumab treated CD52Tg mice and showed no acute rejection while untreated recipients acutely rejected their grafts. However, approximately half of long-term recipients showed increased degree of vasculopathy, fibrosis and perivascular C3d depositions at posttransplant day 100. The development of CR correlated with DSA and C3d deposition in the graft. Using novel tracking tools to monitor donor-specific B cells, alloreactive B cells were shown to increase in accordance with DSA detection. The current animal model could provide a means of testing strategies to understand mechanisms and developing therapeutic approaches to prevent chronic rejection.

Authors
Kwun, J; Oh, BC; Gibby, AC; Ruhil, R; Lu, VT; Kim, DW; Page, EK; Bulut, OP; Song, MQ; Farris, AB; Kirk, AD; Knechtle, SJ; Iwakoshi, NN
MLA Citation
Kwun, J, Oh, BC, Gibby, AC, Ruhil, R, Lu, VT, Kim, DW, Page, EK, Bulut, OP, Song, MQ, Farris, AB, Kirk, AD, Knechtle, SJ, and Iwakoshi, NN. "Patterns of de novo allo B cells and antibody formation in chronic cardiac allograft rejection after alemtuzumab treatment." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 12.10 (October 2012): 2641-2651.
Website
http://hdl.handle.net/10161/10058
PMID
22759336
Source
epmc
Published In
American Journal of Transplantation
Volume
12
Issue
10
Publish Date
2012
Start Page
2641
End Page
2651
DOI
10.1111/j.1600-6143.2012.04181.x

A Novel Monoclonal Antibody to CD40 Prolongs Islet Allograft Survival

Authors
Lowe, M; Badell, IR; Thompson, P; Martin, B; Leopardi, F; Strobert, E; Price, AA; Abdulkerim, HS; Wang, R; Iwakoshi, NN; Adams, AB; Kirk, AD; Larsen, CP; Reimann, KA
MLA Citation
Lowe, M, Badell, IR, Thompson, P, Martin, B, Leopardi, F, Strobert, E, Price, AA, Abdulkerim, HS, Wang, R, Iwakoshi, NN, Adams, AB, Kirk, AD, Larsen, CP, and Reimann, KA. "A Novel Monoclonal Antibody to CD40 Prolongs Islet Allograft Survival." American Journal of Transplantation 12.8 (August 2012): 2079-2087.
Source
crossref
Published In
American Journal of Transplantation
Volume
12
Issue
8
Publish Date
2012
Start Page
2079
End Page
2087
DOI
10.1111/j.1600-6143.2012.04054.x

CTLA4Ig Prevents Alloantibody Formation Following Nonhuman Primate Islet Transplantation Using the CD40-Specific Antibody 3A8

Authors
Badell, IR; Russell, MC; Cardona, K; Shaffer, VO; Turner, AP; Avila, JG; Cano, JA; Leopardi, FV; Song, M; Strobert, EA; Ford, ML; Pearson, TC; Kirk, AD; Larsen, CP
MLA Citation
Badell, IR, Russell, MC, Cardona, K, Shaffer, VO, Turner, AP, Avila, JG, Cano, JA, Leopardi, FV, Song, M, Strobert, EA, Ford, ML, Pearson, TC, Kirk, AD, and Larsen, CP. "CTLA4Ig Prevents Alloantibody Formation Following Nonhuman Primate Islet Transplantation Using the CD40-Specific Antibody 3A8." American Journal of Transplantation 12.7 (July 2012): 1918-1923.
Source
crossref
Published In
American Journal of Transplantation
Volume
12
Issue
7
Publish Date
2012
Start Page
1918
End Page
1923
DOI
10.1111/j.1600-6143.2012.04029.x

Alternative Immunomodulatory Strategies for Xenotransplantation: CD40/154 Pathway-Sparing Regimens Promote Xenograft Survival

Authors
Thompson, P; Badell, IR; Lowe, M; Turner, A; Cano, J; Avila, J; Azimzadeh, A; Cheng, X; Pierson III, RN; Johnson, B; Robertson, J; Song, M; Leopardi, F; Strobert, E; Korbutt, G; Rayat, G; Rajotte, R; Larsen, CP; Kirk, AD
MLA Citation
Thompson, P, Badell, IR, Lowe, M, Turner, A, Cano, J, Avila, J, Azimzadeh, A, Cheng, X, Pierson III, RN, Johnson, B, Robertson, J, Song, M, Leopardi, F, Strobert, E, Korbutt, G, Rayat, G, Rajotte, R, Larsen, CP, and Kirk, AD. "Alternative Immunomodulatory Strategies for Xenotransplantation: CD40/154 Pathway-Sparing Regimens Promote Xenograft Survival." American Journal of Transplantation 12.7 (July 2012): 1765-1775.
Source
crossref
Published In
American Journal of Transplantation
Volume
12
Issue
7
Publish Date
2012
Start Page
1765
End Page
1775
DOI
10.1111/j.1600-6143.2012.04031.x

Evidence for Kidney Rejection After Combined Bone Marrow and Renal Transplantation Despite Ongoing Whole-Blood Chimerism in Rhesus Macaques

Authors
Ramakrishnan, SK; Page, A; Farris, AB; Singh, K; Leopardi, F; Hamby, K; Sen, S; Polnett, A; Deane, T; Song, M; Stempora, L; Strobert, E; Kirk, AD; Larsen, CP; Kean, LS
MLA Citation
Ramakrishnan, SK, Page, A, Farris, AB, Singh, K, Leopardi, F, Hamby, K, Sen, S, Polnett, A, Deane, T, Song, M, Stempora, L, Strobert, E, Kirk, AD, Larsen, CP, and Kean, LS. "Evidence for Kidney Rejection After Combined Bone Marrow and Renal Transplantation Despite Ongoing Whole-Blood Chimerism in Rhesus Macaques." American Journal of Transplantation 12.7 (July 2012): 1755-1764.
Source
crossref
Published In
American Journal of Transplantation
Volume
12
Issue
7
Publish Date
2012
Start Page
1755
End Page
1764
DOI
10.1111/j.1600-6143.2012.04045.x

Regulatory T Cells Exhibit Decreased Proliferation but Enhanced Suppression After Pulsing With Sirolimus

Authors
Singh, K; Kozyr, N; Stempora, L; Kirk, AD; Larsen, CP; Blazar, BR; Kean, LS
MLA Citation
Singh, K, Kozyr, N, Stempora, L, Kirk, AD, Larsen, CP, Blazar, BR, and Kean, LS. "Regulatory T Cells Exhibit Decreased Proliferation but Enhanced Suppression After Pulsing With Sirolimus." American Journal of Transplantation 12.6 (June 2012): 1441-1457.
Source
crossref
Published In
American Journal of Transplantation
Volume
12
Issue
6
Publish Date
2012
Start Page
1441
End Page
1457
DOI
10.1111/j.1600-6143.2011.03963.x

The Impact of Renal Function on Outcomes of Bariatric Surgery

Authors
Turgeon, NA; Perez, S; Mondestin, M; Davis, SS; Lin, E; Tata, S; Kirk, AD; Larsen, CP; Pearson, TC; Sweeney, JF
MLA Citation
Turgeon, NA, Perez, S, Mondestin, M, Davis, SS, Lin, E, Tata, S, Kirk, AD, Larsen, CP, Pearson, TC, and Sweeney, JF. "The Impact of Renal Function on Outcomes of Bariatric Surgery." Journal of the American Society of Nephrology 23.5 (May 1, 2012): 885-894.
Source
crossref
Published In
Journal of the American Society of Nephrology : JASN
Volume
23
Issue
5
Publish Date
2012
Start Page
885
End Page
894
DOI
10.1681/ASN.2011050476

Cumulative Exposure to Gamma Interferon-Dependent Chemokines CXCL9 and CXCL10 Correlates with Worse Outcome After Lung Transplant

Authors
Neujahr, DC; Perez, SD; Mohammed, A; Ulukpo, O; Lawrence, EC; Fernandez, F; Pickens, A; Force, SD; Song, M; Larsen, CP; Kirk, AD
MLA Citation
Neujahr, DC, Perez, SD, Mohammed, A, Ulukpo, O, Lawrence, EC, Fernandez, F, Pickens, A, Force, SD, Song, M, Larsen, CP, and Kirk, AD. "Cumulative Exposure to Gamma Interferon-Dependent Chemokines CXCL9 and CXCL10 Correlates with Worse Outcome After Lung Transplant." American Journal of Transplantation 12.2 (February 2012): 438-446.
Source
crossref
Published In
American Journal of Transplantation
Volume
12
Issue
2
Publish Date
2012
Start Page
438
End Page
446
DOI
10.1111/j.1600-6143.2011.03857.x

CD40 Blockade Combines with CTLA4Ig and Sirolimus to Produce Mixed Chimerism in an MHC-Defined Rhesus Macaque Transplant Model

Authors
Page, A; Srinivasan, S; Singh, K; Russell, M; Hamby, K; Deane, T; Sen, S; Stempora, L; Leopardi, F; Price, AA; Strobert, E; Reimann, KA; Kirk, AD; Larsen, CP; Kean, LS
MLA Citation
Page, A, Srinivasan, S, Singh, K, Russell, M, Hamby, K, Deane, T, Sen, S, Stempora, L, Leopardi, F, Price, AA, Strobert, E, Reimann, KA, Kirk, AD, Larsen, CP, and Kean, LS. "CD40 Blockade Combines with CTLA4Ig and Sirolimus to Produce Mixed Chimerism in an MHC-Defined Rhesus Macaque Transplant Model." American Journal of Transplantation 12.1 (January 2012): 115-125.
Source
crossref
Published In
American Journal of Transplantation
Volume
12
Issue
1
Publish Date
2012
Start Page
115
End Page
125
DOI
10.1111/j.1600-6143.2011.03737.x

Integrin Antagonists Prevent Costimulatory Blockade-Resistant Transplant Rejection by CD8+ Memory T Cells

Authors
Kitchens, WH; Haridas, D; Wagener, ME; Song, M; Kirk, AD; Larsen, CP; Ford, ML
MLA Citation
Kitchens, WH, Haridas, D, Wagener, ME, Song, M, Kirk, AD, Larsen, CP, and Ford, ML. "Integrin Antagonists Prevent Costimulatory Blockade-Resistant Transplant Rejection by CD8+ Memory T Cells." American Journal of Transplantation 12.1 (January 2012): 69-80.
Source
crossref
Published In
American Journal of Transplantation
Volume
12
Issue
1
Publish Date
2012
Start Page
69
End Page
80
DOI
10.1111/j.1600-6143.2011.03762.x

Nondepleting Anti-CD40-Based Therapy Prolongs Allograft Survival in Nonhuman Primates

Authors
Badell, IR; Thompson, PW; Turner, AP; Russell, MC; Avila, JG; Cano, JA; Robertson, JM; Leopardi, FV; Strobert, EA; Iwakoshi, NN; Reimann, KA; Ford, ML; Kirk, AD; Larsen, CP
MLA Citation
Badell, IR, Thompson, PW, Turner, AP, Russell, MC, Avila, JG, Cano, JA, Robertson, JM, Leopardi, FV, Strobert, EA, Iwakoshi, NN, Reimann, KA, Ford, ML, Kirk, AD, and Larsen, CP. "Nondepleting Anti-CD40-Based Therapy Prolongs Allograft Survival in Nonhuman Primates." American Journal of Transplantation 12.1 (January 2012): 126-135.
Source
crossref
Published In
American Journal of Transplantation
Volume
12
Issue
1
Publish Date
2012
Start Page
126
End Page
135
DOI
10.1111/j.1600-6143.2011.03736.x

Liver and pancreas transplantation immunobiology

Authors
Bruno, DA; Dhanireddy, KK; Kirk, AD
MLA Citation
Bruno, DA, Dhanireddy, KK, and Kirk, AD. "Liver and pancreas transplantation immunobiology." 2012. 1652-1661.
Source
scival
Volume
2
Publish Date
2012
Start Page
1652
End Page
1661
DOI
10.1016/B978-1-4377-1454-8.00096-5

Combination and Adjuvant Therapies to Facilitate the Efficacy of Costimulatory Blockade

Many drugs are used to prevent allograft rejection. Most target T cells but inhibit pathways that are not exclusive to T cells and thus evoke off-target side effects. Many, particularly calcineurin inhibitors, hinder T cell receptor (TCR) signaling and thus inhibit T cells in a non-antigen-specific manner. Recently, agents targeting T cell costimulation have been developed. Costimulation molecules supplement TCR signaling and are necessary for full T cell activation. Costimulatory molecule-specific monoclonal antibodies and fusion proteins have been shown to prevent rejection in preclinical settings, and by sparing the TCR, their effects have retained antigen specificity. The CD28-CD80/86 and CD40-CD154 pathways are the most studied targets, and agents inhibiting these pathways have reached clinical trials. However, these agents cannot by themselves prevent clinical rejection. This chapter will review costimulation blockade-based agents particularly in regard to their use in combination with adjuvant therapies, including conventional immunosuppressants and agents inhibiting adhesion molecule function. © 2012 Blackwell Publishing Ltd.

Authors
Srinivasan, SK; Triemer, HL; Kirk, AD
MLA Citation
Srinivasan, SK, Triemer, HL, and Kirk, AD. "Combination and Adjuvant Therapies to Facilitate the Efficacy of Costimulatory Blockade." 2012. 407-428.
Source
scival
Publish Date
2012
Start Page
407
End Page
428
DOI
10.1002/9781444355628.ch28

Antigen-specific induced Foxp3+ regulatory T cells are generated following CD40/CD154 blockade

Authors
Ferrer, IR; Wagener, ME; Song, M; Kirk, AD; Larsen, CP; Ford, ML
MLA Citation
Ferrer, IR, Wagener, ME, Song, M, Kirk, AD, Larsen, CP, and Ford, ML. "Antigen-specific induced Foxp3+ regulatory T cells are generated following CD40/CD154 blockade." Proceedings of the National Academy of Sciences 108.51 (December 20, 2011): 20701-20706.
Source
crossref
Published In
Proceedings of the National Academy of Sciences of USA
Volume
108
Issue
51
Publish Date
2011
Start Page
20701
End Page
20706
DOI
10.1073/pnas.1105500108

Associations of ABCB1 3435C>T and IL-10-1082G>A Polymorphisms With Long-Term Sirolimus Dose Requirements in Renal Transplant Patients

Authors
Sam, W-J; Chamberlain, CE; Lee, S-J; Goldstein, JA; Hale, DA; Mannon, RB; Kirk, AD; Yi Hon, Y
MLA Citation
Sam, W-J, Chamberlain, CE, Lee, S-J, Goldstein, JA, Hale, DA, Mannon, RB, Kirk, AD, and Yi Hon, Y. "Associations of ABCB1 3435C>T and IL-10-1082G>A Polymorphisms With Long-Term Sirolimus Dose Requirements in Renal Transplant Patients." Transplantation 92.12 (December 2011): 1342-1347.
Source
crossref
Published In
Transplantation
Volume
92
Issue
12
Publish Date
2011
Start Page
1342
End Page
1347
DOI
10.1097/TP.0b013e3182384ae2

Islet Xenotransplantation Using Gal-Deficient Neonatal Donors Improves Engraftment and Function

Authors
Thompson, P; Badell, IR; Lowe, M; Cano, J; Song, M; Leopardi, F; Avila, J; Ruhil, R; Strobert, E; Korbutt, G; Rayat, G; Rajotte, R; Iwakoshi, N; Larsen, CP; Kirk, AD
MLA Citation
Thompson, P, Badell, IR, Lowe, M, Cano, J, Song, M, Leopardi, F, Avila, J, Ruhil, R, Strobert, E, Korbutt, G, Rayat, G, Rajotte, R, Iwakoshi, N, Larsen, CP, and Kirk, AD. "Islet Xenotransplantation Using Gal-Deficient Neonatal Donors Improves Engraftment and Function." American Journal of Transplantation 11.12 (December 2011): 2593-2602.
Source
crossref
Published In
American Journal of Transplantation
Volume
11
Issue
12
Publish Date
2011
Start Page
2593
End Page
2602
DOI
10.1111/j.1600-6143.2011.03720.x

Cumulative Exposure to CD8+ Granzyme Bhi T Cells Is Associated with Reduced Lung Function Early after Lung Transplantation

Authors
Mohammed, A; Ulukpo, O; Lawrence, EC; Fernandez, F; Pickens, A; Gal, AA; Force, SD; Easley, KC; Larsen, CP; Kirk, AD; Neujahr, DC
MLA Citation
Mohammed, A, Ulukpo, O, Lawrence, EC, Fernandez, F, Pickens, A, Gal, AA, Force, SD, Easley, KC, Larsen, CP, Kirk, AD, and Neujahr, DC. "Cumulative Exposure to CD8+ Granzyme Bhi T Cells Is Associated with Reduced Lung Function Early after Lung Transplantation." Transplantation Proceedings 43.10 (December 2011): 3892-3898.
Source
crossref
Published In
Transplantation Proceedings
Volume
43
Issue
10
Publish Date
2011
Start Page
3892
End Page
3898
DOI
10.1016/j.transproceed.2011.09.072

LFA-1 blockade induces effector and regulatory T-cell enrichment in lymph nodes and synergizes with CTLA-4Ig to inhibit effector function

Authors
Reisman, NM; Floyd, TL; Wagener, ME; Kirk, AD; Larsen, CP; Ford, ML
MLA Citation
Reisman, NM, Floyd, TL, Wagener, ME, Kirk, AD, Larsen, CP, and Ford, ML. "LFA-1 blockade induces effector and regulatory T-cell enrichment in lymph nodes and synergizes with CTLA-4Ig to inhibit effector function." Blood 118.22 (November 24, 2011): 5851-5861.
Source
crossref
Published In
Blood
Volume
118
Issue
22
Publish Date
2011
Start Page
5851
End Page
5861
DOI
10.1182/blood-2011-04-347252

Urinary Chemokines CXCL9 and CXCL10 Are Noninvasive Markers of Renal Allograft Rejection and BK Viral Infection

Authors
Jackson, JA; Kim, EJ; Begley, B; Cheeseman, J; Harden, T; Perez, SD; Thomas, S; Warshaw, B; Kirk, AD
MLA Citation
Jackson, JA, Kim, EJ, Begley, B, Cheeseman, J, Harden, T, Perez, SD, Thomas, S, Warshaw, B, and Kirk, AD. "Urinary Chemokines CXCL9 and CXCL10 Are Noninvasive Markers of Renal Allograft Rejection and BK Viral Infection." American Journal of Transplantation 11.10 (October 2011): 2228-2234.
Source
crossref
Published In
American Journal of Transplantation
Volume
11
Issue
10
Publish Date
2011
Start Page
2228
End Page
2234
DOI
10.1111/j.1600-6143.2011.03680.x

The Risk and Opportunity of Homeostatic Repopulation

Authors
Stock, P; Kirk, AD
MLA Citation
Stock, P, and Kirk, AD. "The Risk and Opportunity of Homeostatic Repopulation." American Journal of Transplantation 11.7 (July 2011): 1349-1350.
Source
crossref
Published In
American Journal of Transplantation
Volume
11
Issue
7
Publish Date
2011
Start Page
1349
End Page
1350
DOI
10.1111/j.1600-6143.2011.03543.x

Antibody-Mediated Rejection-An Ounce of Prevention Is Worth a Pound of Cure

Authors
Bradley, JA; Baldwin, WM; Bingaman, A; Ellenrieder, C; Gebel, HM; Glotz, D; Kirk, AD
MLA Citation
Bradley, JA, Baldwin, WM, Bingaman, A, Ellenrieder, C, Gebel, HM, Glotz, D, and Kirk, AD. "Antibody-Mediated Rejection-An Ounce of Prevention Is Worth a Pound of Cure." American Journal of Transplantation 11.6 (June 2011): 1131-1139.
Source
crossref
Published In
American Journal of Transplantation
Volume
11
Issue
6
Publish Date
2011
Start Page
1131
End Page
1139
DOI
10.1111/j.1600-6143.2011.03581.x

Miles to go….

Authors
Kirk, AD; Knechtle, SJ; Larsen, CP; Newell, KA; Pearson, TC
MLA Citation
Kirk, AD, Knechtle, SJ, Larsen, CP, Newell, KA, and Pearson, TC. "Miles to go…." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 11.6 (June 2011): 1119-1120.
PMID
21645248
Source
epmc
Published In
American Journal of Transplantation
Volume
11
Issue
6
Publish Date
2011
Start Page
1119
End Page
1120
DOI
10.1111/j.1600-6143.2011.03542.x

CD40-Specific Costimulation Blockade Enhances Neonatal Porcine Islet Survival in Nonhuman Primates

Authors
Thompson, P; Cardona, K; Russell, M; Badell, IR; Shaffer, V; Korbutt, G; Rayat, GR; Cano, J; Song, M; Jiang, W; Strobert, E; Rajotte, R; Pearson, T; Kirk, AD; Larsen, CP
MLA Citation
Thompson, P, Cardona, K, Russell, M, Badell, IR, Shaffer, V, Korbutt, G, Rayat, GR, Cano, J, Song, M, Jiang, W, Strobert, E, Rajotte, R, Pearson, T, Kirk, AD, and Larsen, CP. "CD40-Specific Costimulation Blockade Enhances Neonatal Porcine Islet Survival in Nonhuman Primates." American Journal of Transplantation 11.5 (May 2011): 947-957.
Source
crossref
Published In
American Journal of Transplantation
Volume
11
Issue
5
Publish Date
2011
Start Page
947
End Page
957
DOI
10.1111/j.1600-6143.2011.03509.x

Sirolimus Enhances the Magnitude and Quality of Viral-Specific CD8+ T-Cell Responses to Vaccinia Virus Vaccination in Rhesus Macaques

Authors
Turner, AP; Shaffer, VO; Araki, K; Martens, C; Turner, PL; Gangappa, S; Ford, ML; Ahmed, R; Kirk, AD; Larsen, CP
MLA Citation
Turner, AP, Shaffer, VO, Araki, K, Martens, C, Turner, PL, Gangappa, S, Ford, ML, Ahmed, R, Kirk, AD, and Larsen, CP. "Sirolimus Enhances the Magnitude and Quality of Viral-Specific CD8+ T-Cell Responses to Vaccinia Virus Vaccination in Rhesus Macaques." American Journal of Transplantation 11.3 (March 2011): 613-618.
Source
crossref
Published In
American Journal of Transplantation
Volume
11
Issue
3
Publish Date
2011
Start Page
613
End Page
618
DOI
10.1111/j.1600-6143.2010.03407.x

Surgeons and Research: Talent, Training, Time, Teachers and Teams

Authors
Kirk, AD; Feng, S
MLA Citation
Kirk, AD, and Feng, S. "Surgeons and Research: Talent, Training, Time, Teachers and Teams." American Journal of Transplantation 11.2 (February 2011): 191-193.
Source
crossref
Published In
American Journal of Transplantation
Volume
11
Issue
2
Publish Date
2011
Start Page
191
End Page
193
DOI
10.1111/j.1600-6143.2010.03399.x

New in AJT

Authors
Kirk, AD
MLA Citation
Kirk, AD. "New in AJT." American Journal of Transplantation 11.1 (January 2011): 5-5.
Source
crossref
Published In
American Journal of Transplantation
Volume
11
Issue
1
Publish Date
2011
Start Page
5
End Page
5
DOI
10.1111/j.1600-6143.2010.03392.x

Selective Targeting of Human Alloresponsive CD8+ Effector Memory T Cells Based on CD2 Expression

Authors
Lo, DJ; Weaver, TA; Stempora, L; Mehta, AK; Ford, ML; Larsen, CP; Kirk, AD
MLA Citation
Lo, DJ, Weaver, TA, Stempora, L, Mehta, AK, Ford, ML, Larsen, CP, and Kirk, AD. "Selective Targeting of Human Alloresponsive CD8+ Effector Memory T Cells Based on CD2 Expression." American Journal of Transplantation 11.1 (January 2011): 22-33.
Source
crossref
Published In
American Journal of Transplantation
Volume
11
Issue
1
Publish Date
2011
Start Page
22
End Page
33
DOI
10.1111/j.1600-6143.2010.03317.x

Chemokines and Their Receptors in Human Renal Allotransplantation

Authors
Lo, DJ; Weaver, TA; Kleiner, DE; Mannon, RB; Jacobson, LM; Becker, BN; Swanson, SJ; Hale, DA; Kirk, AD
MLA Citation
Lo, DJ, Weaver, TA, Kleiner, DE, Mannon, RB, Jacobson, LM, Becker, BN, Swanson, SJ, Hale, DA, and Kirk, AD. "Chemokines and Their Receptors in Human Renal Allotransplantation." Transplantation 91.1 (January 2011): 70-77.
Source
crossref
Published In
Transplantation
Volume
91
Issue
1
Publish Date
2011
Start Page
70
End Page
77
DOI
10.1097/TP.0b013e3181fe12fc

LFA-1–specific therapy prolongs allograft survival in rhesus macaques

Authors
Badell, IR; Russell, MC; Thompson, PW; Turner, AP; Weaver, TA; Robertson, JM; Avila, JG; Cano, JA; Johnson, BE; Song, M; Leopardi, FV; Swygert, S; Strobert, EA; Ford, ML; Kirk, AD; Larsen, CP
MLA Citation
Badell, IR, Russell, MC, Thompson, PW, Turner, AP, Weaver, TA, Robertson, JM, Avila, JG, Cano, JA, Johnson, BE, Song, M, Leopardi, FV, Swygert, S, Strobert, EA, Ford, ML, Kirk, AD, and Larsen, CP. "LFA-1–specific therapy prolongs allograft survival in rhesus macaques." Journal of Clinical Investigation 120.12 (December 1, 2010): 4520-4531.
Source
crossref
Published In
Journal of Clinical Investigation
Volume
120
Issue
12
Publish Date
2010
Start Page
4520
End Page
4531
DOI
10.1172/JCI43895

Now What?

Authors
Kirk, AD
MLA Citation
Kirk, AD. "Now What?." American Journal of Transplantation 10.11 (November 2010): 2385-2386.
Source
crossref
Published In
American Journal of Transplantation
Volume
10
Issue
11
Publish Date
2010
Start Page
2385
End Page
2386
DOI
10.1111/j.1600-6143.2010.03287.x

B cells and transplantation tolerance

Authors
Kirk, AD; Turgeon, NA; Iwakoshi, NN
MLA Citation
Kirk, AD, Turgeon, NA, and Iwakoshi, NN. "B cells and transplantation tolerance." Nature Reviews Nephrology 6.10 (October 2010): 584-593.
Source
crossref
Published In
Nature Reviews Nephrology
Volume
6
Issue
10
Publish Date
2010
Start Page
584
End Page
593
DOI
10.1038/nrneph.2010.111

Surgical Correction of Gastroesophageal Reflux in Lung Transplant Patients Is Associated With Decreased Effector CD8 Cells in Lung Lavages

Authors
Neujahr, DC; Mohammed, A; Ulukpo, O; Force, SD; Ramirez, AM; Pelaez, A; Lawrence, EC; Larsen, CP; Kirk, AD
MLA Citation
Neujahr, DC, Mohammed, A, Ulukpo, O, Force, SD, Ramirez, AM, Pelaez, A, Lawrence, EC, Larsen, CP, and Kirk, AD. "Surgical Correction of Gastroesophageal Reflux in Lung Transplant Patients Is Associated With Decreased Effector CD8 Cells in Lung Lavages." Chest 138.4 (October 2010): 937-943.
Source
crossref
Published In
Chest
Volume
138
Issue
4
Publish Date
2010
Start Page
937
End Page
943
DOI
10.1378/chest.09-2888

Immunogenetics and transplantation

Authors
Kirk, A; Strom, TB
MLA Citation
Kirk, A, and Strom, TB. "Immunogenetics and transplantation." Current Opinion in Immunology 22.5 (October 2010): 631-633.
Source
crossref
Published In
Current Opinion in Immunology
Volume
22
Issue
5
Publish Date
2010
Start Page
631
End Page
633
DOI
10.1016/j.coi.2010.09.003

Experience with a Novel Efalizumab-Based Immunosuppressive Regimen to Facilitate Single Donor Islet Cell Transplantation

Authors
Turgeon, NA; Avila, JG; Cano, JA; Hutchinson, JJ; Badell, IR; Page, AJ; Adams, AB; Sears, MH; Bowen, PH; Kirk, AD; Pearson, TC; Larsen, CP
MLA Citation
Turgeon, NA, Avila, JG, Cano, JA, Hutchinson, JJ, Badell, IR, Page, AJ, Adams, AB, Sears, MH, Bowen, PH, Kirk, AD, Pearson, TC, and Larsen, CP. "Experience with a Novel Efalizumab-Based Immunosuppressive Regimen to Facilitate Single Donor Islet Cell Transplantation." American Journal of Transplantation 10.9 (September 2010): 2082-2091.
Source
crossref
Published In
American Journal of Transplantation
Volume
10
Issue
9
Publish Date
2010
Start Page
2082
End Page
2091
DOI
10.1111/j.1600-6143.2010.03212.x

Evaluation of tacrolimus abbreviated area-under-the-curve monitoring in renal transplant patients who are potientially at risk for adverse events

Authors
Hon, YY; Chamberlain, CE; Kleiner, DE; Ring, MS; Hale, DA; Kirk, AD; Mannon, RB
MLA Citation
Hon, YY, Chamberlain, CE, Kleiner, DE, Ring, MS, Hale, DA, Kirk, AD, and Mannon, RB. "Evaluation of tacrolimus abbreviated area-under-the-curve monitoring in renal transplant patients who are potientially at risk for adverse events." Clinical Transplantation 24.4 (July 2010): 557-563.
Source
crossref
Published In
Clinical Transplantation
Volume
24
Issue
4
Publish Date
2010
Start Page
557
End Page
563
DOI
10.1111/j.1399-0012.2009.01143.x

Identification of a B cell signature associated with renal transplant tolerance in humans

Authors
Newell, KA; Asare, A; Kirk, AD; Gisler, TD; Bourcier, K; Suthanthiran, M; Burlingham, WJ; Marks, WH; Sanz, I; Lechler, RI; Hernandez-Fuentes, MP; Turka, LA; Seyfert-Margolis, VL
MLA Citation
Newell, KA, Asare, A, Kirk, AD, Gisler, TD, Bourcier, K, Suthanthiran, M, Burlingham, WJ, Marks, WH, Sanz, I, Lechler, RI, Hernandez-Fuentes, MP, Turka, LA, and Seyfert-Margolis, VL. "Identification of a B cell signature associated with renal transplant tolerance in humans." Journal of Clinical Investigation 120.6 (June 1, 2010): 1836-1847.
Source
crossref
Published In
Journal of Clinical Investigation
Volume
120
Issue
6
Publish Date
2010
Start Page
1836
End Page
1847
DOI
10.1172/JCI39933

High-Frequency Alloreactive T Cells Augment Effector Function of Low-Frequency CD8+ T-Cell Responses Under CD28/CD154 Blockade

Authors
Floyd, TL; Orr, SB; Coley, SM; Hanna, SS; Wagener, ME; Kirk, AD; Larsen, CP; Ford, ML
MLA Citation
Floyd, TL, Orr, SB, Coley, SM, Hanna, SS, Wagener, ME, Kirk, AD, Larsen, CP, and Ford, ML. "High-Frequency Alloreactive T Cells Augment Effector Function of Low-Frequency CD8+ T-Cell Responses Under CD28/CD154 Blockade." Transplantation 89.10 (May 2010): 1208-1217.
Source
crossref
Published In
Transplantation
Volume
89
Issue
10
Publish Date
2010
Start Page
1208
End Page
1217
DOI
10.1097/TP.0b013e3181df53dc

Transient CD86 expression on hepatitis C virus-specific CD8+ T cells in acute infection is linked to sufficient IL-2 signaling.

Costimulatory signals via B7/CD28 family molecules (signal 2) are critical for effective adaptive CD8(+) T cell immune responses. In addition to costimulatory signals, B7/CD28 family coinhibitory receptor/ligands that modulate immune responses have been identified. In acute hepatitis C virus (HCV) infection, programmed death receptor 1, an inhibitory receptor in the CD28 family, is highly expressed on virus-specific CD8(+) T cells, yet vigorous immune responses often develop. We hypothesized that other costimulatory signals present during the acute phase of HCV infection would be important to counter this negative signaling. In this study, we found that CD86 was highly expressed on HCV-specific CD8(+) T cells early in acute HCV infection and was lost on transition to chronic HCV infection; the expression of CD86 was different from other activation markers, because expression was delayed after in vitro TCR stimulation and required sufficient IL-2 signaling; and HCV-specific CD8(+) T cells in the liver of patients with chronic HCV infection were highly activated (CD69, CD38, and HLA-DR expression), but only a minority expressed CD86 or showed evidence of recent IL-2 signaling (low basal phosphorylated STAT5), despite persistent viremia. Our study identified B7 ligand expression on HCV-specific CD8(+) T cells as a distinct marker of effective T cell stimulation with IL-2 signaling in acute HCV infection. Expression of costimulatory molecules, such as CD86, early in HCV infection may be essential in overcoming inhibitory signals from the high level of programmed death receptor 1 expression also seen at this phase of infection.

Authors
Radziewicz, H; Ibegbu, CC; Hon, H; Bédard, N; Bruneau, J; Workowski, KA; Knechtle, SJ; Kirk, AD; Larsen, CP; Shoukry, NH; Grakoui, A
MLA Citation
Radziewicz, H, Ibegbu, CC, Hon, H, Bédard, N, Bruneau, J, Workowski, KA, Knechtle, SJ, Kirk, AD, Larsen, CP, Shoukry, NH, and Grakoui, A. "Transient CD86 expression on hepatitis C virus-specific CD8+ T cells in acute infection is linked to sufficient IL-2 signaling." Journal of immunology (Baltimore, Md. : 1950) 184.5 (March 2010): 2410-2422.
PMID
20100932
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
184
Issue
5
Publish Date
2010
Start Page
2410
End Page
2422
DOI
10.4049/jimmunol.0902994

Editorial: What should work, may not

Authors
Kirk, AD
MLA Citation
Kirk, AD. "Editorial: What should work, may not." American Journal of Transplantation 10.3 (2010): 447-448.
Source
scival
Published In
American Journal of Transplantation
Volume
10
Issue
3
Publish Date
2010
Start Page
447
End Page
448
DOI
10.1111/j.1600-6143.2010.03025.x

Transplantation and autosomal recessive polycystic kidney disease.

Authors
Jackson, J; Greenbaum, L; Kirk, AD
MLA Citation
Jackson, J, Greenbaum, L, and Kirk, AD. "Transplantation and autosomal recessive polycystic kidney disease." Nephrology news & issues 24.7 (2010): 28-29.
Source
scival
Published In
Nephrology News and Issues: balancing economics and quality in renal care
Volume
24
Issue
7
Publish Date
2010
Start Page
28
End Page
29

Rapamycin augments pathogen-specific but not graft-reactive CD8+ T cell responses

Recent evidence demonstrating that exposure to rapamycin during viral infection increased the quantity and quality of Ag-specific T cells poses an intriguing paradox, because rapamycin is used in transplantation to dampen, rather than enhance, donor-reactive T cell responses. In this report, we compared the effects of rapamycin on the Ag-specific T cell response to a bacterial infection versus a transplant. Using a transgenic system in which the Ag and the responding T cell population were identical in both cases, we observed that treatment with rapamycin augmented the Ag-specific T cell response to a pathogen, whereas it failed to do sowhen the Ag was presented in the context of a transplant. These results suggest that the environment in which an Ag is presented alters the influence of rapamycin on Ag-specific T cell expansion and highlights a fundamental difference between Ag presented by an infectious agent as compared with an allograft. Copyright © 2010 by The American Association of Immunologists, Inc.

Authors
Ferrer, IR; Wagener, ME; Robertson, JM; Turner, AP; Araki, K; Ahmed, R; Kirk, AD; Larsen, CP; Ford, ML
MLA Citation
Ferrer, IR, Wagener, ME, Robertson, JM, Turner, AP, Araki, K, Ahmed, R, Kirk, AD, Larsen, CP, and Ford, ML. "Rapamycin augments pathogen-specific but not graft-reactive CD8+ T cell responses." Journal of Immunology 185.4 (2010): 2004-2008.
Source
scival
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
185
Issue
4
Publish Date
2010
Start Page
2004
End Page
2008
DOI
10.4049/jimmunol.1001176

Memory T-cell-specific therapeutics in organ transplantation

Authors
Page, AJ; Ford, ML; Kirk, AD
MLA Citation
Page, AJ, Ford, ML, and Kirk, AD. "Memory T-cell-specific therapeutics in organ transplantation." Current Opinion in Organ Transplantation 14.6 (December 2009): 643-649.
Source
crossref
Published In
Current Opinion in Organ Transplantation
Volume
14
Issue
6
Publish Date
2009
Start Page
643
End Page
649
DOI
10.1097/MOT.0b013e328332bd4a

Special Issue: KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients

MLA Citation
"Special Issue: KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients." American Journal of Transplantation 9 (November 2009): S1-S155.
Source
crossref
Published In
American Journal of Transplantation
Volume
9
Publish Date
2009
Start Page
S1
End Page
S155
DOI
10.1111/j.1600-6143.2009.02834.x

4D11: The Second Mouse?

Authors
Kirk, AD
MLA Citation
Kirk, AD. "4D11: The Second Mouse?." American Journal of Transplantation 9.8 (August 2009): 1701-1702.
Source
crossref
Published In
American Journal of Transplantation
Volume
9
Issue
8
Publish Date
2009
Start Page
1701
End Page
1702
DOI
10.1111/j.1600-6143.2009.02749.x

Dynamics of Human Regulatory T Cells in Lung Lavages of Lung Transplant Recipients

Authors
Neujahr, DC; Cardona, AC; Ulukpo, O; Rigby, M; Pelaez, A; Ramirez, A; Gal, AA; Force, SD; Lawrence, EC; Kirk, AD; Larsen, CP
MLA Citation
Neujahr, DC, Cardona, AC, Ulukpo, O, Rigby, M, Pelaez, A, Ramirez, A, Gal, AA, Force, SD, Lawrence, EC, Kirk, AD, and Larsen, CP. "Dynamics of Human Regulatory T Cells in Lung Lavages of Lung Transplant Recipients." Transplantation 88.4 (August 2009): 521-527.
Source
crossref
Published In
Transplantation
Volume
88
Issue
4
Publish Date
2009
Start Page
521
End Page
527
DOI
10.1097/TP.0b013e3181b0e719

Renal epithelial cell-derived monocyte colony stimulating factor as a local informant of renal injury and means of monocyte activation

Authors
Singh, KA; Kampen, RL; Hoffmann, SC; Eldaif, SM; Kirk, AD
MLA Citation
Singh, KA, Kampen, RL, Hoffmann, SC, Eldaif, SM, and Kirk, AD. "Renal epithelial cell-derived monocyte colony stimulating factor as a local informant of renal injury and means of monocyte activation." Transplant International 22.7 (July 2009): 730-737.
Source
crossref
Published In
Transplant International
Volume
22
Issue
7
Publish Date
2009
Start Page
730
End Page
737
DOI
10.1111/j.1432-2277.2009.00840.x

Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates

Authors
Weaver, TA; Charafeddine, AH; Agarwal, A; Turner, AP; Russell, M; Leopardi, FV; Kampen, RL; Stempora, L; Song, M; Larsen, CP; Kirk, AD
MLA Citation
Weaver, TA, Charafeddine, AH, Agarwal, A, Turner, AP, Russell, M, Leopardi, FV, Kampen, RL, Stempora, L, Song, M, Larsen, CP, and Kirk, AD. "Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates." Nature Medicine 15.7 (July 2009): 746-749.
Source
crossref
Published In
Nature Medicine
Volume
15
Issue
7
Publish Date
2009
Start Page
746
End Page
749
DOI
10.1038/nm.1993

Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis

Authors
Dalakas, MC; Rakocevic, G; Schmidt, J; Salajegheh, M; McElroy, B; Harris-Love, MO; Shrader, JA; Levy, EW; Dambrosia, J; Kampen, RL; Bruno, DA; Kirk, AD
MLA Citation
Dalakas, MC, Rakocevic, G, Schmidt, J, Salajegheh, M, McElroy, B, Harris-Love, MO, Shrader, JA, Levy, EW, Dambrosia, J, Kampen, RL, Bruno, DA, and Kirk, AD. "Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis." Brain 132.6 (June 1, 2009): 1536-1544.
Source
crossref
Published In
Brain
Volume
132
Issue
6
Publish Date
2009
Start Page
1536
End Page
1544
DOI
10.1093/brain/awp104

Donor-Reactive T-Cell Stimulation History and Precursor Frequency: Barriers to Tolerance Induction

Authors
Ford, ML; Kirk, AD; Larsen, CP
MLA Citation
Ford, ML, Kirk, AD, and Larsen, CP. "Donor-Reactive T-Cell Stimulation History and Precursor Frequency: Barriers to Tolerance Induction." Transplantation 87.Supplement (May 2009): S69-S74.
Source
crossref
Published In
Transplantation
Volume
87
Issue
Supplement
Publish Date
2009
Start Page
S69
End Page
S74
DOI
10.1097/TP.0b013e3181a2a701

Clinical Tolerance 2008

Authors
Kirk, AD
MLA Citation
Kirk, AD. "Clinical Tolerance 2008." Transplantation 87.7 (April 2009): 953-955.
Source
crossref
Published In
Transplantation
Volume
87
Issue
7
Publish Date
2009
Start Page
953
End Page
955
DOI
10.1097/TP.0b013e31819d415e

Assessment of Cadaveric Organ Viability During Pulsatile Perfusion Using Infrared Imaging

Authors
Gorbach, AM; Leeser, DB; Wang, H; Tadaki, DK; Fernandez, C; DeStephano, D; Hale, D; Kirk, AD; Gage, FA; Elster, EA
MLA Citation
Gorbach, AM, Leeser, DB, Wang, H, Tadaki, DK, Fernandez, C, DeStephano, D, Hale, D, Kirk, AD, Gage, FA, and Elster, EA. "Assessment of Cadaveric Organ Viability During Pulsatile Perfusion Using Infrared Imaging." Transplantation 87.8 (April 2009): 1163-1166.
Source
crossref
Published In
Transplantation
Volume
87
Issue
8
Publish Date
2009
Start Page
1163
End Page
1166
DOI
10.1097/TP.0b013e31819e3e02

Differential effects of donor-specific alloantibody

Authors
Turgeon, NA; Kirk, AD; Iwakoshi, NN
MLA Citation
Turgeon, NA, Kirk, AD, and Iwakoshi, NN. "Differential effects of donor-specific alloantibody." Transplantation Reviews 23.1 (January 2009): 25-33.
Source
crossref
Published In
Transplantation Reviews
Volume
23
Issue
1
Publish Date
2009
Start Page
25
End Page
33
DOI
10.1016/j.trre.2008.08.001

Portal Venous Donor-Specific Transfusion in Conjunction with Sirolimus Prolongs Renal Allograft Survival in Nonhuman Primates

Authors
Dhanireddy, KK; Bruno, DA; Weaver, TA; Xu, H; Zhang, X; Leopardi, FV; Hale, DA; Kirk, AD
MLA Citation
Dhanireddy, KK, Bruno, DA, Weaver, TA, Xu, H, Zhang, X, Leopardi, FV, Hale, DA, and Kirk, AD. "Portal Venous Donor-Specific Transfusion in Conjunction with Sirolimus Prolongs Renal Allograft Survival in Nonhuman Primates." American Journal of Transplantation 9.1 (January 2009): 124-131.
Source
crossref
Published In
American Journal of Transplantation
Volume
9
Issue
1
Publish Date
2009
Start Page
124
End Page
131
DOI
10.1111/j.1600-6143.2008.02448.x

Platelets Influence Vascularized Organ Transplants from Start to Finish

Authors
Kirk, AD; Morrell, CN; Baldwin III, WM
MLA Citation
Kirk, AD, Morrell, CN, and Baldwin III, WM. "Platelets Influence Vascularized Organ Transplants from Start to Finish." American Journal of Transplantation 9.1 (January 2009): 14-22.
Source
crossref
Published In
American Journal of Transplantation
Volume
9
Issue
1
Publish Date
2009
Start Page
14
End Page
22
DOI
10.1111/j.1600-6143.2008.02473.x

IFN-γ dictates allograft fate via opposing effects on the graft and on recipient CD8 T cell responses

CD8 T cells are necessary for costimulation blockade-resistant rejection. However, the mechanism by which CD8 T cells mediate rejection in the absence of major costimulatory signals is poorly understood. IFN-γ promotes CD8 T cell-mediated immune responses, but IFN-γ-deficient mice show early graft loss despite costimulation blockade. In contrast, we found that IFN-γ receptor knockout mice show dramatically prolonged graft survival under costimulation blockade. To investigate this paradox, we addressed the effects of IFN-γ on T cell alloresponses in vivo independent of the effects of IFN-γ on graft survival. We identified a donor-specific CD8 T cell breakthrough response temporally correlated with costimulation blockade-resistant rejection. Neither IFN-γ receptor knockout recipients nor IFN-γ-deficient recipients showed a CD8 breakthrough response. Graft death on IFN-γ-deficient recipients despite costimulation blockade could be explained by the lack of IFN-γ available to act on the graft. Indeed, the presence of IFN-γ was necessary for graft survival on IFN-γ receptor knockout recipients, as either IFN-γ neutralization or the lack of the IFN-γ receptor on the graft precipitated early graft loss. Thus, IFN-γ is required both for the recipient to mount a donor-specific CD8 T cell response under costimulation blockade as well as for the graft to survive after allotransplantation. Copyright © 2008 by The American Association of Immunologists, Inc.

Authors
Coley, SM; Ford, ML; Hanna, SC; Wagener, ME; Kirk, AD; Larsen, CP
MLA Citation
Coley, SM, Ford, ML, Hanna, SC, Wagener, ME, Kirk, AD, and Larsen, CP. "IFN-γ dictates allograft fate via opposing effects on the graft and on recipient CD8 T cell responses." Journal of Immunology 182.1 (2009): 225-233.
Source
scival
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
182
Issue
1
Publish Date
2009
Start Page
225
End Page
233

Non-invasive monitoring of tissue oxygenation during laparoscopic donor nephrectomy

Authors
Crane, NJ; Pinto, PA; Hale, D; Gage, FA; Tadaki, D; Kirk, AD; Levin, IW; Elster, EA
MLA Citation
Crane, NJ, Pinto, PA, Hale, D, Gage, FA, Tadaki, D, Kirk, AD, Levin, IW, and Elster, EA. "Non-invasive monitoring of tissue oxygenation during laparoscopic donor nephrectomy." BMC Surgery 8.1 (December 2008).
Source
crossref
Published In
BMC Surgery
Volume
8
Issue
1
Publish Date
2008
DOI
10.1186/1471-2482-8-8

The role of alemtuzumab in facilitating maintenance immunosuppression minimization following solid organ transplantation

Authors
Agarwal, A; Shen, LY; Kirk, AD
MLA Citation
Agarwal, A, Shen, LY, and Kirk, AD. "The role of alemtuzumab in facilitating maintenance immunosuppression minimization following solid organ transplantation." Transplant Immunology 20.1-2 (November 2008): 6-11.
Source
crossref
Published In
Transplant Immunology
Volume
20
Issue
1-2
Publish Date
2008
Start Page
6
End Page
11
DOI
10.1016/j.trim.2008.09.003

Assessment of Critical Renal Ischemia With Real-Time Infrared Imaging

Authors
Gorbach, AM; Wang, H; Dhanani, NN; Gage, FA; Pinto, PA; Smith, PD; Kirk, AD; Elster, EA
MLA Citation
Gorbach, AM, Wang, H, Dhanani, NN, Gage, FA, Pinto, PA, Smith, PD, Kirk, AD, and Elster, EA. "Assessment of Critical Renal Ischemia With Real-Time Infrared Imaging." Journal of Surgical Research 149.2 (October 2008): 310-318.
Source
crossref
Published In
Journal of Surgical Research
Volume
149
Issue
2
Publish Date
2008
Start Page
310
End Page
318
DOI
10.1016/j.jss.2008.02.007

What's Next in the Pipeline

Authors
Vincenti, F; Kirk, AD
MLA Citation
Vincenti, F, and Kirk, AD. "What's Next in the Pipeline." American Journal of Transplantation 8.10 (October 2008): 1972-1981.
Source
crossref
Published In
American Journal of Transplantation
Volume
8
Issue
10
Publish Date
2008
Start Page
1972
End Page
1981
DOI
10.1111/j.1600-6143.2008.02403.x

AJT's Response to the National Institutes of Health Public Access Regulations

Authors
Kirk, AD; Salomon, DR
MLA Citation
Kirk, AD, and Salomon, DR. "AJT's Response to the National Institutes of Health Public Access Regulations." American Journal of Transplantation 8.10 (October 2008): 1969-1969.
Source
crossref
Published In
American Journal of Transplantation
Volume
8
Issue
10
Publish Date
2008
Start Page
1969
End Page
1969
DOI
10.1111/j.1600-6143.2008.02363.x

The Banff 2007 working classification of skin-containing composite tissue allograft pathology.

Composite tissue allotransplantation (CTA) is a recently introduced option for limb replacement and reconstruction of tissue defects. As with other allografts, CTA can undergo immune-mediated rejection; therefore standardized criteria are required for characterizing and reporting severity and types of rejection. This article documents the conclusions of a symposium on CTA rejection held at the Ninth Banff Conference on Allograft Pathology in La-Coruna, Spain, on 26 June 2007, and proposes a working classification, the Banff CTA-07, for the categorization of CTA rejection. This classification was derived from a consensus discussion session attended by the first authors of three published classification systems, pathologists and researchers from international centers where clinical CTA has been performed. It was open to all attendees to the Banff conference. To the extent possible, the format followed the established National Institutes of Health (NIH) guidelines on Consensus Development Programs. By consensus, the defining features to diagnose acute skin rejection include inflammatory cell infiltration with involvement of epidermis and/or adnexal structures, epithelial apoptosis, dyskeratosis and necrosis. Five grades of severity of rejection are defined. This classification refines proposed schemas, represents international consensus on this topic, and establishes a working collective classification system for CTA reporting of rejection in skin-containing CTAs.

Authors
Cendales, LC; Kanitakis, J; Schneeberger, S; Burns, C; Ruiz, P; Landin, L; Remmelink, M; Hewitt, CW; Landgren, T; Lyons, B; Drachenberg, CB; Solez, K; Kirk, AD; Kleiner, DE; Racusen, L
MLA Citation
Cendales, LC, Kanitakis, J, Schneeberger, S, Burns, C, Ruiz, P, Landin, L, Remmelink, M, Hewitt, CW, Landgren, T, Lyons, B, Drachenberg, CB, Solez, K, Kirk, AD, Kleiner, DE, and Racusen, L. "The Banff 2007 working classification of skin-containing composite tissue allograft pathology." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 8.7 (July 2008): 1396-1400.
PMID
18444912
Source
epmc
Published In
American Journal of Transplantation
Volume
8
Issue
7
Publish Date
2008
Start Page
1396
End Page
1400
DOI
10.1111/j.1600-6143.2008.02243.x

Finding the right job for the tool: alemtuzumab and its role in renal transplantation.

Authors
Newell, KA; Cendales, LC; Kirk, AD
MLA Citation
Newell, KA, Cendales, LC, and Kirk, AD. "Finding the right job for the tool: alemtuzumab and its role in renal transplantation." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 8.7 (July 2008): 1363-1364.
PMID
18557735
Source
epmc
Published In
American Journal of Transplantation
Volume
8
Issue
7
Publish Date
2008
Start Page
1363
End Page
1364
DOI
10.1111/j.1600-6143.2008.02291.x

Intraoperative Assessment of Critical Biliary Structures with Visible Range/Infrared Image Fusion

Authors
Hanna, BV; Gorbach, AM; Gage, FA; Pinto, PA; Silva, JS; Gilfillan, LG; Kirk, AD; Elster, EA
MLA Citation
Hanna, BV, Gorbach, AM, Gage, FA, Pinto, PA, Silva, JS, Gilfillan, LG, Kirk, AD, and Elster, EA. "Intraoperative Assessment of Critical Biliary Structures with Visible Range/Infrared Image Fusion." Journal of the American College of Surgeons 206.6 (June 2008): 1227-1231.
Source
crossref
Published In
Journal of The American College of Surgeons
Volume
206
Issue
6
Publish Date
2008
Start Page
1227
End Page
1231
DOI
10.1016/j.jamcollsurg.2007.10.012

Pharmacokinetics of Low and Maintenance Dose Valganciclovir in Kidney Transplant Recipients

Authors
Chamberlain, CE; Penzak, SR; Alfaro, RM; Wesley, R; Daniels, CE; Hale, D; Kirk, AD; Mannon, RB
MLA Citation
Chamberlain, CE, Penzak, SR, Alfaro, RM, Wesley, R, Daniels, CE, Hale, D, Kirk, AD, and Mannon, RB. "Pharmacokinetics of Low and Maintenance Dose Valganciclovir in Kidney Transplant Recipients." American Journal of Transplantation 8.6 (June 2008): 1297-1302.
Source
crossref
Published In
American Journal of Transplantation
Volume
8
Issue
6
Publish Date
2008
Start Page
1297
End Page
1302
DOI
10.1111/j.1600-6143.2008.02220.x

Obesity following kidney transplantation and steroid avoidance immunosuppression

Authors
Elster, EA; Leeser, DB; Morrissette, C; Pepek, JM; Quiko, A; Hale, DA; Chamberlain, C; Salaita, C; Kirk, AD; Mannon, RB
MLA Citation
Elster, EA, Leeser, DB, Morrissette, C, Pepek, JM, Quiko, A, Hale, DA, Chamberlain, C, Salaita, C, Kirk, AD, and Mannon, RB. "Obesity following kidney transplantation and steroid avoidance immunosuppression." Clinical Transplantation 22.3 (May 2008): 354-359.
Source
crossref
Published In
Clinical Transplantation
Volume
22
Issue
3
Publish Date
2008
Start Page
354
End Page
359
DOI
10.1111/j.1399-0012.2008.00792.x

Monocyte Infiltration and Kidney Allograft Dysfunction During Acute Rejection

Authors
Girlanda, R; Kleiner, DE; Duan, Z; Ford, EAS; Wright, EC; Mannon, RB; Kirk, AD
MLA Citation
Girlanda, R, Kleiner, DE, Duan, Z, Ford, EAS, Wright, EC, Mannon, RB, and Kirk, AD. "Monocyte Infiltration and Kidney Allograft Dysfunction During Acute Rejection." American Journal of Transplantation 8.3 (March 2008): 600-607.
Source
crossref
Published In
American Journal of Transplantation
Volume
8
Issue
3
Publish Date
2008
Start Page
600
End Page
607
DOI
10.1111/j.1600-6143.2007.02109.x

Translational research in composite tissue allotransplantation

© 2008 Springer Science+Business Media, LLC. All rights reserved.Patients suffering from severe tissue loss secondary to burns, traumatic injuries, or tumor resections have limited options for reconstruction when autologous tissue for reconstruction is scarce. Composite tissue allotransplantation (CTA) has recently been introduced as a potential clinical treatment for functionally significant tissue loss. CTA has emerged as an amalgamation of advanced microsurgical techniques for limb and flap autotransplantation, and improved immunosuppressive agents to prevent rejection. However, as a developing field, it is yet to have its unique immunological properties established.

Authors
Cendales, LC; Kleiner, DE; Kirk, AD
MLA Citation
Cendales, LC, Kleiner, DE, and Kirk, AD. "Translational research in composite tissue allotransplantation." Transplantation of Composite Tissue Allografts. January 1, 2008. 43-54.
Source
scopus
Publish Date
2008
Start Page
43
End Page
54
DOI
10.1007/978-0-387-74682-1_5

Costimulation blockade: Towards clinical application

Organ transplantation is an increasingly successful therapy for many forms of organ failure, but its success depends upon drug therapies to prevent immunologic destruction of the transplanted organ also known as rejection. Most therapies designed to prevent rejection alter the immune system in a rather broad, antigen independent way, and thus alter protective immunity as well as immune responses directed against the transplanted organ. Over the past 3 decades, however, it has been realized that a class of surface molecules known as costimulatory receptors are required to generate a fully productive immune response, and that blockade of these receptors during allo-antigen recognition can be used to influence the immune system's future response to that particular allo-antigen. Costimulation blockade has thus been developed as a specific field of interest towards achieving improved antigen specific control over transplant rejection while minimizing broad attenuation of protective immunity seen with conventional immunosuppressives. This field has grown rapidly in the past decade and is now poised to become a valuable therapeutic option for transplant clinicians. This review will outline the basic premise of costimulation biology, review the seminal experimental basis for its use in preventing organ rejection, and discuss the relevant data derived from its initial use in clinical transplant trials. Specific attention will be focused on two major costimulatory pathways, the CD28/CD80-CD86 and the CD40-CD154 pathways, and the clinically applicable data supporting their validity as therapeutic targets. Newly discovered costimulatory pathways will also be discussed as potential therapeutic targets for future clinical drugs.

Authors
Weaver, TA; Charafeddine, AH; Kirk, AD
MLA Citation
Weaver, TA, Charafeddine, AH, and Kirk, AD. "Costimulation blockade: Towards clinical application." Frontiers in Bioscience 13.6 (2008): 2120-2139.
Source
manual
Published In
Frontiers in bioscience : a journal and virtual library
Volume
13
Issue
6
Publish Date
2008
Start Page
2120
End Page
2139
DOI
10.2741/2829

A critical precursor frequency of donor-reactive CD4 + T cell help is required for CD8 + T cell-mediated CD28/CD154-independent rejection

Ag-specific precursor frequency is increasingly being appreciated as an important factor in determining the kinetics, magnitude, and degree of differentiation of T cell responses, and recently was found to play a critical role in determining the relative requirement of CD8 + T cells for CD28- and CD154-mediated costimulatory signals during transplantation. We addressed the possibility that variations in CD4 + T cell precursor frequency following transplantation might affect CD4 + T cell proliferation, effector function, and provision of help for donor-reactive B cell and CD8 + T cell responses. Using a transgenic model system wherein increasing frequencies of donor-reactive CD4 + T cells were transferred into skin graft recipients, we observed that a critical CD4 + T cell threshold precursor frequency was necessary to provide help following blockade of the CD28 and CD154 costimulatory pathways, as measured by increased B cell and CD8 + T cell responses and precipitation of graft rejection. In contrast to high-frequency CD8 + T cell responses, this effect was observed even though the proliferative and cytokine responses of Ag-specific CD4 + T cells were inhibited. Thus, we conclude that an initial high frequency of donor-reactive CD4 + T cells uncouples T cell proliferative and effector cytokine production from the provision of T cell help. Copyright © 2008 by The American Association of Immunologists, Inc.

Authors
Ford, ML; Wagener, ME; Hanna, SS; Pearson, TC; Kirk, AD; Larsen, CP
MLA Citation
Ford, ML, Wagener, ME, Hanna, SS, Pearson, TC, Kirk, AD, and Larsen, CP. "A critical precursor frequency of donor-reactive CD4 + T cell help is required for CD8 + T cell-mediated CD28/CD154-independent rejection." Journal of Immunology 180.11 (2008): 7203-7211.
Source
scival
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
180
Issue
11
Publish Date
2008
Start Page
7203
End Page
7211

PD-1-dependent mechanisms maintain peripheral tolerance of donor-reactive CD8+ T cells to transplanted tissue

Peripheral mechanisms of self-tolerance often depend on the quiescent state of the immune system. To what degree such mechanisms can be engaged in the enhancement of allograft survival is unclear. To examine the role of the PD-1 pathway in the maintenance of graft survival following blockade of costimulatory pathways, we used a single-Ag mismatch model of graft rejection where we could track the donor-specific cells as they developed endogenously and emerged from the thymus. We found that graft-specific T cells arising under physiologic developmental conditions at low frequency were actively deleted at the time of transplantation under combined CD28/CD40L blockade. However, this deletion was incomplete, and donor-specific cells that failed to undergo deletion up-regulated expression of PD-1. Furthermore, blockade of PD-1 signaling on these cells via in vivo treatment with anti-PD-1 mAb resulted in rapid expansion of donor-specific T cells and graft loss. These results suggest that the PD-1 pathway was engaged in the continued regulation of the low-frequency graft-specific immune response and thus in maintenance of graft survival. Copyright © 2008 by The American Association of Immunologists, Inc.

Authors
Koehn, BH; Ford, ML; Ferrer, IR; Borom, K; Gangappa, S; Kirk, AD; Larsen, CP
MLA Citation
Koehn, BH, Ford, ML, Ferrer, IR, Borom, K, Gangappa, S, Kirk, AD, and Larsen, CP. "PD-1-dependent mechanisms maintain peripheral tolerance of donor-reactive CD8+ T cells to transplanted tissue." Journal of Immunology 181.8 (2008): 5313-5322.
Source
scival
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
181
Issue
8
Publish Date
2008
Start Page
5313
End Page
5322

Antibodies and Fusion Proteins

Authors
Kirk, AD
MLA Citation
Kirk, AD. "Antibodies and Fusion Proteins." 2008. 309-332.
Source
scival
Publish Date
2008
Start Page
309
End Page
332
DOI
10.1016/B978-1-4160-3343-1.50024-4

Immunology of transplantation

Tissues transferred between genetically nonidentical individuals are destroyed through a process known broadly as rejection. It has been apparent throughout most of medical history that these tissues could provide relief from disease if they were not rejected. Thus, the field of transplantation has grown in tandem with the understanding of the biology of rejection and, to the extent that rejection is an immune-mediated process, of the immune system in general. This close relationship between immunological science and clinical transplantation has fueled remarkable progress in our understanding of immune function and of the fundamental nature of our existence as individuals. The components of the immune system that have been defined in this context are now widely recognized not only for their importance in graft rejection but also for their roles in infection control, shock, tumor growth, autoimmune disease, and the systemic response to trauma. As such, the understanding of immunology that has been born of the study of transplantation has become key to the thorough understanding of the biology of modern medicine and surgery. © 2008 Springer New York.

Authors
Kirk, AD; Elster, EA
MLA Citation
Kirk, AD, and Elster, EA. "Immunology of transplantation." 2008. 1705-1736.
Source
scival
Publish Date
2008
Start Page
1705
End Page
1736
DOI
10.1007/978-0-387-68113-9_81

Alemtuzumab

Authors
Weaver, TA; Kirk, AD
MLA Citation
Weaver, TA, and Kirk, AD. "Alemtuzumab." Transplantation 84.12 (December 2007): 1545-1547.
Source
crossref
Published In
Transplantation
Volume
84
Issue
12
Publish Date
2007
Start Page
1545
End Page
1547
DOI
10.1097/01.tp.0000296680.75175.67

Dissociation of depletional induction and posttransplant lymphoproliferative disease in kidney recipients treated with alemtuzumab.

Transplant patients are at the risk for posttransplant lymphoproliferative disease (PTLD), a virally-driven malignancy. Induction with the depleting antibody preparations Thymoglobulin and OKT3 is associated with PTLD suggesting that the T-cell depletion increases PTLD risk. We therefore studied 59 560 kidney recipients from the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) database for a relationship between induction agent use and PTLD. Two agents with comparable T-cell depletional effects, alemtuzumab and Thymoglobulin, were compared to nondepletional induction agents or no induction. The overall incidence of PTLD was 0.46% and differed significantly by induction strategy (p < 0.01): without induction (0.43%), basiliximab (0.38%), daclizumab (0.33%), Thymoglobulin (0.67%) and alemtuzumab (0.37%). Thymoglobulin was associated with significantly increased PTLD risk (p = 0.0025), but alemtuzumab (p = 0.74), basiliximab (p = 0.33) and daclizumab, which trended toward a protective effect (p = 0.06), were not. Alemtuzumab and Thymoglobulin treated patients did not differ in any established parameter affecting PTLD risk although alemtuzumab is known to have a more pronounced B-cell depleting effect. Interestingly, maintenance therapy with an mTOR inhibitor was strongly associated with PTLD (0.71%, p < 0.0001). Thus, depletional induction is not an independent risk factor for PTLD. Rather, maintenance drug selection or perhaps the balance between B- and T-cell depletion may be more relevant determinants of PTLD risk.

Authors
Kirk, AD; Cherikh, WS; Ring, M; Burke, G; Kaufman, D; Knechtle, SJ; Potdar, S; Shapiro, R; Dharnidharka, VR; Kauffman, HM
MLA Citation
Kirk, AD, Cherikh, WS, Ring, M, Burke, G, Kaufman, D, Knechtle, SJ, Potdar, S, Shapiro, R, Dharnidharka, VR, and Kauffman, HM. "Dissociation of depletional induction and posttransplant lymphoproliferative disease in kidney recipients treated with alemtuzumab." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 7.11 (November 2007): 2619-2625.
PMID
17868060
Source
epmc
Published In
American Journal of Transplantation
Volume
7
Issue
11
Publish Date
2007
Start Page
2619
End Page
2625
DOI
10.1111/j.1600-6143.2007.01972.x

Diagnostic Tools for Monitoring Kidney Transplant Recipients

Authors
Girlanda, R; Mannon, RB; Kirk, AD
MLA Citation
Girlanda, R, Mannon, RB, and Kirk, AD. "Diagnostic Tools for Monitoring Kidney Transplant Recipients." Seminars in Nephrology 27.4 (July 2007): 462-478.
Source
crossref
Published In
Seminars in Nephrology
Volume
27
Issue
4
Publish Date
2007
Start Page
462
End Page
478
DOI
10.1016/j.semnephrol.2007.03.007

Frontiers in Nephrology: Immune Tolerance to Allografts in Humans

Authors
Girlanda, R; Kirk, AD
MLA Citation
Girlanda, R, and Kirk, AD. "Frontiers in Nephrology: Immune Tolerance to Allografts in Humans." Journal of the American Society of Nephrology 18.8 (June 28, 2007): 2242-2251.
Source
crossref
Published In
Journal of the American Society of Nephrology : JASN
Volume
18
Issue
8
Publish Date
2007
Start Page
2242
End Page
2251
DOI
10.1681/ASN.2007020180

American Society of Transplantation Symposium on B Cells in Transplantation: Harnessing Humoral Immunity from Rodent Models to Clinical Practice

Authors
Kirk, AD; Baldwin, WM; Cascalho, MI; Chong, AS; Sykes, M; West, LJ
MLA Citation
Kirk, AD, Baldwin, WM, Cascalho, MI, Chong, AS, Sykes, M, and West, LJ. "American Society of Transplantation Symposium on B Cells in Transplantation: Harnessing Humoral Immunity from Rodent Models to Clinical Practice." American Journal of Transplantation 7.6 (June 2007): 1464-1470.
Source
crossref
Published In
American Journal of Transplantation
Volume
7
Issue
6
Publish Date
2007
Start Page
1464
End Page
1470
DOI
10.1111/j.1600-6143.2007.01815.x

CD154 Blockade, Sirolimus, and Donor-Specific Transfusion Prevents Renal Allograft Rejection in Cynomolgus Monkeys Despite Homeostatic T-Cell Activation

Authors
Pearl, JP; Xu, H; Leopardi, F; Preston, E; Kirk, AD
MLA Citation
Pearl, JP, Xu, H, Leopardi, F, Preston, E, and Kirk, AD. "CD154 Blockade, Sirolimus, and Donor-Specific Transfusion Prevents Renal Allograft Rejection in Cynomolgus Monkeys Despite Homeostatic T-Cell Activation." Transplantation 83.9 (May 2007): 1219-1225.
Source
crossref
Published In
Transplantation
Volume
83
Issue
9
Publish Date
2007
Start Page
1219
End Page
1225
DOI
10.1097/01.tp.0000259929.04596.d5

Protocol Biopsies in Renal Transplantation: Insights into Patient Management and Pathogenesis

Authors
Mengel, M; Chapman, JR; Cosio, FG; Cavaillé-Coll, MW; Haller, H; Halloran, PF; Kirk, AD; Mihatsch, MJ; Nankivell, BJ; Racusen, LC; Roberts, IS; Rush, DN; Schwarz, A; Serón, D; Stegall, MD; Colvin, RB
MLA Citation
Mengel, M, Chapman, JR, Cosio, FG, Cavaillé-Coll, MW, Haller, H, Halloran, PF, Kirk, AD, Mihatsch, MJ, Nankivell, BJ, Racusen, LC, Roberts, IS, Rush, DN, Schwarz, A, Serón, D, Stegall, MD, and Colvin, RB. "Protocol Biopsies in Renal Transplantation: Insights into Patient Management and Pathogenesis." American Journal of Transplantation 7.3 (March 2007): 512-517.
Source
crossref
Published In
American Journal of Transplantation
Volume
7
Issue
3
Publish Date
2007
Start Page
512
End Page
517
DOI
10.1111/j.1600-6143.2006.01677.x

Nonhuman primates for the study of composite tissue allotransplantation.

Authors
Cendales, LC; Kirk, AD
MLA Citation
Cendales, LC, and Kirk, AD. "Nonhuman primates for the study of composite tissue allotransplantation." Transplantation 83.2 (January 2007): 241-.
PMID
17264827
Source
epmc
Published In
Transplantation
Volume
83
Issue
2
Publish Date
2007
Start Page
241
DOI
10.1097/01.tp.0000242527.32735.0d

Of Ends and Means

Authors
Kirk, AD; Light, JA
MLA Citation
Kirk, AD, and Light, JA. "Of Ends and Means." American Journal of Transplantation 6.10 (October 2006): 2228-2229.
Source
crossref
Published In
American Journal of Transplantation
Volume
6
Issue
10
Publish Date
2006
Start Page
2228
End Page
2229
DOI
10.1111/j.1600-6143.2006.01500.x

Induction Immunosuppression

Authors
Kirk, AD
MLA Citation
Kirk, AD. "Induction Immunosuppression." Transplantation 82.5 (September 2006): 593-602.
Source
crossref
Published In
Transplantation
Volume
82
Issue
5
Publish Date
2006
Start Page
593
End Page
602
DOI
10.1097/01.tp.0000234905.56926.7f

Tacrolimus and Sirolimus: When Bad Things Happen to Good Drugs.

Authors
Kaplan, B; Kirk, AD
MLA Citation
Kaplan, B, and Kirk, AD. "Tacrolimus and Sirolimus: When Bad Things Happen to Good Drugs." American Journal of Transplantation 6.7 (July 2006): 1501-1502.
Source
crossref
Published In
American Journal of Transplantation
Volume
6
Issue
7
Publish Date
2006
Start Page
1501
End Page
1502
DOI
10.1111/j.1600-6143.2006.01392.x

A new look at blockade of T-cell costimulation: a therapeutic strategy for long-term maintenance immunosuppression.

Activated T cells orchestrate the immune response that results in graft rejection; therefore, a common goal among current immunosuppressive therapies is to block T-cell activation, proliferation and function. Current immunosuppressive regimens that inhibit T cells and immune cells have greatly reduced the incidence of acute rejection following solid-organ transplant. However, the expected improvements in long-term outcomes have not been realized. This may be related to the non-immune side effects of current maintenance immunosuppressants, which target ubiquitously expressed molecules. The focus in transplantation research is shifting in search of maintenance immunosuppressive regimens that might offer improved long-term outcomes by providing efficacy in prevention of acute rejection combined with reduced toxicities. An emerging therapeutic strategy involves an immunoselective maintenance immunosuppressant that inhibits full T-cell activation by blocking the interaction between costimulatory receptor-ligand pairs. This review describes costimulatory pathways and the development of molecules, which inhibit them in the context of transplantation research. Recent clinical data using the selective costimulation blocker, belatacept (LEA29Y), as a part of a CNI-free maintenance immunosuppressive regimen in renal transplantation is highlighted.

Authors
Larsen, CP; Knechtle, SJ; Adams, A; Pearson, T; Kirk, AD
MLA Citation
Larsen, CP, Knechtle, SJ, Adams, A, Pearson, T, and Kirk, AD. "A new look at blockade of T-cell costimulation: a therapeutic strategy for long-term maintenance immunosuppression." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 6.5 Pt 1 (May 2006): 876-883. (Review)
PMID
16611323
Source
epmc
Published In
American Journal of Transplantation
Volume
6
Issue
5 Pt 1
Publish Date
2006
Start Page
876
End Page
883
DOI
10.1111/j.1600-6143.2006.01259.x

Autoimmune Thyroid Disease After Renal Transplantation Using Depletional Induction with Alemtuzumab 1

Authors
Kirk, AD; Hale, DA; Swanson, SJ; Mannon, RB
MLA Citation
Kirk, AD, Hale, DA, Swanson, SJ, and Mannon, RB. "Autoimmune Thyroid Disease After Renal Transplantation Using Depletional Induction with Alemtuzumab 1." American Journal of Transplantation 6.5p1 (May 2006): 1084-1085.
Source
crossref
Published In
American Journal of Transplantation
Volume
6
Issue
5p1
Publish Date
2006
Start Page
1084
End Page
1085
DOI
10.1111/j.1600-6143.2006.01258.x

Beyond Histology: Novel Tools to Diagnose Allograft Dysfunction

Authors
Mannon, RB
MLA Citation
Mannon, RB. "Beyond Histology: Novel Tools to Diagnose Allograft Dysfunction." Clinical Journal of the American Society of Nephrology 1.3 (April 19, 2006): 358-366.
Source
crossref
Published In
Clinical journal of the American Society of Nephrology : CJASN
Volume
1
Issue
3
Publish Date
2006
Start Page
358
End Page
366
DOI
10.2215/CJN.01681105

Meteorology and Tolerance

Authors
Kirk, AD
MLA Citation
Kirk, AD. "Meteorology and Tolerance." American Journal of Transplantation 6.4 (April 2006): 645-646.
Source
crossref
Published In
American Journal of Transplantation
Volume
6
Issue
4
Publish Date
2006
Start Page
645
End Page
646
DOI
10.1111/j.1600-6143.2006.01244.x

Successful Renal Transplantation in Patients with Chronic Granulomatous Disease

Authors
Bolanowski, A; Mannon, RB; Holland, SM; Malech, HL; Aschan, J; Palmblad, J; Hale, DA; Kirk, AD
MLA Citation
Bolanowski, A, Mannon, RB, Holland, SM, Malech, HL, Aschan, J, Palmblad, J, Hale, DA, and Kirk, AD. "Successful Renal Transplantation in Patients with Chronic Granulomatous Disease." American Journal of Transplantation 6.3 (March 2006): 636-639.
Source
crossref
Published In
American Journal of Transplantation
Volume
6
Issue
3
Publish Date
2006
Start Page
636
End Page
639
DOI
10.1111/j.1600-6143.2006.01232.x

Composite tissue allotransplantation: classification of clinical acute skin rejection.

BACKGROUND: Composite tissue allotransplantation (CTA) is a recently introduced option for limb replacement and reconstruction of other nonreconstructible tissue defects. As with recipients of other allotransplants, CTA recipients can experience rejection episodes that are presumed to be mediated by immune mechanisms similar to those affecting solid organ grafts. However, a systematic examination of this process has not been performed, and there are no standardized criteria for the description of severity or type of rejection. METHODS: We collected biopsies from human limb allografts and abdominal walls in various stages of rejection for histological and immunohistochemical analysis to formulate a CTA rejection scheme. Biopsies were ranked by severity and reproducibility of the system was tested using a second set of biopsies. Tissue slides were examined blindly by three pathologists and the nonparametric Kendall coefficient of concordance (W) was used to assess the amount of agreement among the pathologists in their classification grades. RESULTS: Rejection initially appeared as a perivascular infiltrate progressing to involve the dermis. Arteritis was observed only in the medium to large size arteries of the subcutis. Myositis was seen occasionally. Perineural involvement without frank neuritis was present in advanced rejection. The infiltrate was predominantly CD4+ in milder cases and CD8+ in advanced cases. HLA-DR was minimally expressed in keratinocytes even in severe rejection. Kendall's W was 0.9375 (p< or =0.0001). CONCLUSIONS: Based on this survey, we proposed an initial classification system for acute rejection in the skin of a CTA and demonstrated that this system is easily reproduced by independent pathologists.

Authors
Cendales, LC; Kirk, AD; Moresi, JM; Ruiz, P; Kleiner, DE
MLA Citation
Cendales, LC, Kirk, AD, Moresi, JM, Ruiz, P, and Kleiner, DE. "Composite tissue allotransplantation: classification of clinical acute skin rejection." Transplantation 81.3 (February 2006): 418-422.
PMID
16477229
Source
epmc
Published In
Transplantation
Volume
81
Issue
3
Publish Date
2006
Start Page
418
End Page
422
DOI
10.1097/01.tp.0000185304.49987.d8

Transplant Tolerance: Converging on a Moving Target

Authors
Newell, KA; Larsen, CP; Kirk, AD
MLA Citation
Newell, KA, Larsen, CP, and Kirk, AD. "Transplant Tolerance: Converging on a Moving Target." Transplantation 81.1 (January 2006): 1-6.
Source
crossref
Published In
Transplantation
Volume
81
Issue
1
Publish Date
2006
Start Page
1
End Page
6
DOI
10.1097/01.tp.0000179149.12979.13

Visual enhancement of laparoscopic nephrectomies using the 3-CCD camera

Many surgical techniques are currently shifting from the more conventional, open approach towards minimally invasive laparoscopic procedures. Laparoscopy results in smaller incisions, potentially leading to less postoperative pain and more rapid recoveries. One key disadvantage of laparoscopic surgery is the loss of three-dimensional assessment of organs and tissue perfusion. Advances in laparoscopic technology include high-definition monitors for improved visualization and upgraded single charge coupled device (CCD) detectors to 3-CCD cameras, to provide a larger, more sensitive color palette to increase the perception of detail. In this discussion, we further advance existing laparoscopic technology to create greater enhancement of images obtained during radical and partial nephrectomies in which the assessment of tissue perfusion is crucial but limited with current 3-CCD cameras. By separating the signals received by each CCD in the 3-CCD camera and by introducing a straight forward algorithm, rapid differentiation of renal vessels and perfusion is accomplished and could be performed real time. The newly acquired images are overlaid onto conventional images for reference and comparison. This affords the surgeon the ability to accurately detect changes in tissue oxygenation despite inherent limitations of the visible light image. Such additional capability should impact procedures in which visual assessment of organ vitality is critical.

Authors
Crane, NJ; Kansal, NS; Dhanani, N; Alemozaffar, M; Kirk, AD; Pinto, PA; Elster, EA; Huffman, SW; Levin, IW
MLA Citation
Crane, NJ, Kansal, NS, Dhanani, N, Alemozaffar, M, Kirk, AD, Pinto, PA, Elster, EA, Huffman, SW, and Levin, IW. "Visual enhancement of laparoscopic nephrectomies using the 3-CCD camera." 2006.
Source
scival
Published In
Proceedings of SPIE - The International Society for Optical Engineering
Volume
6081
Publish Date
2006
DOI
10.1117/12.663940

Human monocytes as intermediaries between allogeneic endothelial cells and allospecific T cells: A role for direct scavenger receptor-mediated endothelial membrane uptake in the initiation of alloimmunity

Recipient monocytes, T cells, and donor endothelial cells (ECs) are recognized as critical components of allograft rejection. We have recently shown that human monocytes infiltrate vascularized allografts before clinical rejection and have thus hypothesized that monocytes, rather than costimulation-poor ECs, initiate an alloimmune response. However, the nature of the interactions between ECs, monocytes, and T cells has been incompletely defined. Specifically, it is not clear whether these cells interact in a hierarchical manner, nor is it apparent what constitutes an interaction. We therefore studied human ECs, monocytes, and T cells in various isolated in vitro combinations to define the salient features of their contact and to determine whether their interactions were sequential in nature. We find that T cells proliferate poorly to allogeneic ECs and autologous monocytes but well to autologous monocytes following allogeneic EC contact. We show that monocytes gain their stimulatory capacity by phagocytizing allogeneic but not autologous EC membranes in a process governed by scavenger receptors. This process facilitates the subsequent presentation of intact donor HLA molecules to T cells (semidirect presentation). Moreover, monocytes are receptive to T cell help only after exposure to ECs and require CD4+ T cells to optimally express costimulatory molecules and foster Ag presentation. Our results indicate that monocytes engage allogeneic ECs through scavenger receptors and are then primed to facilitate T cell activation in a codependent manner. This reciprocal codependence allows for monocytes to serve as a regulated bridge between the allograft and T cells. Copyright © 2006 by The American Association of Immunologists, Inc.

Authors
Xu, H; Dhanireddy, KK; Kirk, AD
MLA Citation
Xu, H, Dhanireddy, KK, and Kirk, AD. "Human monocytes as intermediaries between allogeneic endothelial cells and allospecific T cells: A role for direct scavenger receptor-mediated endothelial membrane uptake in the initiation of alloimmunity." Journal of Immunology 176.2 (2006): 750-761.
Source
scival
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
176
Issue
2
Publish Date
2006
Start Page
750
End Page
761

Platelet-derived or soluble CD154 induces vascularized allograft rejection independent of cell-bound CD154

CD154 is a cell surface molecule expressed on activated T cells that binds to CD40, an activating molecule on APCs. Its blockade has been shown to prevent allograft rejection, presumably by interrupting interactions between T cells and APCs. It is known that activated human platelets express and shed CD154 and can induce APC activation and other immune processes in vitro. Here we show that platelet-derived CD154 is sufficient to initiate cardiac allograft rejection independent of any cellular source of this molecule. CD154-KO mice reject cardiac allografts after receiving CD154-expressing human platelets or recombinant CD154 (rCD154) trimers. Treatment with the human CD154-specific mAb 5c8 specifically prevents this induced rejection. Soluble trimers, but not platelets, induce rejection when infused temporally remote from the surgical procedure, suggesting that surgically induced platelet activation is required for CD154 release. Allograft rejection can thus be instigated by activated platelets through CD154. These data implicate platelets as a proximal component of acquired alloimmunity, providing insight into the mechanisms of allograft rejection and the physiological response to trauma in general.

Authors
Xu, H; Zhang, X; Mannon, RB; Kirk, AD
MLA Citation
Xu, H, Zhang, X, Mannon, RB, and Kirk, AD. "Platelet-derived or soluble CD154 induces vascularized allograft rejection independent of cell-bound CD154." Journal of Clinical Investigation 116.3 (2006): 769-774.
Source
manual
Published In
Journal of Clinical Investigation
Volume
116
Issue
3
Publish Date
2006
Start Page
769
End Page
774
DOI
10.1172/JCI27155

Molecular Evaluation of BK Polyomavirus Nephropathy

Authors
Mannon, RB; Hoffmann, SC; Kampen, RL; Cheng, OC; Kleiner, DE; Ryschkewitsch, C; Curfman, B; Major, E; Hale, DA; Kirk, AD
MLA Citation
Mannon, RB, Hoffmann, SC, Kampen, RL, Cheng, OC, Kleiner, DE, Ryschkewitsch, C, Curfman, B, Major, E, Hale, DA, and Kirk, AD. "Molecular Evaluation of BK Polyomavirus Nephropathy." American Journal of Transplantation 5.12 (December 2005): 2883-2893.
Source
crossref
Published In
American Journal of Transplantation
Volume
5
Issue
12
Publish Date
2005
Start Page
2883
End Page
2893
DOI
10.1111/j.1600-6143.2005.01096.x

Challenges in therapeutic strategies for transplantation: Where now from here?

Authors
Bruno, DA; Dhanireddy, KK; Kirk, AD
MLA Citation
Bruno, DA, Dhanireddy, KK, and Kirk, AD. "Challenges in therapeutic strategies for transplantation: Where now from here?." Transplant Immunology 15.2 (December 2005): 149-155.
Source
crossref
Published In
Transplant Immunology
Volume
15
Issue
2
Publish Date
2005
Start Page
149
End Page
155
DOI
10.1016/j.trim.2005.07.001

Composite tissue allotransplantation: development of a preclinical model in nonhuman primates.

Composite tissue allotransplantation (CTA) has been recently introduced as a potential treatment for tissue loss secondary to burns, injuries, or resections. However, the optimal strategies to prevent CTA rejection remain undefined. Presently, no CTA model exists to evaluate human-specific immunosuppressants or the relative immunogenicity of all CTA tissues.We established a NHP CTA model utilizing a sensate osteomyocutaneous radial forearm flap that avoids functional impairment even in the case of graft loss. The model was evaluated in19 monkeys that underwent auto- or allotransplantation, with or without subtherapeutic immunosuppression to temporarily characterize rejection.Autografts showed no evidence of rejection. Nonimmunosuppressed allografts were rapidly rejected showing a perivenular T-cell infiltrate. This was associated with subsequent alloantibody formation and led to graft thrombosis without prominent dermal infiltration. Subtherapeutically immunosuppressed animals also developed alloantibody and rejected in a delayed fashion exhibiting a marked dermal lymphocytic infiltrate similar in magnitude and distribution to previously reported human cases.Our NHP model for CTA is well tolerated by NHPs, results in allosensitization, is responsive to immunosuppression, allows for the evaluation of CTA histology and can be used for the systematic preclinical evaluation of therapeutic maneuvers to improve allograft survival.

Authors
Cendales, LC; Xu, H; Bacher, J; Eckhaus, MA; Kleiner, DE; Kirk, AD
MLA Citation
Cendales, LC, Xu, H, Bacher, J, Eckhaus, MA, Kleiner, DE, and Kirk, AD. "Composite tissue allotransplantation: development of a preclinical model in nonhuman primates." Transplantation 80.10 (November 2005): 1447-1454.
PMID
16340790
Source
epmc
Published In
Transplantation
Volume
80
Issue
10
Publish Date
2005
Start Page
1447
End Page
1454
DOI
10.1097/01.tp.0000183292.57349.27

Results from a human renal allograft tolerance trial evaluating T-cell depletion with alemtuzumab combined with deoxyspergualin.

Perioperative lymphocyte depletion induces allograft tolerance in some animal models, but in humans has only been shown to reduce immunosuppressive requirements. Without maintenance immunosuppression, depleted human renal allograft recipients experience rejection characterized by infiltration of the allograft with monocytes and macrophages. T-cell depletion combined with a brief course of deoxyspergualin (DSG), a drug with inhibitory effects on monocytes and macrophages, induces tolerance in nonhuman primates. We therefore performed a trial to determine if lymphocyte depletion with alemtuzumab combined with DSG would induce tolerance in humans.Five recipients of live donor kidneys were treated perioperatively with alemtuzumab and DSG and followed postoperatively without maintenance immunosuppression. Patients were evaluated clinically, by flow cytometry, and by protocol biopsies analyzed immunohistochemically and with real-time polymerase chain reaction. Results were compared to previously studied patients receiving alemtuzumab alone or standard immunosuppression.Despite profound T-cell depletion and therapeutic DSG dosing, all alemtuzumab/DSG patients developed reversible rejection that was similar in timing, histology, and transcriptional profile to that seen in patients treated with alemtuzumab alone. Chemokine expression was marked prior to and during rejections.We conclude that treatment with alemtuzumab and DSG does not induce tolerance in humans. Chemokine production may not be adequately suppressed using this approach.

Authors
Kirk, AD; Mannon, RB; Kleiner, DE; Swanson, JS; Kampen, RL; Cendales, LK; Elster, EA; Wakefield, T; Chamberlain, C; Hoffmann, SC; Hale, DA
MLA Citation
Kirk, AD, Mannon, RB, Kleiner, DE, Swanson, JS, Kampen, RL, Cendales, LK, Elster, EA, Wakefield, T, Chamberlain, C, Hoffmann, SC, and Hale, DA. "Results from a human renal allograft tolerance trial evaluating T-cell depletion with alemtuzumab combined with deoxyspergualin." Transplantation 80.8 (October 2005): 1051-1059.
PMID
16278585
Source
epmc
Published In
Transplantation
Volume
80
Issue
8
Publish Date
2005
Start Page
1051
End Page
1059
DOI
10.1097/01.tp.0000174341.49741.8f

Induction of transplantation tolerance in non-human primate preclinical models

Authors
Hale, DA; Dhanireddy, K; Bruno, D; Kirk, AD
MLA Citation
Hale, DA, Dhanireddy, K, Bruno, D, and Kirk, AD. "Induction of transplantation tolerance in non-human primate preclinical models." Philosophical Transactions of the Royal Society B: Biological Sciences 360.1461 (September 29, 2005): 1723-1737.
Source
crossref
Published In
Philosophical Transactions B
Volume
360
Issue
1461
Publish Date
2005
Start Page
1723
End Page
1737
DOI
10.1098/rstb.2005.1703

Idiopathic intracranial hypertension following kidney transplantation: A case report and review of the literature

Authors
Chamberlain, CE; FitzGibbon, E; Wassermann, EM; Butman, JA; Kettl, D; Hale, D; Kirk, AD; Mannon, RB
MLA Citation
Chamberlain, CE, FitzGibbon, E, Wassermann, EM, Butman, JA, Kettl, D, Hale, D, Kirk, AD, and Mannon, RB. "Idiopathic intracranial hypertension following kidney transplantation: A case report and review of the literature." Pediatric Transplantation 9.4 (August 2005): 545-550.
Source
crossref
Published In
Pediatric Transplantation
Volume
9
Issue
4
Publish Date
2005
Start Page
545
End Page
550
DOI
10.1111/j.1399-3046.2005.00329.x

Workshop on Late Renal Allograft Dysfunction

Authors
Meyers, CM; Kirk, AD
MLA Citation
Meyers, CM, and Kirk, AD. "Workshop on Late Renal Allograft Dysfunction." American Journal of Transplantation 5.7 (July 2005): 1600-1605.
Source
crossref
Published In
American Journal of Transplantation
Volume
5
Issue
7
Publish Date
2005
Start Page
1600
End Page
1605
DOI
10.1111/j.1600-6143.2005.00926.x

Is tolerance induction the answer to adolescent non-adherence?

Authors
Dhanireddy, KK; Maniscalco, J; Kirk, AD
MLA Citation
Dhanireddy, KK, Maniscalco, J, and Kirk, AD. "Is tolerance induction the answer to adolescent non-adherence?." Pediatric Transplantation 9.3 (June 2005): 357-363.
Source
crossref
Published In
Pediatric Transplantation
Volume
9
Issue
3
Publish Date
2005
Start Page
357
End Page
363
DOI
10.1111/j.1399-3046.2005.00285.x

Laparoscopic Kidney Donation: Looking More than Skin Deep

Authors
Kirk, AD; Pinto, PA
MLA Citation
Kirk, AD, and Pinto, PA. "Laparoscopic Kidney Donation: Looking More than Skin Deep." American Journal of Transplantation 5.6 (June 2005): 1177-1178.
Source
crossref
Published In
American Journal of Transplantation
Volume
5
Issue
6
Publish Date
2005
Start Page
1177
End Page
1178
DOI
10.1111/j.1600-6143.2005.00956.x

IDEC-131 (Anti-CD154), Sirolimus and Donor-Specific Transfusion Facilitate Operational Tolerance in Non-Human Primates

Authors
Preston, EH; Xu, H; Dhanireddy, KK; Pearl, JP; Leopardi, FV; Starost, MF; Hale, DA; Kirk, AD
MLA Citation
Preston, EH, Xu, H, Dhanireddy, KK, Pearl, JP, Leopardi, FV, Starost, MF, Hale, DA, and Kirk, AD. "IDEC-131 (Anti-CD154), Sirolimus and Donor-Specific Transfusion Facilitate Operational Tolerance in Non-Human Primates." American Journal of Transplantation 5.5 (May 2005): 1032-1041.
Source
crossref
Published In
American Journal of Transplantation
Volume
5
Issue
5
Publish Date
2005
Start Page
1032
End Page
1041
DOI
10.1111/j.1600-6143.2005.00796.x

Surgical transplant physical examination: correlation of renal resistance index and biopsy-proven chronic allograft nephropathy.

BACKGROUND: Chronic allograft nephropathy (CAN) remains the leading cause of late renal allograft loss that is minimally responsive to therapy once graft dysfunction is clinically evident. A screening test capable of identifying individuals at high risk for CAN would be a valuable adjunct to patient care, but to be cost effective, should be administered during routine evaluations by transplantation clinicians. STUDY DESIGN: We have compared the resistive index (RI) as measured by Doppler ultrasonography with subsequent biopsy findings on 91 renal allograft recipients who had a subsequent protocol-directed biopsy at least 3 months after renal transplant. All ultrasonography was performed by the transplantation surgical staff without involving the radiology department or a separate appointment time. RESULTS: Twenty-one patients had RI >/= 80 (average 621 days posttransplantation). Among these individuals, the subsequent incidence of CAN was 38%. Length of time between initial assessment of increased RI and biopsy-proved CAN averaged 233 days. The remaining 70 patients with RI < 80 had an incidence of CAN of 11.4% (p = 0.018). There were minimal complications from these biopsies. Sensitivity and specificity of an elevated RI in predicting CAN were 50% and 83%, respectively. The negative predicted value of an elevated RI in determination of CAN was 89%. CONCLUSIONS: These results suggest that elevated RI is an early predictor of histologically relevant CAN, possibly a result of burgeoning vasculopathy. The technical expertise required to make this appraisal is well within the capabilities of transplantation surgeons and trainees. Early evidence of CAN may allow for a targeted change in therapy before clinically significant injury. Ultrasonography should become a routine part of a transplantation clinic evaluation.

Authors
Elster, EA; Hale, DA; Mannon, RB; Cendales, LC; Kleiner, D; Swanson, SJ; Kirk, AD
MLA Citation
Elster, EA, Hale, DA, Mannon, RB, Cendales, LC, Kleiner, D, Swanson, SJ, and Kirk, AD. "Surgical transplant physical examination: correlation of renal resistance index and biopsy-proven chronic allograft nephropathy." Journal of the American College of Surgeons 200.4 (April 2005): 552-556.
PMID
15804469
Source
epmc
Published In
Journal of The American College of Surgeons
Volume
200
Issue
4
Publish Date
2005
Start Page
552
End Page
556
DOI
10.1016/j.jamcollsurg.2004.12.009

Proposal for the American Journal of Transplantation Policy for Review of Ethical Standards of Clinical Research Involving Live Human Subjects

Authors
Bromberg, JS; Silverstein, JH; Kirk, AD
MLA Citation
Bromberg, JS, Silverstein, JH, and Kirk, AD. "Proposal for the American Journal of Transplantation Policy for Review of Ethical Standards of Clinical Research Involving Live Human Subjects." American Journal of Transplantation 5.4 (April 2005): 648-650.
Source
crossref
Published In
American Journal of Transplantation
Volume
5
Issue
4
Publish Date
2005
Start Page
648
End Page
650
DOI
10.1111/j.1600-6143.2005.00872.x

Immunocompetent T-Cells with a Memory-Like Phenotype are the Dominant Cell Type Following Antibody-Mediated T-Cell Depletion

Authors
Pearl, JP; Parris, J; Hale, DA; Hoffmann, SC; Bernstein, WB; McCoy, KL; Swanson, SJ; Mannon, RB; Roederer, M; Kirk, AD
MLA Citation
Pearl, JP, Parris, J, Hale, DA, Hoffmann, SC, Bernstein, WB, McCoy, KL, Swanson, SJ, Mannon, RB, Roederer, M, and Kirk, AD. "Immunocompetent T-Cells with a Memory-Like Phenotype are the Dominant Cell Type Following Antibody-Mediated T-Cell Depletion." American Journal of Transplantation 5.3 (March 2005): 465-474.
Source
crossref
Published In
American Journal of Transplantation
Volume
5
Issue
3
Publish Date
2005
Start Page
465
End Page
474
DOI
10.1111/j.1600-6143.2005.00759.x

Functionally significant renal allograft rejection is defined by transcriptional criteria.

Renal allograft acute cellular rejection (ACR) is a T-cell mediated disease that is diagnosed histologically. However, many normally functioning allografts have T-cell infiltrates and histological ACR, and many nonimmune processes cause allograft dysfunction. Thus, neither histological nor functional criteria are sufficient to establish a significant rejection, and the fundamental features of clinical rejection remain undefined. To differentiate allograft lymphocyte infiltration from clinically significant ACR, we compared renal biopsies from patients with ACR to patients with: sub-clinical rejection (SCR, stable function with histological rejection); no rejection; and nontransplanted kidneys. Biopsies were compared histologically and transcriptionally by RT-PCR for 72 relevant immune function genes. Neither the degree nor the composition of the infiltrate defined ACR. However, transcripts up-regulated during effector T(H)1 T-cell activation, most significantly the transcription factor T-bet, the effector receptor Fas ligand and the costimulation molecule CD152 clearly (p = 0.001) distinguished the patient categories. Transcripts from other genes were equivalently elevated in SCR and ACR, indicating their association with infiltration, not dysfunction. Clinically significant ACR is not defined solely by the magnitude nor composition of the infiltrate, but rather by the transcriptional activity of the infiltrating cells. Quantitative analysis of selected gene transcripts may enhance the clinical assessment of allografts.

Authors
Hoffmann, SC; Hale, DA; Kleiner, DE; Mannon, RB; Kampen, RL; Jacobson, LM; Cendales, LC; Swanson, SJ; Becker, BN; Kirk, AD
MLA Citation
Hoffmann, SC, Hale, DA, Kleiner, DE, Mannon, RB, Kampen, RL, Jacobson, LM, Cendales, LC, Swanson, SJ, Becker, BN, and Kirk, AD. "Functionally significant renal allograft rejection is defined by transcriptional criteria." American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 5.3 (March 2005): 573-581.
PMID
15707413
Source
epmc
Published In
American Journal of Transplantation
Volume
5
Issue
3
Publish Date
2005
Start Page
573
End Page
581
DOI
10.1111/j.1600-6143.2005.00719.x

Strategies for minimizing immunosuppression in kidney transplantation

Authors
Kirk, AD; Mannon, RB; John Swanson, S; Hale, DA
MLA Citation
Kirk, AD, Mannon, RB, John Swanson, S, and Hale, DA. "Strategies for minimizing immunosuppression in kidney transplantation." Transplant International 18.1 (January 2005): 2-14.
Source
crossref
Published In
Transplant International
Volume
18
Issue
1
Publish Date
2005
Start Page
2
End Page
14
DOI
10.1111/j.1432-2277.2004.00019.x

Solid organ transplantation at the National Institutes of Health: development of a research-based transplantation practice.

The National Institutes of Health has established a clinical transplant research program focusing on translational research in kidney transplantation. The program has been developed with a multidisciplinary approach under a common administrative structure that integrates transplant physicians and surgeons with clinical laboratory and data analysis support personnel. The program has achieved excellent clinical outcomes despite focusing exclusively on investigational methods and serving a diverse and medically complex patient population. Novel approaches toward consenting, computer integration, and tissue acquisition have been layered over interventional and observational studies to serve the scientific mission while delivering quality transplant care.

Authors
Kirk, AD; Hale, DA; Ford, E; Kleiner, DE; Kampen, RL; Elster, EA; Swanson, SJ; Cendales, LC; Cropper, T; Hale, L; Jordan, S; Koussis, T; Peretti, J; Sloane, A; Salaita, C; Ring, M; Chamberlain, C; Mannon, RB
MLA Citation
Kirk, AD, Hale, DA, Ford, E, Kleiner, DE, Kampen, RL, Elster, EA, Swanson, SJ, Cendales, LC, Cropper, T, Hale, L, Jordan, S, Koussis, T, Peretti, J, Sloane, A, Salaita, C, Ring, M, Chamberlain, C, and Mannon, RB. "Solid organ transplantation at the National Institutes of Health: development of a research-based transplantation practice." January 2005. 131-144.
PMID
17424731
Source
epmc
Publish Date
2005
Start Page
131
End Page
144

Human platelets exhibit chemotaxis using functional N-formyl peptide receptors

Authors
Czapiga, M; Gao, J-L; Kirk, A; Lekstrom-Himes, J
MLA Citation
Czapiga, M, Gao, J-L, Kirk, A, and Lekstrom-Himes, J. "Human platelets exhibit chemotaxis using functional N-formyl peptide receptors." Experimental Hematology 33.1 (January 2005): 73-84.
Source
crossref
Published In
Experimental Hematology
Volume
33
Issue
1
Publish Date
2005
Start Page
73
End Page
84
DOI
10.1016/j.exphem.2004.09.010

Composite tissue allotransplantation: Classification of clinical acute skin rejection

Background. Composite tissue allotransplantation (CTA) is a recently introduced option for limb replacement and reconstruction of other nonreconstructible tissue defects. As with recipients of other allotransplants, CTA recipients can experience rejection episodes that are presumed to be mediated by immune mechanisms similar to those affecting solid organ grafts. However, a systematic examination of this process has not been performed, and there are no standardized criteria for the description of severity or type of rejection Methods. We collected biopsies from human limb allografts and abdominal walls in various stages of rejection for histological and immunohistochemical analysis to formulate a CTA rejection scheme. Biopsies were ranked by severity and reproducibility of the system was tested using a second set of biopsies. Tissue slides were examined blindly by three pathologists and the nonparametric Kendall coefficient of concordance (W) was used to assess the amount of agreement among the pathologists in their classification grades. Results. Rejection initially appeared as a perivascular infiltrate progressing to involve the dermis. Arteritis was observed only in the medium to large size arteries of the subcutis. Myositis was seen occasionally. Perineural involvement without frank neuritis was present in advanced rejection. The infiltrate was predominantly CD4+ in milder cases and CD8+ in advanced cases. HLA-DR was minimally expressed in keratinocytes even in severe rejection. Kendall's W was 0.9375 (p≤0.0001). Conclusions. Based on this survey, we proposed an initial classification system for acute rejection in the skin of a CTA and demonstrated that this system is easily reproduced by independent pathologists. Copyright © 2005 by Lippincott Williams & Wilkins.

Authors
Cendales, LC; Kirk, AD; Moresi, JM; Ruiz, P; Kleiner, DE
MLA Citation
Cendales, LC, Kirk, AD, Moresi, JM, Ruiz, P, and Kleiner, DE. "Composite tissue allotransplantation: Classification of clinical acute skin rejection." Transplantation 80.12 (2005): 1676-1680.
Source
scival
Published In
Transplantation
Volume
80
Issue
12
Publish Date
2005
Start Page
1676
End Page
1680
DOI
10.1097/01.tp.0000185304.49987.d8

Mammalian target of rapamycin inhibitors in transplantation: novel immunosuppressive strategies with sirolimus

Authors
Hale, DA; Kirk, AD
MLA Citation
Hale, DA, and Kirk, AD. "Mammalian target of rapamycin inhibitors in transplantation: novel immunosuppressive strategies with sirolimus." Current Opinion in Organ Transplantation 9.4 (December 2004): 400-405.
Source
crossref
Published In
Current Opinion in Organ Transplantation
Volume
9
Issue
4
Publish Date
2004
Start Page
400
End Page
405
DOI
10.1097/01.mot.0000145087.34739.14

What's New-What's Hot in Basic Science: American Transplant Congress 2004

Authors
Kirk, AD
MLA Citation
Kirk, AD. "What's New-What's Hot in Basic Science: American Transplant Congress 2004." American Journal of Transplantation 4.11 (November 2004): 1741-1746.
Source
crossref
Published In
American Journal of Transplantation
Volume
4
Issue
11
Publish Date
2004
Start Page
1741
End Page
1746
DOI
10.1111/j.1600-6143.2004.00632.x

Donor genomics influence graft events: The effect of donor polymorphisms on acute rejection and chronic allograft nephropathy

Authors
Hoffmann, S; Park, J; Jacobson, LM; Muehrer, RJ; Lorentzen, D; Kleiner, D; Becker, YT; Hullett, DA; Mannon, R; Kirk, AD; Becker, BN
MLA Citation
Hoffmann, S, Park, J, Jacobson, LM, Muehrer, RJ, Lorentzen, D, Kleiner, D, Becker, YT, Hullett, DA, Mannon, R, Kirk, AD, and Becker, BN. "Donor genomics influence graft events: The effect of donor polymorphisms on acute rejection and chronic allograft nephropathy." Kidney International 66.4 (October 2004): 1686-1693.
Source
crossref
Published In
Kidney international
Volume
66
Issue
4
Publish Date
2004
Start Page
1686
End Page
1693
DOI
10.1111/j.1523-1755.2004.00936.x

The road to tolerance: renal transplant tolerance induction in nonhuman primate studies and clinical trials.

Organ transplantation has become a standard life-saving therapy for many causes of end stage organ failure. Although valuable, it remains hampered by the requirement for, and complications of, immunosuppression to prevent immune rejection of the transplanted organ. It is now clear that rejection can be avoided in some experimental systems without a requirement of immunosuppressive medication, and these experimental concepts are now making their way into the clinic in the form of early transplantation tolerance trials. This manuscript will discuss the most promising techniques for tolerance induction, namely, costimulation blockade, lymphocyte depletion, and mixed chimerism. Seminal preclinical studies will be cited and the results of initial clinical trials will be reviewed. The data to date indicate that while tolerance remains elusive, immunosuppression minimization is a feasible near-term alternative.

Authors
Elster, EA; Hale, DA; Mannon, RB; Cendales, LC; Swanson, SJ; Kirk, AD
MLA Citation
Elster, EA, Hale, DA, Mannon, RB, Cendales, LC, Swanson, SJ, and Kirk, AD. "The road to tolerance: renal transplant tolerance induction in nonhuman primate studies and clinical trials." Transplant immunology 13.2 (September 2004): 87-99.
PMID
15380539
Source
epmc
Published In
Transplant Immunology
Volume
13
Issue
2
Publish Date
2004
Start Page
87
End Page
99
DOI
10.1016/j.trim.2004.05.010

The clinical application of monoclonal antibody therapies in renal transplantation

Authors
Dhanireddy, KK; Xu, H; Mannon, RB; Hale, DA; Kirk, AD
MLA Citation
Dhanireddy, KK, Xu, H, Mannon, RB, Hale, DA, and Kirk, AD. "The clinical application of monoclonal antibody therapies in renal transplantation." Expert Opinion on Emerging Drugs 9.1 (May 2004): 23-37.
Source
crossref
Published In
Expert Opinion on Emerging Drugs
Volume
9
Issue
1
Publish Date
2004
Start Page
23
End Page
37
DOI
10.1517/14728214.9.1.23

Successful Renal Transplantation in a Patient with Congenital Generalized Lipodystrophy: A Case Report

Authors
McNally, M; Mannon, RB; Javor, ED; Swanson, SJ; Hale, DA; Gorden, P; Kirk, AD
MLA Citation
McNally, M, Mannon, RB, Javor, ED, Swanson, SJ, Hale, DA, Gorden, P, and Kirk, AD. "Successful Renal Transplantation in a Patient with Congenital Generalized Lipodystrophy: A Case Report." American Journal of Transplantation 4.3 (March 2004): 447-449.
Source
crossref
Published In
American Journal of Transplantation
Volume
4
Issue
3
Publish Date
2004
Start Page
447
End Page
449
DOI
10.1111/j.1600-6143.2004.00358.x

Ethics in the quest for transplant tolerance

Authors
Kirk, AD
MLA Citation
Kirk, AD. "Ethics in the quest for transplant tolerance." Transplantation 77.6 (March 2004): 947-951.
Source
crossref
Published In
Transplantation
Volume
77
Issue
6
Publish Date
2004
Start Page
947
End Page
951
DOI
10.1097/01.TP.0000117778.83216.29

Human Renal Allograft Rejection Despite the Absence of Allogeneic Passenger Leukocytes

Authors
Preston, EH; Light, JA; Kampen, RL; Kirk, AD
MLA Citation
Preston, EH, Light, JA, Kampen, RL, and Kirk, AD. "Human Renal Allograft Rejection Despite the Absence of Allogeneic Passenger Leukocytes." American Journal of Transplantation 4.2 (February 2004): 283-285.
Source
crossref
Published In
American Journal of Transplantation
Volume
4
Issue
2
Publish Date
2004
Start Page
283
End Page
285
DOI
10.1046/j.1600-6143.2003.00320.x

Transplantation: Integrating the concepts of innate and acquired immunity with translational trials

Authors
Kirk, AD
MLA Citation
Kirk, AD. "Transplantation: Integrating the concepts of innate and acquired immunity with translational trials." Current Opinion in Immunology 16.5 (2004): 535-537.
Source
scival
Published In
Current Opinion in Immunology
Volume
16
Issue
5
Publish Date
2004
Start Page
535
End Page
537
DOI
10.1016/j.coi.2004.07.020

The contribution of Fc effector mechanisms in the efficacy of anti-CD154 immunotherapy depends on the nature of the immune challenge

Blockade of the CD154-CD40 co-stimulatory pathway with anti-CD154 mAbs has shown impressive efficacy in models of autoimmunity and allotransplantation. Clinical benefit was also demonstrated in systemic lupus erythematosus (SLE) and idiopathic thrombocytopenia patients with the humanized anti-CD154 mAb, 5C8 (hu5C8). However, thromboembolic complications that occurred during the course of the hu5C8 clinical trials have proven to be a major setback to the field and safe alternative therapeutics targeting the CD154-CD40 pathway are of great interest. Recently, effector mechanisms have been shown to play a part in anti-CD154 mAb-induced transplant acceptance in murine models, while this issue remains unresolved for humoral-mediated models. Herein, aglycosyl anti-CD154 mAbs with reduced binding to FcγR and complement were used as a novel means to test the role of effector mechanisms in non-human primate and murine models not amenable to gene knockout technology. While aglycosyl hu5C8 mAb was relatively ineffective in rhesus renal and islet allotransplantation, it inhibited primary and secondary humoral responses to a protein immunogen in cynomolgus monkeys. Moreover, an aglycosyl, chimeric MR1 mAb (muMR1) prolonged survival and inhibited pathogenic auto-antibody production in a murine model of SLE. Thus, the mechanisms required for efficacy of anti-CD154 mAbs depend on the nature of the immune challenge. © 2004 The Japanese Society for Immunology.

Authors
Ferrant, JL; Benjamin, CD; Cutler, AH; Kalled, SL; Hsu, Y; Garber, EA; Hess, DM; Shapiro, RI; Kenyon, NS; et al.,
MLA Citation
Ferrant, JL, Benjamin, CD, Cutler, AH, Kalled, SL, Hsu, Y, Garber, EA, Hess, DM, Shapiro, RI, Kenyon, NS, and et al., . "The contribution of Fc effector mechanisms in the efficacy of anti-CD154 immunotherapy depends on the nature of the immune challenge." International Immunology 16.11 (2004): 1583-1594.
Source
manual
Published In
International Immunology
Volume
16
Issue
11
Publish Date
2004
Start Page
1583
End Page
1594
DOI
10.1093/intimm/dxh162

Platelets deliver costimulatory signals to antigen-presenting cells: A potential bridge between injury and immune activation

The danger model of immunity and tolerance holds that antigen-presenting cells (APCs), activated by stress, injury, or necrosis, but not by physiological (apoptotic) cell death, initiate adaptive immune responses. APC activation is fundamentally associated with binding of CD40 to its ligand CD154. Platelets express CD154 upon activation and are thus potential primal danger signals linking the homeostatic response to trauma to activation of the acquired immune system. Previously, we showed that platelets can undergo gradient-driven migration, or chemotaxis, toward supernatants from cells injured by repeated freeze/thaws, UV light, or ischemia/reperfusion. Herein, we demonstrate that platelet-derived CD154 induces immature dendritic cell maturation with upregulation of costimulatory molecules and IL-12p40 production. Overall, these results provide a mechanism for platelet activation of APC facilitating the induction of adaptive immunity in environments of cell injury. © 2004 International Society for Experimental Hematology. Published by Elsevier Inc.

Authors
Czapiga, M; Kirk, AD; Lekstrom-Himes, J
MLA Citation
Czapiga, M, Kirk, AD, and Lekstrom-Himes, J. "Platelets deliver costimulatory signals to antigen-presenting cells: A potential bridge between injury and immune activation." Experimental Hematology 32.2 (2004): 135-139.
Source
manual
Published In
Experimental Hematology
Volume
32
Issue
2
Publish Date
2004
Start Page
135
End Page
139
DOI
10.1016/j.exphem.2003.11.004

Crossing the bridge: large animal models in translational transplantation research

Authors
Kirk, AD
MLA Citation
Kirk, AD. "Crossing the bridge: large animal models in translational transplantation research." Immunological Reviews 196.1 (December 2003): 176-196.
Source
crossref
Published In
Immunological Reviews
Volume
196
Issue
1
Publish Date
2003
Start Page
176
End Page
196
DOI
10.1046/j.1600-065X.2003.00081.x

Tolerance: is it achievable in pediatric solid organ transplantation?

Authors
Pearl, JP; Preston, E; Kirk, AD
MLA Citation
Pearl, JP, Preston, E, and Kirk, AD. "Tolerance: is it achievable in pediatric solid organ transplantation?." Pediatric Clinics of North America 50.6 (December 2003): 1261-1281.
Source
crossref
Published In
Pediatric Clinics of North America
Volume
50
Issue
6
Publish Date
2003
Start Page
1261
End Page
1281
DOI
10.1016/S0031-3955(03)00120-2

Effects of Combined Treatment with CD25- and CD154-Specific Monoclonal Antibodies in Non-Human Primate Allotransplantation

Authors
Xu, H; Elster, EA; Blair, PJ; Burkly, LC; Tadaki, DK; Harlan, DM; Kirk, AD
MLA Citation
Xu, H, Elster, EA, Blair, PJ, Burkly, LC, Tadaki, DK, Harlan, DM, and Kirk, AD. "Effects of Combined Treatment with CD25- and CD154-Specific Monoclonal Antibodies in Non-Human Primate Allotransplantation." American Journal of Transplantation 3.11 (November 2003): 1350-1354.
Source
crossref
Published In
American Journal of Transplantation
Volume
3
Issue
11
Publish Date
2003
Start Page
1350
End Page
1354
DOI
10.1046/j.1600-6135.2003.00235.x

Immunologic monitoring of the transplant recipient: challenges and approaches with antibody induction

Authors
Hale, DA; Swanson, SJ; Mannon, RB; Kleiner, DE; Hoffmann, SC; Kampen, RL; Cendales, LK; Tadaki, DK; Harlan, DM; Kirk, AD
MLA Citation
Hale, DA, Swanson, SJ, Mannon, RB, Kleiner, DE, Hoffmann, SC, Kampen, RL, Cendales, LK, Tadaki, DK, Harlan, DM, and Kirk, AD. "Immunologic monitoring of the transplant recipient: challenges and approaches with antibody induction." Transplantation Reviews 17.4 (October 2003): S20-S25.
Source
crossref
Published In
Transplantation Reviews
Volume
17
Issue
4
Publish Date
2003
Start Page
S20
End Page
S25
DOI
10.1016/j.trre.2003.07.003

Objective, Real-Time, Intraoperative Assessment of Renal Perfusion Using Infrared Imaging

Authors
Gorbach, A; Simonton, D; Hale, DA; Swanson, SJ; Kirk, AD
MLA Citation
Gorbach, A, Simonton, D, Hale, DA, Swanson, SJ, and Kirk, AD. "Objective, Real-Time, Intraoperative Assessment of Renal Perfusion Using Infrared Imaging." American Journal of Transplantation 3.8 (August 2003): 988-993.
Source
crossref
Published In
American Journal of Transplantation
Volume
3
Issue
8
Publish Date
2003
Start Page
988
End Page
993
DOI
10.1034/j.1600-6143.2003.00158.x

Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (CAMPATH-1H).

BACKGROUND: Profound T-cell depletion before allotransplantation with gradual posttransplant T-cell repopulation induces a state of donor-specific immune hyporesponsiveness or tolerance in some animal models. Alemtuzumab (Campath-1H, Millennium Pharmaceuticals, Cambridge, MA) is a humanized CD52-specific monoclonal antibody that produces profound T-cell depletion in humans and reduces the need for maintenance immunosuppression after renal transplantation. We therefore performed a study to determine if pretransplant T-cell depletion with alemtuzumab would induce tolerance in human renal allografts and to evaluate the nature of the alloimmune response in the setting of T-cell depletion. METHODS: Seven nonsensitized recipients of living-donor kidneys were treated perioperatively with alemtuzumab and followed postoperatively without maintenance immunosuppression. Patients were evaluated clinically by peripheral flow cytometry, protocol biopsies evaluated immunohistochemically, and real-time polymerase chain reaction-based transcriptional analysis. RESULTS: Lymphocyte depletion was profound in the periphery and secondary lymphoid tissues. All patients developed reversible rejection episodes within the first month that were characterized by predominantly monocytic (not lymphocytic) infiltrates with only rare T cells in the peripheral blood or allograft. These episodes were responsive to treatment with steroids or sirolimus or both. After therapy, patients remained rejection-free on reduced immunosuppression, generally monotherapy sirolimus, despite the recovery of lymphocytes to normal levels. CONCLUSIONS: T-cell depletion alone does not induce tolerance in humans. These data underscore a prominent role for early responding monocytes in human allograft rejection.

Authors
Kirk, AD; Hale, DA; Mannon, RB; Kleiner, DE; Hoffmann, SC; Kampen, RL; Cendales, LK; Tadaki, DK; Harlan, DM; Swanson, SJ
MLA Citation
Kirk, AD, Hale, DA, Mannon, RB, Kleiner, DE, Hoffmann, SC, Kampen, RL, Cendales, LK, Tadaki, DK, Harlan, DM, and Swanson, SJ. "Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (CAMPATH-1H)." Transplantation 76.1 (July 2003): 120-129.
PMID
12865797
Source
epmc
Published In
Transplantation
Volume
76
Issue
1
Publish Date
2003
Start Page
120
End Page
129
DOI
10.1097/01.tp.0000071362.99021.d9

Less Is More: Maintenance Minimization as a Step Toward Tolerance

Authors
Kirk, AD
MLA Citation
Kirk, AD. "Less Is More: Maintenance Minimization as a Step Toward Tolerance." American Journal of Transplantation 3.6 (June 2003): 643-645.
Source
crossref
Published In
American Journal of Transplantation
Volume
3
Issue
6
Publish Date
2003
Start Page
643
End Page
645
DOI
10.1034/j.1600-6143.2003.00138.x

Porcine CD80: cloning, characterization, and evidence for its role in direct human T-cell activation

Authors
Tadaki, DK; Williams, A; Lee, KP; Kirk, AD; Harlan, DM
MLA Citation
Tadaki, DK, Williams, A, Lee, KP, Kirk, AD, and Harlan, DM. "Porcine CD80: cloning, characterization, and evidence for its role in direct human T-cell activation." Xenotransplantation 10.3 (May 2003): 252-258.
Source
crossref
Published In
Xenotransplantation
Volume
10
Issue
3
Publish Date
2003
Start Page
252
End Page
258
DOI
10.1034/j.1399-3089.2003.02004.x

Delayed autotransplantation of a solitary kidney facilitated by pump perfusion preservation.

Authors
Cendales, LC; Swanson, SJ; Kirk, AD; Mannon, RB; Hale, DA
MLA Citation
Cendales, LC, Swanson, SJ, Kirk, AD, Mannon, RB, and Hale, DA. "Delayed autotransplantation of a solitary kidney facilitated by pump perfusion preservation." Surgery 133.4 (April 2003): 438-439.
PMID
12717362
Source
epmc
Published In
Surgery
Volume
133
Issue
4
Publish Date
2003
Start Page
438
End Page
439
DOI
10.1067/msy.2003.129

Kidney transplantation with rabbit antithymocyte globulin and sirolimus monotherapy

Authors
Swanson, SJ; Hale, DA; Mannon, RB; Harlan, DM; Kirk, AD
MLA Citation
Swanson, SJ, Hale, DA, Mannon, RB, Harlan, DM, and Kirk, AD. "Kidney transplantation with rabbit antithymocyte globulin and sirolimus monotherapy." The Lancet 361.9361 (March 2003): 969-970.
Source
crossref
Published In
The Lancet
Volume
361
Issue
9361
Publish Date
2003
Start Page
969
End Page
970
DOI
10.1016/S0140-6736(03)12753-5

Immune profiling: molecular monitoring in renal transplantation.

Molecular techniques have become a mainstay for most biomedical research. In particular, sensitive methods for gene transcript detection and advanced flow cytometry have been crucial in fostering our understanding of the basic mechanisms promoting allosensitization and adaptive immune regulation. These technologies have been validated in vitro, and in pre-clinical settings, and as such their clinical application is now clearly appropriate. It is becoming increasingly clear that these robust techniques hold much promise to better elucidate human transplant biology, and more importantly, guide clinical decision making with mechanistically-based information. This article will discuss our laboratory's use of several novel technologies, including gene polymorphism analysis, real-time polymerase chain reaction transcript quantification, and multi-color flow cytometry in clinical human renal transplantation. Specific technical methodology will be presented outlining keys for effective clinical application. Clinical correlations will be presented as examples of how these techniques may have clinical relevance. Suggestions for the adaptation of these methods for therapeutic intervention will be given. We propose that clinical transplantation should proceed in close step with modern molecular diagnostics.

Authors
Hoffmann, SC; Pearl, JP; Blair, PJ; Kirk, AD
MLA Citation
Hoffmann, SC, Pearl, JP, Blair, PJ, and Kirk, AD. "Immune profiling: molecular monitoring in renal transplantation." Frontiers in bioscience : a journal and virtual library 8 (2003): e444-e462.
Source
scival
Published In
Frontiers in bioscience : a journal and virtual library
Volume
8
Publish Date
2003
Start Page
e444
End Page
e462

Studies investigating pretransplant donor-specific blood transfusion, rapamycin, and the CD154-specific antibody IDEC-131 in a nonhuman primate model of skin allotransplantation

Anti-CD154 variably prolongs allograft survival in nonhuman primates. Rodent studies suggest that adding pretransplant donor-specific transfusion (DST) and/or rapamycin to anti-CD154 improves survival. The CD154-specific Ab IDEC-131 was tested alone and in combination with rapamycin for its ability to inhibit rhesus MLRs. The ability of the Ab to block endothelial activation was also assessed. IDEC-131 was then tested alone and in combination with DST and/or rapamycin for its ability to prevent rejection of full-thickness, MHC-mismatched rhesus skin allografts. Animals were monitored for donor-specific hyporesponsiveness by MLR and alloantibody determination. IDEC-131 modestly inhibited rhesus MLRs and inhibited CD154-dependent endothelial cell activation. Rapamycin combined with IDEC-131 additively inhibited MLRs. IDEC-131 modestly prolonged allograft survival when compared with no treatment, rapamycin alone, or DST plus rapamycin. Adding DST to IDEC-131 did not prolong survival beyond IDEC-131 alone. IDEC-131 plus rapamycin was effective in prolonging graft survival, although animals had episodes of acute rejection before graft demise. Therapy with IDEC-131, rapamycin, and DST induced long-term allograft survival without intermittent acute rejection. However, no evidence for MLR inhibition was seen, and most animals eventually developed alloantibody. All animals ultimately rejected their grafts after drug withdrawal. IDEC-131 modestly prolongs rhesus skin allograft survival. Rapamycin and rapamycin plus DST improves the efficacy of IDEC-131 in prolonging allograft survival. IDEC-131, rapamycin, and DST are a promising combination for clinical evaluation in allotransplantation.

Authors
Xu, H; Montgomery, SP; Preston, EH; Tadaki, DK; Hale, DA; Harlan, DM; Kirk, AD
MLA Citation
Xu, H, Montgomery, SP, Preston, EH, Tadaki, DK, Hale, DA, Harlan, DM, and Kirk, AD. "Studies investigating pretransplant donor-specific blood transfusion, rapamycin, and the CD154-specific antibody IDEC-131 in a nonhuman primate model of skin allotransplantation." Journal of Immunology 170.5 (2003): 2776-2782.
Source
scival
Published In
Journal of Immunology
Volume
170
Issue
5
Publish Date
2003
Start Page
2776
End Page
2782

Rabbit antithymocyte globulin induction and sirolimus monotherapy supports prolonged islet allograft function in a nonhuman primate islet transplantation model

Background. We reported that rabbit anti-thymocyte globulin (RATG) induction followed by maintenance immunosuppression with sirolimus supports human kidney allograft survival and asked if this combination would promote islet allograft survival in our primate model. Methods. Using intra-arterial streptozotocin infusion, we rendered four cynomolgus primates diabetic with undetectable C-peptide levels. Animals were maintained on insulin therapy for at least 1 month, and then islets from mixed lymphocyte reaction mismatched primates were infused into the portal vein. Immediately before the islet allotransplant and for 6 additional days, primates were infused with RATG (20 mg/kg) and given a sirolimus dose to achieve a 24-hr trough level of 8 to 14 ng/mL. Results. The regimen resulted in profound peripheral and lymph node lymphocyte depletion for up to 1 month. Repopulation was gradual thereafter. One primate remained insulin-independent for 169 days and rejected after a sirolimus-dose reduction. Two primates died on day 23 while insulin independent because of wound dehiscence, and a third died on day 30 with high sirolimus levels. Liver sections revealed well-vascularized islets with no signs of inflammation. Conclusion. Using a nonhuman primate islet transplant model, RATG plus sirolimus supports islet survival as long as proper sirolimus levels are maintained, but the therapy is limited by sirolimus toxicity. Our findings suggest that RATG is not toxic for islets and thus may be considered in future clinical trails while recognizing that sirolimus monotherapy, with its difficult-to-achieve therapeutic dosing, may not be sufficient to maintain long-term islet allograft function in an autoimmune environment.

Authors
Hirshberg, B; Preston, EH; Xu, H; Tal, MG; Neeman, Z; Bunnell, D; Soleimanpour, S; Hale, DA; Kirk, AD; Harlan, DM
MLA Citation
Hirshberg, B, Preston, EH, Xu, H, Tal, MG, Neeman, Z, Bunnell, D, Soleimanpour, S, Hale, DA, Kirk, AD, and Harlan, DM. "Rabbit antithymocyte globulin induction and sirolimus monotherapy supports prolonged islet allograft function in a nonhuman primate islet transplantation model." Transplantation 76.1 (2003): 55-60.
Source
scival
Published In
Transplantation
Volume
76
Issue
1
Publish Date
2003
Start Page
55
End Page
60

BK virus and SV40 co-infection in polyomavirus nehropathy1

Authors
Li, R-M; Mannon, RB; Kleiner, D; Tsokos, M; Bynum, M; Kirk, AD; Kopp, JB
MLA Citation
Li, R-M, Mannon, RB, Kleiner, D, Tsokos, M, Bynum, M, Kirk, AD, and Kopp, JB. "BK virus and SV40 co-infection in polyomavirus nehropathy1." Transplantation 74.11 (December 2002): 1497-1504.
Source
crossref
Published In
Transplantation
Volume
74
Issue
11
Publish Date
2002
Start Page
1497
End Page
1504
DOI
10.1097/00007890-200212150-00004

Kidney transplantation with rabbit antithymocyte globulin induction and sirolimus monotherapy.

Renal allograft recipients generally need to take several immunosuppressive agents for life. Calcineurin inhibitors and glucocorticosteroids are the mainstays of most regimens but have undesirable chronic effects. We postulated that aggressive T-cell depletion combined with the newer immunosuppressant sirolimus would permit transplantation without multidrug treatment. We therefore tested T-cell depletion with rabbit antithymocyte globulin followed by sirolimus monotherapy in 12 patients in an open-label study. This approach was tolerated well, and all patients achieved excellent renal function, and most did not need chronic steroid treatment or calcineurin inhibitors. Rejection was typically correlated with low concentrations of sirolimus, indicating continued dependence on maintenance immunosuppression.

Authors
Swanson, SJ; Hale, DA; Mannon, RB; Kleiner, DE; Cendales, LC; Chamberlain, CE; Polly, SM; Harlan, DM; Kirk, AD
MLA Citation
Swanson, SJ, Hale, DA, Mannon, RB, Kleiner, DE, Cendales, LC, Chamberlain, CE, Polly, SM, Harlan, DM, and Kirk, AD. "Kidney transplantation with rabbit antithymocyte globulin induction and sirolimus monotherapy." Lancet (London, England) 360.9346 (November 2002): 1662-1664.
PMID
12457792
Source
epmc
Published In
The Lancet
Volume
360
Issue
9346
Publish Date
2002
Start Page
1662
End Page
1664
DOI
10.1016/s0140-6736(02)11606-0

Humanized anti-CD154 antibody therapy for the treatment of allograft rejection in nonhuman primates

Authors
Xu, H; Tadaki, DK; Elster, EA; Burkly, LC; Berning, JD; Cruzata, F; Kampen, RL; Montgomery, SP; Patterson, NB; Harlan, DM; Kirk, AD
MLA Citation
Xu, H, Tadaki, DK, Elster, EA, Burkly, LC, Berning, JD, Cruzata, F, Kampen, RL, Montgomery, SP, Patterson, NB, Harlan, DM, and Kirk, AD. "Humanized anti-CD154 antibody therapy for the treatment of allograft rejection in nonhuman primates." Transplantation 74.7 (October 2002): 940-943.
Source
crossref
Published In
Transplantation
Volume
74
Issue
7
Publish Date
2002
Start Page
940
End Page
943
DOI
10.1097/00007890-200210150-00007

Molecular and immunohistochemical characterization of the onset and resolution of human renal allograft ischemia-reperfusion injury

Authors
Hoffmann, SC; Kampen, RL; Amur, S; Sharaf, MA; Kleiner, DE; Hunter, K; John Swanson, S; Hale, DA; Mannon, RB; Blair, PJ; Kirk, AD
MLA Citation
Hoffmann, SC, Kampen, RL, Amur, S, Sharaf, MA, Kleiner, DE, Hunter, K, John Swanson, S, Hale, DA, Mannon, RB, Blair, PJ, and Kirk, AD. "Molecular and immunohistochemical characterization of the onset and resolution of human renal allograft ischemia-reperfusion injury." Transplantation 74.7 (October 2002): 916-923.
Source
crossref
Published In
Transplantation
Volume
74
Issue
7
Publish Date
2002
Start Page
916
End Page
923
DOI
10.1097/00007890-200210150-00003

Impact of HIV seropositivity on graft and patient survival after cadaveric renal transplantation in the United States in the pre highly active antiretroviral therapy (HAART) era: an historical cohort analysis of the United States Renal Data System

Authors
Swanson, SJ; Kirk, AD; Ko, CW; Jones, CA; Agodoa, LY; Abbott, KC; Swanson, SJ; Kirk, AD; Ko, CW; Jones, CA; Agodoa, LY; Abbott, KC
MLA Citation
Swanson, SJ, Kirk, AD, Ko, CW, Jones, CA, Agodoa, LY, Abbott, KC, Swanson, SJ, Kirk, AD, Ko, CW, Jones, CA, Agodoa, LY, and Abbott, KC. "Impact of HIV seropositivity on graft and patient survival after cadaveric renal transplantation in the United States in the pre highly active antiretroviral therapy (HAART) era: an historical cohort analysis of the United States Renal Data System." Transplant Infectious Disease 4.3 (September 2002): 144-147.
Source
crossref
Published In
Transplant Infectious Disease
Volume
4
Issue
3
Publish Date
2002
Start Page
144
End Page
147
DOI
10.1034/j.1399-3062.2002.01009.x

Pancreatic Islet Transplantation Using the Nonhuman Primate (Rhesus) Model Predicts That the Portal Vein Is Superior to the Celiac Artery as the Islet Infusion Site

Authors
Hirshberg, B; Montgomery, S; Wysoki, MG; Xu, H; Tadaki, D; Lee, J; Hines, K; Gaglia, J; Patterson, N; Leconte, J; Hale, D; Chang, R; Kirk, AD; Harlan, DM
MLA Citation
Hirshberg, B, Montgomery, S, Wysoki, MG, Xu, H, Tadaki, D, Lee, J, Hines, K, Gaglia, J, Patterson, N, Leconte, J, Hale, D, Chang, R, Kirk, AD, and Harlan, DM. "Pancreatic Islet Transplantation Using the Nonhuman Primate (Rhesus) Model Predicts That the Portal Vein Is Superior to the Celiac Artery as the Islet Infusion Site." Diabetes 51.7 (July 1, 2002): 2135-2140.
Source
crossref
Published In
Diabetes
Volume
51
Issue
7
Publish Date
2002
Start Page
2135
End Page
2140
DOI
10.2337/diabetes.51.7.2135

Ethnicity Greatly Influences Cytokine Gene Polymorphism Distribution

Authors
Hoffmann, SC; Stanley, EM; Cox, ED; DiMercurio, BS; Koziol, DE; Harlan, DM; Kirk, AD; Blair, PJ
MLA Citation
Hoffmann, SC, Stanley, EM, Cox, ED, DiMercurio, BS, Koziol, DE, Harlan, DM, Kirk, AD, and Blair, PJ. "Ethnicity Greatly Influences Cytokine Gene Polymorphism Distribution." American Journal of Transplantation 2.6 (July 2002): 560-567.
Source
crossref
Published In
American Journal of Transplantation
Volume
2
Issue
6
Publish Date
2002
Start Page
560
End Page
567
DOI
10.1034/j.1600-6143.2002.20611.x

Location, location, location: Regional immune mechanisms critically influence rejection

Authors
Kirk, AD
MLA Citation
Kirk, AD. "Location, location, location: Regional immune mechanisms critically influence rejection." Nature Medicine 8.6 (June 1, 2002): 553-555.
Source
crossref
Published In
Nature Medicine
Volume
8
Issue
6
Publish Date
2002
Start Page
553
End Page
555
DOI
10.1038/nm0602-553

Campath-1H in intestinal and multivisceral transplantation: preliminary data

Authors
Tzakis, AG; Kato, T; Nishida, S; Levi, D; Madariaga, J; Faria, WDE; Nery, J; Neff, G; Kirk, AD; Ruiz, P
MLA Citation
Tzakis, AG, Kato, T, Nishida, S, Levi, D, Madariaga, J, Faria, WDE, Nery, J, Neff, G, Kirk, AD, and Ruiz, P. "Campath-1H in intestinal and multivisceral transplantation: preliminary data." Transplantation Proceedings 34.3 (May 2002): 937-937.
Source
crossref
Published In
Transplantation Proceedings
Volume
34
Issue
3
Publish Date
2002
Start Page
937
End Page
937
DOI
10.1016/S0041-1345(02)02679-9

Efficacy and Toxicity of a Protocol Using Sirolimus, Tacrolimus and Daclizumab in a Nonhuman Primate Renal Allotransplant Model

Authors
Montgomery, SP; Mog, SR; Xu, H; Tadaki, DK; Hirshberg, B; Berning, JD; Leconte, J; Harlan, DM; Hale, D; Kirk, AD
MLA Citation
Montgomery, SP, Mog, SR, Xu, H, Tadaki, DK, Hirshberg, B, Berning, JD, Leconte, J, Harlan, DM, Hale, D, and Kirk, AD. "Efficacy and Toxicity of a Protocol Using Sirolimus, Tacrolimus and Daclizumab in a Nonhuman Primate Renal Allotransplant Model." American Journal of Transplantation 2.4 (April 2002): 381-385.
Source
crossref
Published In
American Journal of Transplantation
Volume
2
Issue
4
Publish Date
2002
Start Page
381
End Page
385
DOI
10.1034/j.1600-6143.2002.20415.x

Effect of Donor Factors on Early Graft Survival in Adult Cadaveric Renal Transplantation

Authors
Swanson, SJ; Hypolite, IO; Agodoa, LYC; Batty Jr, DS; Hshieh, PB; Cruess, D; Kirk, AD; Peters, TG; Abbott, KC
MLA Citation
Swanson, SJ, Hypolite, IO, Agodoa, LYC, Batty Jr, DS, Hshieh, PB, Cruess, D, Kirk, AD, Peters, TG, and Abbott, KC. "Effect of Donor Factors on Early Graft Survival in Adult Cadaveric Renal Transplantation." American Journal of Transplantation 2.1 (January 2002): 68-75.
Source
crossref
Published In
American Journal of Transplantation
Volume
2
Issue
1
Publish Date
2002
Start Page
68
End Page
75
DOI
10.1034/j.1600-6143.2002.020112.x

Type 2 angiotensin II receptor expression in human renal allografts: An association with chronic allograft nephropathy

Aims: The renin-angiotensin system (RAS) has been implicated in renal fibrosis through activation of the type 1 angiotensin II (Ang II) receptor (AT1R). Whether the other predominant Ang II receptor, the type 2 Ang II receptor (AT2R), has a fibrotic or sparing role in adult human renal tissue is unknown. Materials and methods: We used the reverse-transcription polymerase chain reaction (RT-PCR) to assess intragraft AT2R mRNA expression in biopsy samples from 23 renal transplant recipients. Potential correlations between intragraft AT2R mRNA, matrix-modulating genes and histologic evidence of chronic rejection were assessed. Results: AT2R mRNA was confirmed by sequence analysis of the RT-PCR product. AT2R mRNA expression directly correlated with angiotensinogen (Spearman correlation coefficient (rs) 0.72; p = 0.0011) mRNA expression, and interestingly, AT2R mRNA inversely correlated with inflammatory gene expression in the biopsy samples. However, AT2R mRNA directly correlated with transforming growth factor-β (TGF-β) (rs 0.59; p = 0.044), matrix metalloproteinase-1 (MMP-1) (rs 0.83; p = 0.001), tissue inhibitor of metalloproteinase-2 (TIMP-2) (rs 0.74; p = 0.001) and TIMP-3 (rs 0.80; p = 0.001) mRNA expression. Moreover, AT2R mRNA and protein expression was significantly greater in the patients with biopsy-proven chronic allograft nephropathy (n = 9; p = 0.045 vs. no chronic allograft nephropathy and donor biopsy samples for mRNA analyses). Conclusions: These data demonstrate that AT2R mRNA is expressed in adult human renal tissue in the setting of renal transplantation. Its apparent association with matrix-modulating genes raises the hypothesis that AT2R mRNA expression may be linked with extracellular matrix regulation in the setting of chronic allograft nephropathy.

Authors
Becker, BN; Jacobson, LM; Hullett, DA; Radke, NA; Oberley, TD; Brazy, PC; Kirk, AD
MLA Citation
Becker, BN, Jacobson, LM, Hullett, DA, Radke, NA, Oberley, TD, Brazy, PC, and Kirk, AD. "Type 2 angiotensin II receptor expression in human renal allografts: An association with chronic allograft nephropathy." Clinical Nephrology 57.1 (2002): 19-26.
Source
scival
Published In
Clinical Nephrology
Volume
57
Issue
1
Publish Date
2002
Start Page
19
End Page
26

Context-based therapy: A conceptual framework for transplantation tolerance

Allotransplantation has improved dramatically in the past 2 decades, mostly as a result of more potent immunosuppression and increasingly effective prophylaxis against opportunistic infections. It is likely, however, that the field has entered a period of diminishing returns, such that increased immunosuppression will minimally increase graft survival and markedly augment morbidity. The authors suggest that gains in graft and patient survival will best be achieved by pursuing strategies promoting immune tolerance and selecting therapies that enhance physiologic immune adaptation rather than those that indiscriminately suppress immune function. Principles of tolerance as they relate to allotransplantation are discussed. The authors introduce the concept of context-based therapy. This approach places an emphasis on preserving specificity during immune intervention by augmenting or avoiding interference with antigen receptor function. Graft acceptance is fostered by altering contextual signals influencing the outcome of antigen recognition such as intrinsic indicators of cell injury, costimulatory signals, the activation state of antigen presenting cells, or the local environment of immune engagement. The manipulation of immune thresholds is also introduced as an additional concept influencing tolerance. Supportive data from nonhuman primate and human trial are presented. This is a US government work. There are no restrictions on its use.

Authors
Preston, E; Kirk, AD
MLA Citation
Preston, E, and Kirk, AD. "Context-based therapy: A conceptual framework for transplantation tolerance." Transplantation Reviews 16.3 (2002): 142-162.
Source
scival
Published In
Transplantation Reviews
Volume
16
Issue
3
Publish Date
2002
Start Page
142
End Page
162

Combination induction therapy with monoclonal antibodies specific for CD80, CD86, and CD154 in nonhuman primate renal transplantation

Background. Antibodies and fusion proteins specific for CD80, CD86, and CD154 have shown promise as agents capable of inducing donor-specific tolerance in rodents. These agents have also been shown to be synergistic with one another in many settings of counter-adaptive immunity. In the nonhuman primate, monoclonal antibodies specific for CD80 and CD86 have prolonged the time to rejection of renal allografts but have not resulted in tolerance. A monoclonal antibody specific for CD154 has resulted in markedly prolonged survival of kidney, islet, cardiac, and skin allografts, but again most animals have eventually developed rejection after prolonged periods of rejection-free survival off therapy. Methods. A combination of monoclonal antibodies specific for CD80, CD86, and CD154 were used in a mismatched nonhuman primate renal-allograft model. Doses used were based on optimized treatment protocols for each agent individually. Results. Treatment of four rhesus macaques with this combination yielded a mean rejection-free survival of 565 days (311-911 days), significantly greater than untreated controls (mean survival=7.0 days, P=0.001) and animals treated with only a combination of anti-CD80 and CD86 (mean survival=191 days, P=0.01). The survival of animals treated with this combination of monoclonal antibodies was not significantly greater than those treated with anti-CD154 alone, but the production of alloantibody was delayed compared with monotherapy anti-CD154. Conclusion. These data suggest that a synergy exists between these agents, particularly with regard to T-dependent B-cell responses, but that they fail to induce durable tolerance in nonhuman primates.

Authors
Montgomery, SP; Xu, H; Tadaki, DK; Celniker, A; Burkly, LC; Berning, JD; Cruzata, F; Elster, EA; Gray, G; Kampen, RL; Swanson, SJ; Harlan, DM; Kirk, AD
MLA Citation
Montgomery, SP, Xu, H, Tadaki, DK, Celniker, A, Burkly, LC, Berning, JD, Cruzata, F, Elster, EA, Gray, G, Kampen, RL, Swanson, SJ, Harlan, DM, and Kirk, AD. "Combination induction therapy with monoclonal antibodies specific for CD80, CD86, and CD154 in nonhuman primate renal transplantation." Transplantation 74.10 (2002): 1365-1369.
Source
scival
Published In
Transplantation
Volume
74
Issue
10
Publish Date
2002
Start Page
1365
End Page
1369

HUMAN PLATELETS ACTIVATE PORCINE ENDOTHELIAL CELLS THROUGH A CD154-DEPENDENT PATHWAY12

Authors
Xu, H; Arnaud, F; Tadaki, DK; Burkly, LC; Harlan, DM; Kirk, AD
MLA Citation
Xu, H, Arnaud, F, Tadaki, DK, Burkly, LC, Harlan, DM, and Kirk, AD. "HUMAN PLATELETS ACTIVATE PORCINE ENDOTHELIAL CELLS THROUGH A CD154-DEPENDENT PATHWAY12." Transplantation 72.11 (December 2001): 1858-1861.
Source
crossref
Published In
Transplantation
Volume
72
Issue
11
Publish Date
2001
Start Page
1858
End Page
1861
DOI
10.1097/00007890-200112150-00029

TREATMENT WITH THE HUMANIZED CD154-SPECIFIC MONOCLONAL ANTIBODY, hu5C8, PREVENTS ACUTE REJECTION OF PRIMARY SKIN ALLOGRAFTS IN NONHUMAN PRIMATES1

Authors
Elster, EA; Xu, H; Tadaki, DK; Montgomery, S; Burkly, LC; Berning, JD; Baumgartner, RE; Cruzata, F; Marx, R; Harlan, DM; Kirk, AD
MLA Citation
Elster, EA, Xu, H, Tadaki, DK, Montgomery, S, Burkly, LC, Berning, JD, Baumgartner, RE, Cruzata, F, Marx, R, Harlan, DM, and Kirk, AD. "TREATMENT WITH THE HUMANIZED CD154-SPECIFIC MONOCLONAL ANTIBODY, hu5C8, PREVENTS ACUTE REJECTION OF PRIMARY SKIN ALLOGRAFTS IN NONHUMAN PRIMATES1." Transplantation 72.9 (November 2001): 1473-1478.
Source
crossref
Published In
Transplantation
Volume
72
Issue
9
Publish Date
2001
Start Page
1473
End Page
1478
DOI
10.1097/00007890-200111150-00001

Hospitalizations for Fractures after Renal Transplantation in the United States

Authors
Abbott, KC; Oglesby, RJ; Hypolite, IO; Kirk, AD; Ko, CW; Welch, PG; Agodoa, LY; Duncan, WE
MLA Citation
Abbott, KC, Oglesby, RJ, Hypolite, IO, Kirk, AD, Ko, CW, Welch, PG, Agodoa, LY, and Duncan, WE. "Hospitalizations for Fractures after Renal Transplantation in the United States." Annals of Epidemiology 11.7 (October 2001): 450-457.
Source
crossref
Published In
Annals of Epidemiology
Volume
11
Issue
7
Publish Date
2001
Start Page
450
End Page
457
DOI
10.1016/S1047-2797(01)00226-5

Preclinical evaluation of tolerance induction protocols and islet transplantation in non-human primates

Authors
Montgomery, SP; Hale, DA; Hirshberg, B; Harlan, DM; Kirk, AD
MLA Citation
Montgomery, SP, Hale, DA, Hirshberg, B, Harlan, DM, and Kirk, AD. "Preclinical evaluation of tolerance induction protocols and islet transplantation in non-human primates." Immunological Reviews 183.1 (October 2001): 214-222.
Source
crossref
Published In
Immunological Reviews
Volume
183
Issue
1
Publish Date
2001
Start Page
214
End Page
222
DOI
10.1034/j.1600-065x.2001.1830117.x

ASSOCIATION OF CYTOKINE POLYMORPHIC INHERITANCE AND IN VITRO CYTOKINE PRODUCTION IN ANTI-CD3/CD28-STIMULATED PERIPHERAL BLOOD LYMPHOCYTES1

Authors
Hoffmann, SC; Stanley, EM; Darrin Cox, E; Craighead, N; DiMercurio, BS; Koziol, DE; Harlan, DM; Kirk, AD; Blair, PJ
MLA Citation
Hoffmann, SC, Stanley, EM, Darrin Cox, E, Craighead, N, DiMercurio, BS, Koziol, DE, Harlan, DM, Kirk, AD, and Blair, PJ. "ASSOCIATION OF CYTOKINE POLYMORPHIC INHERITANCE AND IN VITRO CYTOKINE PRODUCTION IN ANTI-CD3/CD28-STIMULATED PERIPHERAL BLOOD LYMPHOCYTES1." Transplantation 72.8 (October 2001): 1444-1450.
Source
crossref
Published In
Transplantation
Volume
72
Issue
8
Publish Date
2001
Start Page
1444
End Page
1450
DOI
10.1097/00007890-200110270-00019

INDUCTION THERAPY WITH MONOCLONAL ANTIBODIES SPECIFIC FOR CD80 AND CD86 DELAYS THE ONSET OF ACUTE RENAL ALLOGRAFT REJECTION IN NON-HUMAN PRIMATES1

Authors
Kirk, AD; Tadaki, DK; Celniker, A; Scott Batty, D; Berning, JD; Colonna, JO; Cruzata, F; Elster, EA; Gray, GS; Kampen, RL; Patterson, NB; Szklut, P; Swanson, J; Xu, H; Harlan, DM
MLA Citation
Kirk, AD, Tadaki, DK, Celniker, A, Scott Batty, D, Berning, JD, Colonna, JO, Cruzata, F, Elster, EA, Gray, GS, Kampen, RL, Patterson, NB, Szklut, P, Swanson, J, Xu, H, and Harlan, DM. "INDUCTION THERAPY WITH MONOCLONAL ANTIBODIES SPECIFIC FOR CD80 AND CD86 DELAYS THE ONSET OF ACUTE RENAL ALLOGRAFT REJECTION IN NON-HUMAN PRIMATES1." Transplantation 72.3 (August 2001): 377-384.
Source
crossref
Published In
Transplantation
Volume
72
Issue
3
Publish Date
2001
Start Page
377
End Page
384
DOI
10.1097/00007890-200108150-00005

CYTOKINE POLYMORPHIC ANALYSES INDICATE ETHNIC DIFFERENCES IN THE ALLELIC DISTRIBUTION OF INTERLEUKIN-2 AND INTERLEUKIN-61

Authors
Cox, ED; Hoffmann, SC; DiMercurio, BS; Wesley, RA; Harlan, DM; Kirk, AD; Blair, PJ
MLA Citation
Cox, ED, Hoffmann, SC, DiMercurio, BS, Wesley, RA, Harlan, DM, Kirk, AD, and Blair, PJ. "CYTOKINE POLYMORPHIC ANALYSES INDICATE ETHNIC DIFFERENCES IN THE ALLELIC DISTRIBUTION OF INTERLEUKIN-2 AND INTERLEUKIN-61." Transplantation 72.4 (August 2001): 720-726.
Source
crossref
Published In
Transplantation
Volume
72
Issue
4
Publish Date
2001
Start Page
720
End Page
726
DOI
10.1097/00007890-200108270-00027

Successful conversion from conventional immunosuppression to anti-CD154 monoclonal antibody costimulatory molecule blockade in rhesus renal allograft recipients.

BACKGROUND: Several conventional forms of immunosuppression have been shown to antagonize the efficacy of anti-CD154 monoclonal antibody- (mAb) based costimulatory molecule blockade immunotherapy. Our objective was to determine if allograft recipients treated with a conventional immunosuppressive regimen could be sequentially converted to anti-CD154 mAb monotherapy without compromising graft survival. METHODS: Outbred juvenile rhesus monkeys underwent renal allotransplantation from MHC-disparate donors. After a 60-day course of triple therapy immunosuppression with steroids, cyclosporine, and mycophenolate mofetil, monkeys were treated with: (1) cessation of all immunosuppression (control); (2) seven monthly doses of 20 mg/kg hu5C8 (maintenance), or; (3) 20 mg/kg hu5C8 on posttransplant days 60, 61, 64, 71, 79, and 88 followed by five monthly doses (induction+maintenance). Graft rejection was defined by elevation in serum creatinine>1.5 mg/dl combined with histologic evidence of rejection. RESULTS: Graft survival for the three groups were as follows: group 1 (control): 70, 75, >279 days; group 2 (maintenance): 83, 349, >293 days, and; group 3 (induction+maintenance): 355, >377, >314 days. Acute rejection developing in two of four monkeys after treatment with conventional immunosuppression was successfully reversed with intensive hu5C8 monotherapy. CONCLUSIONS: Renal allograft recipients can be successfully converted to CD154 blockade monotherapy after 60 days of conventional immunosuppression. An induction phase of anti-CD154 mAb appears to be necessary for optimal conversion. Therefore, although concurrent administration of conventional immunosuppressive agents including steroids and calcineurin inhibitors has been shown to inhibit the efficacy of CD154 blockade, sequential conversion from these agents to CD154 blockade appears to be effective.

Authors
Cho, CS; Burkly, LC; Fechner , JH; Kirk, AD; Oberley, TD; Dong, Y; Brunner, KG; Peters, D; Tenhoor, CN; Nadeau, K; Yagci, G; Ishido, N; Schultz, JM; Tsuchida, M; Hamawy, MM; Knechtle, SJ
MLA Citation
Cho, CS, Burkly, LC, Fechner , JH, Kirk, AD, Oberley, TD, Dong, Y, Brunner, KG, Peters, D, Tenhoor, CN, Nadeau, K, Yagci, G, Ishido, N, Schultz, JM, Tsuchida, M, Hamawy, MM, and Knechtle, SJ. "Successful conversion from conventional immunosuppression to anti-CD154 monoclonal antibody costimulatory molecule blockade in rhesus renal allograft recipients." Transplantation 72.4 (August 2001): 587-597.
PMID
11544416
Source
epmc
Published In
Transplantation
Volume
72
Issue
4
Publish Date
2001
Start Page
587
End Page
597
DOI
10.1097/00007890-200108270-00006

The role of CD154 in organ transplant rejection and acceptance

Authors
Kirk, AD; Blair, PJ; Tadaki, DK; Xu, H; Harlan, DM
MLA Citation
Kirk, AD, Blair, PJ, Tadaki, DK, Xu, H, and Harlan, DM. "The role of CD154 in organ transplant rejection and acceptance." Philosophical Transactions of the Royal Society B: Biological Sciences 356.1409 (May 29, 2001): 691-702.
Source
crossref
Published In
Philosophical Transactions B
Volume
356
Issue
1409
Publish Date
2001
Start Page
691
End Page
702
DOI
10.1098/rstb.2001.0855

Hospitalizations for Bacterial Septicemia after Renal Transplantation in the United States

Authors
Abbott, KC; Oliver, III, JD; Hypolite, I; Lepler, LL; Kirk, AD; Ko, CW; Hawkes, CA; Jones, CA; Agodoa, LY
MLA Citation
Abbott, KC, Oliver, III, JD, Hypolite, I, Lepler, LL, Kirk, AD, Ko, CW, Hawkes, CA, Jones, CA, and Agodoa, LY. "Hospitalizations for Bacterial Septicemia after Renal Transplantation in the United States." American Journal of Nephrology 21.2 (April 1, 2001): 120-127.
Source
crossref
Published In
American journal of nephrology
Volume
21
Issue
2
Publish Date
2001
Start Page
120
End Page
127
DOI
10.1159/000046234

Primate skin allotransplantation with anti-CD154 monotherapy

Authors
Elster, EA; Xu, H; Tadaki, DK; Burkly, LC; Berning, JD; Baumgartner, RE; Cruzata, F; Patterson, NB; Harlan, DM; Kirk, AD
MLA Citation
Elster, EA, Xu, H, Tadaki, DK, Burkly, LC, Berning, JD, Baumgartner, RE, Cruzata, F, Patterson, NB, Harlan, DM, and Kirk, AD. "Primate skin allotransplantation with anti-CD154 monotherapy." Transplantation Proceedings 33.1-2 (February 2001): 675-676.
Source
crossref
Published In
Transplantation Proceedings
Volume
33
Issue
1-2
Publish Date
2001
Start Page
675
End Page
676
DOI
10.1016/S0041-1345(00)02197-7

Effects of dose and duration of anti-CD154 antibody therapy in preventing renal allograft rejection in a nonhuman primate model

Authors
Xu, H; Elster, E; Batty, D; Berning, J; Burkly, L; Kampen, R; Swanson, S; Tadaki, D; Harlan, D; Kirk, A
MLA Citation
Xu, H, Elster, E, Batty, D, Berning, J, Burkly, L, Kampen, R, Swanson, S, Tadaki, D, Harlan, D, and Kirk, A. "Effects of dose and duration of anti-CD154 antibody therapy in preventing renal allograft rejection in a nonhuman primate model." Transplantation Proceedings 33.1-2 (February 2001): 223-224.
Source
crossref
Published In
Transplantation Proceedings
Volume
33
Issue
1-2
Publish Date
2001
Start Page
223
End Page
224
DOI
10.1016/S0041-1345(00)01983-7

Graft Loss Due to Recurrent Focal Segmental Glomerulosclerosis in Renal Transplant Recipients in the United States

Authors
Abbott, KC; Sawyers, ES; Oliver, JD; Ko, CW; Kirk, AD; Welch, PG; Peters, TG; Agodoa, LY
MLA Citation
Abbott, KC, Sawyers, ES, Oliver, JD, Ko, CW, Kirk, AD, Welch, PG, Peters, TG, and Agodoa, LY. "Graft Loss Due to Recurrent Focal Segmental Glomerulosclerosis in Renal Transplant Recipients in the United States." American Journal of Kidney Diseases 37.2 (February 2001): 366-373.
Source
crossref
Published In
American Journal of Kidney Diseases
Volume
37
Issue
2
Publish Date
2001
Start Page
366
End Page
373
DOI
10.1053/ajkd.2001.21311

Hitting the reset button for immune tolerance

Migratory cells can lead both to rejection and tolerance following organ transplantation, suggesting a direction for protolerant immunomodulatory therapies. (pages 80-87).

Authors
Kirk, AD
MLA Citation
Kirk, AD. "Hitting the reset button for immune tolerance." Nature Medicine 7.1 (2001): 24-25.
Source
scival
Published In
Nature Medicine
Volume
7
Issue
1
Publish Date
2001
Start Page
24
End Page
25
DOI
10.1038/83304

Hepatitis C Virus Seropositivity at the Time of Renal Transplantation in the United States: Associated Factors and Patient Survival

National statistics for patient characteristics and survival of renal transplant recipients positive for hepatitis C virus (HCV+) at the time of renal transplant are presented. A historical cohort analysis of 33 479 renal transplant recipients in the United States Renal Data System from 1 July, 1994 to 30 June, 1997 has been carried out. The medical evidence form was also used for additional variables, but because of fewer available values, this was analyzed in a separate model. Outcomes were patient characteristics and survival associated with HCV+. Of 28 692 recipients with valid HCV serologies, 1624 were HCV+ at transplant (5.7% prevalence). In logistic regression analysis, HCV+ was associated with African-American race, male gender, cadaveric donor type, increased duration of pre-transplant dialysis, previous transplant, donor HCV+, recipient (but not donor) age, serum albumin, alcohol use, and increased all-cause hospitalizations. Diabetes and IgA nephropathy were less associated with HCV+. Total all-cause, unadjusted mortality was 13.1% in HCV+ vs. 8.5% in HCV- patients (p <0.01 by log rank test). In Cox regression, mortality was higher for HCV+ (adjusted hazard ratio = 1.23, 95% confidence interval = 1.01-1.49, p =0.04). HCV+ recipients were more likely to be African-American, male, older, and to have received repeat transplants and donor HCV+ transplants. HCV+ recipients also had substantially longer waiting times for transplant. In contrast to recent studies, diabetes did not have an increased association with HCV+, perhaps due to limitations of the database. HCV+ recipients had increased mortality and hospitalization rates compared with other transplant recipients.

Authors
Jr, DSB; Swanson, SJ; Kirk, AD; Ko, CW; Agodoa, LY; Abbott, KC
MLA Citation
Jr, DSB, Swanson, SJ, Kirk, AD, Ko, CW, Agodoa, LY, and Abbott, KC. "Hepatitis C Virus Seropositivity at the Time of Renal Transplantation in the United States: Associated Factors and Patient Survival." American Journal of Transplantation 1.2 (2001): 179-184.
Source
scival
Published In
American Journal of Transplantation
Volume
1
Issue
2
Publish Date
2001
Start Page
179
End Page
184

Convergent theories of transplantation tolerance

Authors
Kirk, AD
MLA Citation
Kirk, AD. "Convergent theories of transplantation tolerance." Current Opinion in Organ Transplantation 5.2 (June 2000): 81-82.
Source
crossref
Published In
Current Opinion in Organ Transplantation
Volume
5
Issue
2
Publish Date
2000
Start Page
81
End Page
82
DOI
10.1097/00075200-200006000-00007

Promise of costimulatory pathway modifying reagents for transplantation

Authors
Harlan, DM; Kirk, AD
MLA Citation
Harlan, DM, and Kirk, AD. "Promise of costimulatory pathway modifying reagents for transplantation." Current Opinion in Organ Transplantation 5.2 (June 2000): 90-95.
Source
crossref
Published In
Current Opinion in Organ Transplantation
Volume
5
Issue
2
Publish Date
2000
Start Page
90
End Page
95
DOI
10.1097/00075200-200006000-00009

Challenges for the clinical application of transplant tolerance strategies

Authors
Kirk, AD; Harlan, DM
MLA Citation
Kirk, AD, and Harlan, DM. "Challenges for the clinical application of transplant tolerance strategies." Current Opinion in Organ Transplantation 5.2 (June 2000): 108-113.
Source
crossref
Published In
Current Opinion in Organ Transplantation
Volume
5
Issue
2
Publish Date
2000
Start Page
108
End Page
113
DOI
10.1097/00075200-200006000-00012

Primate allotransplantation using costimulation blockade.

Authors
Kirk, AD; Tadaki, DK; Xu, H; Elster, EA; Burkley, LC; Celniker, A; Batty, DS; Baumgartner, RE; Berning, JD; Fechner, JH; Kampen, RL; Knechtle, SJ; Patterson, NB; Swanson, SJ; Harlan, DM
MLA Citation
Kirk, AD, Tadaki, DK, Xu, H, Elster, EA, Burkley, LC, Celniker, A, Batty, DS, Baumgartner, RE, Berning, JD, Fechner, JH, Kampen, RL, Knechtle, SJ, Patterson, NB, Swanson, SJ, and Harlan, DM. "Primate allotransplantation using costimulation blockade." TRANSPLANTATION 69.8 (April 27, 2000): S414-S414.
Source
wos-lite
Published In
Transplantation
Volume
69
Issue
8
Publish Date
2000
Start Page
S414
End Page
S414

Simultaneous pancreas-kidney transplantation and living related donor renal transplantation in patients with diabetes: is there a difference in survival?

OBJECTIVE: To compare the outcome of simultaneous pancreas-kidney transplantation (SPK) and living related donor renal transplantation (LRD) in patients with diabetes. SUMMARY BACKGROUND DATA: It remains unanswered whether diabetic patients with end-stage renal failure are better served by LRD or SPK. METHODS: Using a longitudinal database, data from all diabetic patients receiving LRD or cadaveric renal transplants or SPKs from January 1986 through January 1996 were analyzed. Patient and graft survival, early graft function, and the cause of patient and graft loss were compared for 43 HLA-identical LRDs, 87 haplotype-identical LRDs, 379 SPKs, and 296 cadaveric renal transplants. RESULTS: The demographic composition of the SPK and LRD groups were similar, but because of less strict selection criteria in the cadaveric transplant group, patients were 10 years older, more patients received dialysis, and patients had been receiving dialysis longer before transplantation. Patient survival was similar for the SPK and LRD groups but was significantly lower for the cadaveric renal transplant group. Similarly, there was no difference in graft survival between SPK and LRD recipients, but it was significantly lower for recipients in the cadaveric renal transplant group. Delayed graft function was significantly more common in the cadaveric renal transplant group. Discharge creatinine, the strongest predictor of patient and graft survival, was highest in the SPK group and lowest in the HLA-identical LRD group. The rate of rejection within the first year was greatest in SPK patients (77%), intermediate in the haplotype-identical LRD and cadaveric transplant groups (57% and 48%, respectively), and lowest (16%) in the HLA-identical LRD group. Cardiovascular disease was the primary cause of death for all groups. Acute rejection, chronic rejection, and death with a functioning graft were the predominant causes of graft loss. CONCLUSIONS: This study demonstrates that there was no difference in patient or graft survival in diabetic patients receiving LRD or SPK transplants. However, graft and patient survival rates in diabetic recipients of cadaveric renal transplants were significantly lower than in the other groups.

Authors
Rayhill, SC; D'Alessandro, AM; Odorico, JS; Knechtle, SJ; Pirsch, JD; Heisey, DM; Kirk, AD; Van der Werf, W; Sollinger, HW
MLA Citation
Rayhill, SC, D'Alessandro, AM, Odorico, JS, Knechtle, SJ, Pirsch, JD, Heisey, DM, Kirk, AD, Van der Werf, W, and Sollinger, HW. "Simultaneous pancreas-kidney transplantation and living related donor renal transplantation in patients with diabetes: is there a difference in survival?." Annals of surgery 231.3 (March 2000): 417-423.
PMID
10714635
Source
epmc
Published In
Annals of Surgery
Volume
231
Issue
3
Publish Date
2000
Start Page
417
End Page
423
DOI
10.1097/00000658-200003000-00015

Cd40 Ligand (Cd154) Triggers a Short-Term Cd4 + T Cell Activation Response That Results in Secretion of Immunomodulatory Cytokines and Apoptosis

Authors
Blair, PJ; Riley, JL; Harlan, DM; Abe, R; Tadaki, DK; Hoffmann, SC; White, L; Francomano, T; Perfetto, SJ; Kirk, AD; June, CH
MLA Citation
Blair, PJ, Riley, JL, Harlan, DM, Abe, R, Tadaki, DK, Hoffmann, SC, White, L, Francomano, T, Perfetto, SJ, Kirk, AD, and June, CH. "Cd40 Ligand (Cd154) Triggers a Short-Term Cd4 + T Cell Activation Response That Results in Secretion of Immunomodulatory Cytokines and Apoptosis." The Journal of Experimental Medicine 191.4 (February 21, 2000): 651-660.
Source
crossref
Published In
The Journal of Experimental Medicine
Volume
191
Issue
4
Publish Date
2000
Start Page
651
End Page
660
DOI
10.1084/jem.191.4.651

Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand [1] (multiple letters)

Authors
Kawai, T; Andrews, D; Colvin, RB; Sachs, DH; Cosimi, AB; Kirk, AD; Harlan, DM
MLA Citation
Kawai, T, Andrews, D, Colvin, RB, Sachs, DH, Cosimi, AB, Kirk, AD, and Harlan, DM. "Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand [1] (multiple letters)." Nature Medicine 6.2 (2000): 114--.
Source
scival
Published In
Nature Medicine
Volume
6
Issue
2
Publish Date
2000
Start Page
114-

Potential of costimulation-based therapies for composite tissue allotransplantation

Clinical success has not been routinely achieved for composite tissue allotransplantation (CTA). Although most of the technical details of CTA have been overcome, the immunological aspects of these procedures have proved complex. Many traumatic conditions requiring CTA contraindicate acute global immunosuppression. Moreover, the risk of long-term immunosuppression is difficult to reconcile with non-life-threatening defects that can be adequately palliated. Recently, several successful immunomodulating strategies have been introduced for solid organ transplantation. They include therapies that alter costimulatory signals at engraftment. One approach, using treatment with a monoclonal antibody directed against CD154, has shown promise in rodent and nonhuman primate models and is discussed as a potential strategy for CTA. © 2000 Wiley-Liss, Inc.

Authors
Elster, EA; Blair, PJ; Kirk, AD
MLA Citation
Elster, EA, Blair, PJ, and Kirk, AD. "Potential of costimulation-based therapies for composite tissue allotransplantation." Microsurgery 20.8 (2000): 430-434.
Source
scival
Published In
Microsurgery
Volume
20
Issue
8
Publish Date
2000
Start Page
430
End Page
434
DOI
10.1002/1098-2752(2000)20:8<430::AID-MICR14>3.0.CO;2-K

Tumor necrosis factor-α and tumor growth factor-β1 genotype: Partial association with intragraft gene expression in two cases of long-term peripheral tolerance to a kidney transplant

Genomic DNA was obtained from peripheral blood samples of patients JB and DS each of whom received a kidney transplant at 16 years of age from a serologically HLA-DR matched and HLA-class I -mismatched donor. Both patients discontinued immunosuppression after 1-2 years and retained good renal function for an additional 5 years or more. DNA was analyzed for genetic polymorphisms in the tumor necrosis factor-α (TNFα) and tumor growth factor-β1 (TGFβ1) loci. Biopsy samples obtained during stable function (DS, JB) and during rejection (JB) were analyzed by RT/PCR for cytokine gene expression. Both patients had a high responder genotype for TGFβ1. DS had a low responder TNFα genotype, while JB and his donor were both genotypically TNFα intermediate responders. DS had a high TGFβ1: TNFα mRNA ratio in two biopsies obtained during tolerance, while JB, who eventually lost his graft, had more TNFα than TGFβ1 mRNA. The results suggest a possible role for cytokine immunogenetics in the stability of peripheral tolerance.

Authors
Burlingham, WJ; O'Connell, PJ; Jacobson, LM; Becker, BN; Kirk, AD; Pravica, V; Hutchinson, IV
MLA Citation
Burlingham, WJ, O'Connell, PJ, Jacobson, LM, Becker, BN, Kirk, AD, Pravica, V, and Hutchinson, IV. "Tumor necrosis factor-α and tumor growth factor-β1 genotype: Partial association with intragraft gene expression in two cases of long-term peripheral tolerance to a kidney transplant." Transplantation 69.7 (2000): 1527-1530.
Source
scival
Published In
Transplantation
Volume
69
Issue
7
Publish Date
2000
Start Page
1527
End Page
1530

Renin-angiotensin system gene expression in post-transplant hypertension predicts allograft function

Background. Registry analyses and single-center studies have demonstrated that hypertension significantly increases the risk for chronic graft loss. The graft itself may contribute to posttransplant hypertension, and intragraft vasoactive hormones therefore, may be dysregulated in posttransplant hypertension. Methods. We used the reverse-transcription polymerase chain reaction to assess the intragraft regulation of renin- angiotensin system transcripts in biopsy samples from 42 stable renal transplant patients with posttransplant hypertension. We also examined mRNA expression of inducible nitric oxide synthase, transforming growth factor-β (TGF-β), select cytokines, and metalloproteinase transcripts in biopsy tissue. Polymerase chain reaction products were quantitated using high performance liquid chromatography and normalized to β-actin mRNA expression. Serum creatinine, glomerular filtration rate or creatinine clearance and tubular atrophy on biopsy were concurrently assessed. Results. Renin and select Th1 cytokine mRNA expression correlated with blood pressure. Type 1 angiotensin II receptor mRNA expression significantly correlated with glomerular filtration rate or creatinine clearance (P=0.034) and inversely correlated with Th1 cytokines, inducible nitric oxide synthase, and cyclooxygenase-1 mRNA expression (P≤0.013 for each). Type 1 angiotensin II receptor mRNA also approached a significant inverse correlation with TGF-β mRNA expression (P=0.09). Conversely, angiotensin-converting enzyme mRNA expression directly correlated with Th1 cytokine (P≤0.008 for each) and TGF- β mRNA expression (P=0.006). Type 1 angiotensin II receptor mRNA expression also correlated with matrix metalloproteinase-1 promoter region, tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) and tissue inhibitor of matrix metalloproteinase-3 mRNA expression. Notably, matrix metalloproteinase-1 promoter region, tissue inhibitor of matrix metalloproteinase-2, and tissue inhibitor of matrix metalloproteinase-3 inversely correlated with TGF-β mRNA expression (P≤0.0027 for each). Type 1 angiotensin II receptor mRNA expression at biopsy directly correlated with glomerular filtration rate at 2 year's follow-up. However, angiotensin- converting enzyme mRNA expression at biopsy inversely correlated with glomerular filtration rate at 2 year's follow-up. Conclusions. These data suggest that allograft-level RAS gene expression may be predictive of future graft function in the setting of diastolic hypertension.

Authors
Becker, BN; Jacobson, LM; Becker, YT; Radke, NA; Heisey, DM; Oberley, TD; Pirsch, JD; Sollinger, HW; Brazy, PC; Kirk, AD
MLA Citation
Becker, BN, Jacobson, LM, Becker, YT, Radke, NA, Heisey, DM, Oberley, TD, Pirsch, JD, Sollinger, HW, Brazy, PC, and Kirk, AD. "Renin-angiotensin system gene expression in post-transplant hypertension predicts allograft function." Transplantation 69.7 (2000): 1485-1491.
Source
scival
Published In
Transplantation
Volume
69
Issue
7
Publish Date
2000
Start Page
1485
End Page
1491

Costimulatory molecules are active in the human xenoreactive T-cell response but not in natural killer-mediated cytotoxicity

Background. T-cell costimulatory blocking agents inhibit allospecific T- cell responses in vitro and prevent allograft rejection in vivo. Costimulatory requirements for discordant xenospecific cellular responses remain undefined. We have evaluated costimulatory molecule expression by porcine endothelial cells (PEC) after interaction with human cells and tested agents known to inhibit allospecific responses for their ability to inhibit xenospecific responses in vitro. Methods. Human-specific agents were screened for their ability to bind porcine costimulatory molecules by FACS. Up- regulation of B7 molecules on PEC was evaluated by FACS after exposure to human cells or supernatants. The effect of human and/or porcine costimulatory blockade was tested in xeno-mixed lymphocyte reactions (XMLRs) and in natural killer (NK) cell cytotoxicity assays. Results. B7 expression was induced on PEC after exposure to human T and NK cells or T cell-conditioned medium. The human XMLR was attenuated by human CTLA4-Ig and anti-human CD154 (hu5C8), and the combination was synergistic. Anti-human CD80 and CD86 antibodies alone had minor effects in the XMLR, but in combination with hu5C8 were as effective as human CTLA4-Ig plus hu5C8. Anti-hCD80 and hCD86 antibodies that did not cross-react with porcine CD80 or CD86 were as effective in blocking the MLR as those that did cross-react, indicating that the predominant costimulation in vitro was derived from the responding cells. None of the agents affected the xeno-NK response. Conclusions. We conclude that the costimulation-modulating agents block human anti-porcine T-cell responses in vitro predominantly through interruption of costimulation derived from responding cells. They have no effect on NK cell-mediated cytotoxicity.

Authors
Tadaki, DK; Craighead, N; Saini, A; Celniker, A; Burkly, LC; Lee, KP; Chute, JP; Harlan, DM; Kirk, AD
MLA Citation
Tadaki, DK, Craighead, N, Saini, A, Celniker, A, Burkly, LC, Lee, KP, Chute, JP, Harlan, DM, and Kirk, AD. "Costimulatory molecules are active in the human xenoreactive T-cell response but not in natural killer-mediated cytotoxicity." Transplantation 70.1 (2000): 162-167.
Source
scival
Published In
Transplantation
Volume
70
Issue
1
Publish Date
2000
Start Page
162
End Page
167

CLINICALLY STABLE HUMAN RENAL ALLOGRAFTS CONTAIN HISTOLOGICAL AND RNA-BASED FINDINGS THAT CORRELATE WITH DETERIORATING GRAFT FUNCTION1,2

Authors
Kirk, AD; Jacobson, LM; Heisey, DM; Radke, NF; Pirsch, JD; Sollinger, HW
MLA Citation
Kirk, AD, Jacobson, LM, Heisey, DM, Radke, NF, Pirsch, JD, and Sollinger, HW. "CLINICALLY STABLE HUMAN RENAL ALLOGRAFTS CONTAIN HISTOLOGICAL AND RNA-BASED FINDINGS THAT CORRELATE WITH DETERIORATING GRAFT FUNCTION1,2." Transplantation 68.10 (November 1999): 1578-1582.
Source
crossref
Published In
Transplantation
Volume
68
Issue
10
Publish Date
1999
Start Page
1578
End Page
1582
DOI
10.1097/00007890-199911270-00024

Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154

Authors
Kenyon, NS; Chatzipetrou, M; Masetti, M; Ranuncoli, A; Oliveira, M; Wagner, JL; Kirk, AD; Harlan, DM; Burkly, LC; Ricordi, C
MLA Citation
Kenyon, NS, Chatzipetrou, M, Masetti, M, Ranuncoli, A, Oliveira, M, Wagner, JL, Kirk, AD, Harlan, DM, Burkly, LC, and Ricordi, C. "Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154." Proceedings of the National Academy of Sciences 96.14 (July 6, 1999): 8132-8137.
Source
crossref
Published In
Proceedings of the National Academy of Sciences of USA
Volume
96
Issue
14
Publish Date
1999
Start Page
8132
End Page
8137
DOI
10.1073/pnas.96.14.8132

Long-term survival and function of intrahepatic islet allografts in baboons treated with humanized anti-CD154

Authors
Kenyon, NS; Fernandez, LA; Lehmann, R; Masetti, M; Ranuncoli, A; Chatzipetrou, M; Iaria, G; Han, D; Wagner, JL; Ruiz, P; Berho, M; Inverardi, L; Alejandro, R; Mintz, DH; Kirk, AD; Harlan, DM; Burkly, LC; Ricordi, C
MLA Citation
Kenyon, NS, Fernandez, LA, Lehmann, R, Masetti, M, Ranuncoli, A, Chatzipetrou, M, Iaria, G, Han, D, Wagner, JL, Ruiz, P, Berho, M, Inverardi, L, Alejandro, R, Mintz, DH, Kirk, AD, Harlan, DM, Burkly, LC, and Ricordi, C. "Long-term survival and function of intrahepatic islet allografts in baboons treated with humanized anti-CD154." Diabetes 48.7 (July 1, 1999): 1473-1481.
Source
crossref
Published In
Diabetes
Volume
48
Issue
7
Publish Date
1999
Start Page
1473
End Page
1481
DOI
10.2337/diabetes.48.7.1473

Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates.

CD154 is the ligand for the receptor CD40. This ligand-receptor pair mediates endothelial and antigen-presenting cell activation, and facilitates the interaction of these cells with T cells and platelets. We demonstrate here that administration of a CD154-specific monoclonal antibody (hu5C8) allows for renal allotransplantation in outbred, MHC-mismatched rhesus monkeys without acute rejection. The effect persisted for more than 10 months after therapy termination, and no additional drug was required to achieve extended graft survival. Indeed, the use of tacrolimus or chronic steroids seemed to antagonize the anti-rejection effect. Monkeys treated with antibody against CD154 remained healthy during and after therapy. The mechanism of action does not require global depletion of T or B cells. Long-term survivors lost their mixed lymphocyte reactivity in a donor-specific manner, but still formed donor-specific antibody and generated T cells that infiltrated the grafted organ without any obvious effect on graft function. Thus, therapy with antibody against CD154 is a promising agent for clinical use in human allotransplantation.

Authors
Kirk, AD; Burkly, LC; Batty, DS; Baumgartner, RE; Berning, JD; Buchanan, K; Fechner, JH; Germond, RL; Kampen, RL; Patterson, NB; Swanson, SJ; Tadaki, DK; TenHoor, CN; White, L; Knechtle, SJ; Harlan, DM
MLA Citation
Kirk, AD, Burkly, LC, Batty, DS, Baumgartner, RE, Berning, JD, Buchanan, K, Fechner, JH, Germond, RL, Kampen, RL, Patterson, NB, Swanson, SJ, Tadaki, DK, TenHoor, CN, White, L, Knechtle, SJ, and Harlan, DM. "Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates." Nature medicine 5.6 (June 1999): 686-693.
PMID
10371508
Source
epmc
Published In
Nature Medicine
Volume
5
Issue
6
Publish Date
1999
Start Page
686
End Page
693
DOI
10.1038/9536

Inducing unresponsiveness by the use of anti-CD3 immunotoxin, CTLA4-Ig, and anti-CD40 ligand

Authors
Knechtle, SJ; Kirk, AD; Fechner, JH; Hong, X; Dong, Y; Hamawy, MM; Harlan, DM
MLA Citation
Knechtle, SJ, Kirk, AD, Fechner, JH, Hong, X, Dong, Y, Hamawy, MM, and Harlan, DM. "Inducing unresponsiveness by the use of anti-CD3 immunotoxin, CTLA4-Ig, and anti-CD40 ligand." Transplantation Proceedings 31.3 (May 1999): 27S-28S.
Source
crossref
Published In
Transplantation Proceedings
Volume
31
Issue
3
Publish Date
1999
Start Page
27S
End Page
28S
DOI
10.1016/S0041-1345(99)00100-1

Inducing unresponsiveness by the use of anti-CD3 immunotoxin, CTLA4-Ig, and anti-CD40 ligand.

Authors
Knechtle, SJ; Kirk, AD; Fechner, JH; Hong, X; Dong, Y; Hamawy, MM; Harlan, DM
MLA Citation
Knechtle, SJ, Kirk, AD, Fechner, JH, Hong, X, Dong, Y, Hamawy, MM, and Harlan, DM. "Inducing unresponsiveness by the use of anti-CD3 immunotoxin, CTLA4-Ig, and anti-CD40 ligand." Transplantation proceedings 31.3B Suppl (May 1999): 27S-28S.
PMID
10330966
Source
epmc
Published In
Transplantation Proceedings
Volume
31
Issue
3B Suppl
Publish Date
1999
Start Page
27S
End Page
28S
DOI
10.1016/s0041-1345(99)00100-1

Immunosuppression without immunosuppression? How to be a tolerant individual in a dangerous world

The field of transplantation has developed based on two principles: allografts are rejected because they express foreign antigens, and the immune system must be suppressed to prevent rejection. Recently, in vitro and in vivo experimental evidence has accumulated that calls both of these beliefs into question. This article reviews an alternative approach to transplantation that focuses on tissue injury as the instigator of graft rejection and employs physiological mechanisms of tolerance to avoid graft loss. Methods that allow for defense against infectious microbes while at the same time allowing for graft survival are proposed. In particular, the rationale behind the use of anti-CD154 antibody treatment is highlighted. A model is introduced that takes into consideration the experimental successes seen with anti-CD154 therapies1. Copyright © Munksgaard 1999 All rights reserved.

Authors
Kirk, AD
MLA Citation
Kirk, AD. "Immunosuppression without immunosuppression? How to be a tolerant individual in a dangerous world." Transplant Infectious Disease 1.1 (1999): 65-75.
Source
scival
Published In
Transplant Infectious Disease
Volume
1
Issue
1
Publish Date
1999
Start Page
65
End Page
75

Transplantation tolerance: A look at the nonhuman primate literature in the light of modern tolerance theories

Ever since the beginning of clinical transplantation, investigators have searched for a way to transplant tissues from one person to another without chronic immunosuppression. That goal, known as allograft tolerance, has remained clinically elusive. In the past decade, however, many of the fundamental principles of tolerance have been redefined, and biological agents capable of exploiting them in vivo have been developed. Accordingly, experimental methods for tolerance induction have rapidly evolved in concert with a growing understanding of physiological tolerance to self and the development of novel immunoreactive reagents. In general, old world monkeys have become the pro-clinical testing ground for methods that have shown reasonable promise for clinical application, particularly antibodies or other biological agents with limited cross-species reactivity. As such, a survey of the nonhuman primate experience in transplantation is representative of all reasonably successful experimental attempts to develop clinically applicable tolerance regimens. This article summarizes many of the concepts currently unfolding in the tolerance literature. It also reviews the techniques for tolerance induction that have been and are currently being investigated in nonhuman primates. The validity of these models is summarized, and the older literature is reinterpreted in light of recent changes in our understanding of tolerance.

Authors
Kirk, AD
MLA Citation
Kirk, AD. "Transplantation tolerance: A look at the nonhuman primate literature in the light of modern tolerance theories." Critical Reviews in Immunology 19.5-6 (1999): 349-388.
Source
scival
Published In
Critical Reviews in Immunology
Volume
19
Issue
5-6
Publish Date
1999
Start Page
349
End Page
388

The future of organ and tissue transplantation: Can T-cell costimulatory pathway modifiers revolutionize the prevention of graft rejection?

Transplantation therapies have revolutionized care for patients with end-stage organ (kidney, liver, heart, lung, and pancreatic β-cell) failure, yet significant problems persist with treatments designed to prevent graft rejection. Antirejection therapies are not always effective, must be taken daily, and are both expensive and associated with well-known toxic effects. Recent advances have suggested that the immune system has more self- regulatory capability than previously appreciated. In this review, we discuss immune system function and new therapeutic agents that modify so-called costimulatory receptor signaling to support transplant function without generally suppressing the immune system.

Authors
Harlan, DM; Kirk, AD
MLA Citation
Harlan, DM, and Kirk, AD. "The future of organ and tissue transplantation: Can T-cell costimulatory pathway modifiers revolutionize the prevention of graft rejection?." Journal of the American Medical Association 282.11 (1999): 1076-1082.
Source
scival
Published In
JAMA : the journal of the American Medical Association
Volume
282
Issue
11
Publish Date
1999
Start Page
1076
End Page
1082
DOI
10.1001/jama.282.11.1076

Focal infiltrates in kidney allografts: developing a model for clinical transplant peripheral tolerance

Authors
Burlingham, W; Kusaka, S; Chin, L; Hullett, D; Knechtle, S; Sollinger, H; Oberley, T; Pirsch, J; Kirk, AD; Becker, BN
MLA Citation
Burlingham, W, Kusaka, S, Chin, L, Hullett, D, Knechtle, S, Sollinger, H, Oberley, T, Pirsch, J, Kirk, AD, and Becker, BN. "Focal infiltrates in kidney allografts: developing a model for clinical transplant peripheral tolerance." Graft 2 (1999): 253-260. (Academic Article)
Source
manual
Published In
Graft
Volume
2
Publish Date
1999
Start Page
253
End Page
260

Apoptosis regulatory genes BCL-2 and BAX are induced immediately following ischemic/reperfusion injury

Authors
Elster, EA; Kampen, RL; Robson, KA; Tadaki, DK; Perdue, P; McCarron, RM; Kirk, AD
MLA Citation
Elster, EA, Kampen, RL, Robson, KA, Tadaki, DK, Perdue, P, McCarron, RM, and Kirk, AD. "Apoptosis regulatory genes BCL-2 and BAX are induced immediately following ischemic/reperfusion injury." Surgical Forum 50 (1999): 383-384. (Academic Article)
Source
manual
Published In
Surgical Forum
Volume
50
Publish Date
1999
Start Page
383
End Page
384

Let’s blame the little guys: platelets as an instigator of allograft rejection

Authors
Kirk, AD
MLA Citation
Kirk, AD. "Let’s blame the little guys: platelets as an instigator of allograft rejection." Graft 2 (1999): 159-160. (Academic Article)
Source
manual
Published In
Graft
Volume
2
Publish Date
1999
Start Page
159
End Page
160

Infant pediatric liver transplantation results equal those for older pediatric patients.

METHODS: From July 1984 to July 1995, 99 pediatric patients underwent 127 orthotopic liver transplants (OLT) at the University of Wisconsin Children's Hospital. The patients were divided into four groups according to age at time of transplant: group I, 0 to 6 months (n = 20); group II, 6 to 12 months (n = 18); group III, 1 to 2 years (n = 10); and group IV, 2 to 18 years (n = 51). A retrospective analysis was performed to compare these four groups with regard to preoperative indications and demographics, intraoperative technique, complications, and survival. All patients were followed up for 2 to 13 years. RESULTS: Biliary atresia was the most common indication for OLT in all four groups. The average waiting period varied from 19+/-18 days for group I to 44+/-64 days for group IV. Reduced-size liver transplant (I, 41%; II, 52%; III, 28%; IV, 21%), split-liver transplant (I, 0%; II, 7.4%; III, 17%; IV, 2.9%), or whole-liver transplant techniques were used. Although postoperative Intensive Care Unit stay was longer for the 0- to 6-month-old patients (I, 20+/-64; II, 7.6+/-9; III, 13+/-17; IV, 6.8+/-14 days), the total hospital stay (I, 43+/-63; II, 33+/-34; III, 32+/-20; IV, 29+/-31 days) was similar for all patients. The incidence of hepatic artery thrombosis (I, 19%; II, 19%; III, 27%; IV, 16%), biliary tract complications (I, 4.8%; II, 15%; III, 20%; IV, 14%), and retransplantation (I, 9.5%; II, 41%; III, 33%; IV, 14%) were not significantly different between the four groups. Portal vein thrombosis (I, 9.5%; II, 11%; III, 6.6; IV, 0%) and primary nonfunction (I, 9.5%; II, 7.4%; III, 0%; IV, 3.1%) occurred more frequently in the 0- to 6-month and 6- to 12-month groups, however, the 1-, 5-, and 10-year survival rate for patients (I, 85%, 79%, 79%; II, 89%, 74%, 74%; III, 80%, 80%, 80%; IV, 84%, 75%, 75%, respectively) and primary liver allografts (I, 69%, 69%, 69%; II, 72%, 72%, 63%; III, 70%, 70%, 70%; IV, 71%, 57%, 57%, respectively) were not significantly different (P = .98 and P = .83). CONCLUSION: These results demonstrate that OLT can be effectively performed on infants of all ages and that OLT should not be delayed because of age.

Authors
Van der Werf, WJ; D'Alessandro, AM; Knechtle, SJ; Pilli, G; Hoffmann, RM; Judd, RH; Odorico, JS; Kirk, AD; Rayhill, SC; Sollinger, HW; Kalayoglu, M
MLA Citation
Van der Werf, WJ, D'Alessandro, AM, Knechtle, SJ, Pilli, G, Hoffmann, RM, Judd, RH, Odorico, JS, Kirk, AD, Rayhill, SC, Sollinger, HW, and Kalayoglu, M. "Infant pediatric liver transplantation results equal those for older pediatric patients." Journal of pediatric surgery 33.1 (January 1998): 20-23.
PMID
9473092
Source
epmc
Published In
Journal of Pediatric Surgery
Volume
33
Issue
1
Publish Date
1998
Start Page
20
End Page
23
DOI
10.1016/s0022-3468(98)90353-0

Anti-CD154 therapy to prevent graft rejection

Authors
Harlan, DM; Kirk, AD
MLA Citation
Harlan, DM, and Kirk, AD. "Anti-CD154 therapy to prevent graft rejection." Graft 1 (1998): 63-63. (Academic Article)
Source
manual
Published In
Graft
Volume
1
Publish Date
1998
Start Page
63
End Page
63

Analysis of primate renal, allografts after T-cell depletion with anti- CD3-CRM9

Background. FN18-CRM9 is a CD3-specific immunotoxin that is capable of depleting CD3+ T cells. Pretreatment of rhesus monkeys with this agent before transplantation can induce donor-specific tolerance and 'split tolerance' to renal allografts. Methods. Heterotopic renal transplants were performed on monkeys that received posttransplant FN18-CRM9. Histological and immunohistological staining, as well as analysis of the intragraft cytokine profile by reverse transcriptase polymerase chain reaction, was performed on percutaneous allograft biopsies. Results. Experimental monkeys had significant prolongation of allograft survival. Although an interstitial, mononuclear cell infiltrate was seen in all of the renal transplants, there was minimal evidence of acute cellular rejection. Histological evidence of alloantibody-mediated damage was detected 3 to 5 months after transplantation in the monkeys treated with FN18-CRM9. Immunohistology demonstrated the reappearance of CD3+ and CD4+ T cells, as well as CD20+ B cells, in the grafts. Cytokine analysis demonstrated expression of interferon-χ. An intact anti-donor IgG response was seen. Conclusion. Treatment of monkeys with FN18- CRM9 immediately after transplantation significantly prolongs renal allograft survival. Allograft biopsies demonstrate a lack of acute cellular rejection; however, alloantibody-mediated graft damage and rejection occur, with an intact anti-donor IgG response. The intragraft expression of the interferon- χ may reflect this ongoing humoral rejection. These data suggest that even a brief period of T-cell allosensitization may lead to humorally mediated allograft damage. Efforts to achieve tolerance with posttransplant FN18-CRM9 will require modification of the protocol to deplete T cells before allosensitization exposure or to supplement the posttransplant immunomodification strategy.

Authors
Armstrong, N; Buckley, P; Oberley, T; Jr, JF; Dong, Y; Hong, X; Kirk, A; Jr, DN; Knechtle, S
MLA Citation
Armstrong, N, Buckley, P, Oberley, T, Jr, JF, Dong, Y, Hong, X, Kirk, A, Jr, DN, and Knechtle, S. "Analysis of primate renal, allografts after T-cell depletion with anti- CD3-CRM9." Transplantation 66.1 (1998): 5-13.
PMID
9679815
Source
scival
Published In
Transplantation
Volume
66
Issue
1
Publish Date
1998
Start Page
5
End Page
13
DOI
10.1097/00007890-199807150-00002

CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates.

Selective inhibition of T cell costimulation using the B7-specific fusion protein CTLA4-Ig has been shown to induce long-term allograft survival in rodents. Antibodies preventing the interaction between CD40 and its T cell-based ligand CD154 (CD40L) have been shown in rodents to act synergistically with CTLA4-Ig. It has thus been hypothesized that these agents might be capable of inducing long-term acceptance of allografted tissues in primates. To test this hypothesis in a relevant preclinical model, CTLA4-Ig and the CD40L-specific monoclonal antibody 5C8 were tested in rhesus monkeys. Both agents effectively inhibited rhesus mixed lymphocyte reactions, but the combination was 100 times more effective than either drug alone. Renal allografts were transplanted into nephectomized rhesus monkeys shown to be disparate at major histocompatibility complex class I and class II loci. Control animals rejected in 5-8 days. Brief induction doses of CTLA4-Ig or 5C8 alone significantly prolonged rejection-free survival (20-98 days). Two of four animals treated with both agents experienced extended (>150 days) rejection-free allograft survival. Two animals treated with 5C8 alone and one animal treated with both 5C8 and CTLA4-Ig experienced late, biopsy-proven rejection, but a repeat course of their induction regimen successfully restored normal graft function. Neither drug affected peripheral T cell or B cell counts. There were no clinically evident side effects or rejections during treatment. We conclude that CTLA4-Ig and 5C8 can both prevent and reverse acute allograft rejection, significantly prolonging the survival of major histocompatibility complex-mismatched renal allografts in primates without the need for chronic immunosuppression.

Authors
Kirk, AD; Harlan, DM; Armstrong, NN; Davis, TA; Dong, Y; Gray, GS; Hong, X; Thomas, D; Fechner, JH; Knechtle, SJ
MLA Citation
Kirk, AD, Harlan, DM, Armstrong, NN, Davis, TA, Dong, Y, Gray, GS, Hong, X, Thomas, D, Fechner, JH, and Knechtle, SJ. "CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates." Proceedings of the National Academy of Sciences of the United States of America 94.16 (August 1997): 8789-8794.
PMID
9238056
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
94
Issue
16
Publish Date
1997
Start Page
8789
End Page
8794
DOI
10.1073/pnas.94.16.8789

A survivor of breast cancer with immunity to MUC-1 mucin, and lactational mastitis

Authors
Jerome, KR; Kirk, AD; Pecher, G; Ferguson, WW; Finn, OJ
MLA Citation
Jerome, KR, Kirk, AD, Pecher, G, Ferguson, WW, and Finn, OJ. "A survivor of breast cancer with immunity to MUC-1 mucin, and lactational mastitis." Cancer Immunology, Immunotherapy 43.6 (February 1997): 355-360.
Source
crossref
Published In
Cancer Immunology, Immunotherapy
Volume
43
Issue
6
Publish Date
1997
Start Page
355
End Page
360
DOI
10.1007/s002620050344

Posttransplant diastolic hypertension: Associations with intragraft transforming growth factor-β, endothelin, and renin transcription

Background. Diastolic hypertension after renal transplantation leads to significant chronic morbidity and mortality. Recently, calcineurin phosphatase inhibition by cyclosporine or tacrolimus has been postulated to lead to diastolic hypertension through the induction of transforming growth factor-β (TGF-β) and resultant endothelin-mediated renal arteriolar vasospasm. Methods. To investigate this hypothesis in humans, the allografts of 40 stable renal allograft recipients were biopsied 2 to 3 years after transplantation. Both cyclosporine and tacrolimus patients were included. Biopsies were divided and processed for histology and RNA extraction. RNA was then converted to cDNA and evaluated by semiquantitative polymerase chain reaction (actin-standardized, high-performance liquid chromatography- quantitated) for TGF-β, endothelin, and renin transcription. Inflammatory cytokine gene transcription was also evaluated. Blood pressure was measured during the clinic check-in before biopsy. Variables were evaluated by Spearman rank correlation coefficient (r(s)) analysis. Results. Diastolic hypertension was prevalent in the study population, with 40% of individuals having diastolic pressure>90 mmHg. TGF-β and endothelin transcription were detected in 88% of biopsies studied, and renin transcription was detected in 91%. Intragraft transcription of TGF-β (r(s)=0.61, P=0.0003) and endothelin (r(s)=0.43, P=0.0188) was strongly correlated with increasing transcription intragraft renin. In turn, renin transcription was strongly correlated with increasing diastolic blood pressure (r(s)=0.55, P=0.0015). Histological correlation of fibrosis score did not predict the degree of hypertension, nor did it correlate with TGF-β transcription. Inflammatory cytokine transcription was not related to renin transcription or diastolic hypertension but was correlated with histological evidence of immune graft injury. Conclusions. These data support the hypothesis that posttransplant diastolic hypertension is a result of TGF-β-induced, endothelin-mediated arteriolar vasoconstriction and subsequent activation of the renin- angiotensin pathway. These effects are independent of immune-mediated graft injury.

Authors
Kirk, AD; Jacobson, LM; Heisey, DM; Fass, NA; Sollinger, HW; Pirsch, JD
MLA Citation
Kirk, AD, Jacobson, LM, Heisey, DM, Fass, NA, Sollinger, HW, and Pirsch, JD. "Posttransplant diastolic hypertension: Associations with intragraft transforming growth factor-β, endothelin, and renin transcription." Transplantation 64.12 (1997): 1716-1720.
Source
scival
Published In
Transplantation
Volume
64
Issue
12
Publish Date
1997
Start Page
1716
End Page
1720
DOI
10.1097/00007890-199712270-00015

Clinical hepatitis after transplantation of hepatitis C virus-positive kidneys: HLA-DR3 as a risk factor for the development of posttransplant hepatitis.

BACKGROUND: Exposure to hepatitis C virus (HCV) and subsequent infection after renal transplantation lead to significant clinical hepatitis in approximately 50% of graft recipients. METHODS: One hundred thirty-two consecutive renal allotransplant patients, who underwent transplantation of kidneys from HCV-positive cadaveric donors, were studied to investigate the relationship between donor and recipient HLA type and the risk of developing clinical hepatitis. Specific attention was directed toward the DR3 and DR4 alleles, as these had previously been associated with worse prognoses in autoimmune and viral hepatitis. RESULTS: Overall, 42% of patients receiving kidneys from donors seropositive for HCV developed clinical hepatitis. This was unrelated to preoperative recipient HCV serum reactivity (P=0.65). Patients receiving kidneys from seropositive donors with HCV RNA as detected by PCR were more likely to develop hepatitis than those receiving kidneys from PCR-negative donors (56% vs. 11%; P=0.005). The presence of the DR3 allele was associated with a significant risk of clinical hepatitis (P=0.025); 80% of DR3-positive recipients (n=34) progressed to hepatitis compared with 42% of DR3-negative patients. No other recipient HLA type was significantly related to prognosis. All patients receiving a donated kidney that expressed the B41 allele developed hepatitis, compared with 55% of recipients of non-B41 grafts (P=0.039). No association between the development of clinical hepatitis and HLA compatibility was found. CONCLUSIONS: These results suggest that both HLA type and viral presence as assayed by polymerase chain reaction, influence the risk of disease progression after transplantation of HCV-positive kidneys. Application of these associations may decrease the relative risk of a recipient contracting HCV hepatitis after cadaveric renal transplantation.

Authors
Kirk, AD; Heisey, DM; D'Alessandro, AM; Knechtle, SJ; Odorico, JS; Rayhill, SC; Sollinger, HW; Pirsch, JD
MLA Citation
Kirk, AD, Heisey, DM, D'Alessandro, AM, Knechtle, SJ, Odorico, JS, Rayhill, SC, Sollinger, HW, and Pirsch, JD. "Clinical hepatitis after transplantation of hepatitis C virus-positive kidneys: HLA-DR3 as a risk factor for the development of posttransplant hepatitis." Transplantation 62.12 (December 1996): 1758-1762.
PMID
8990357
Source
epmc
Published In
Transplantation
Volume
62
Issue
12
Publish Date
1996
Start Page
1758
End Page
1762
DOI
10.1097/00007890-199612270-00011

Phenotype of infiltrating cells in an ex vivo model of human antiporcine hyperacute cardiac xenograft rejection.

Authors
Ibrahim, S; Kirk, AD; Sanfilippo, F
MLA Citation
Ibrahim, S, Kirk, AD, and Sanfilippo, F. "Phenotype of infiltrating cells in an ex vivo model of human antiporcine hyperacute cardiac xenograft rejection." Transplantation proceedings 28.2 (April 1996): 777-.
PMID
8623397
Source
epmc
Published In
Transplantation Proceedings
Volume
28
Issue
2
Publish Date
1996
Start Page
777

Simultaneous pancreas - kidney transplantation: Recent experience at the University of Wisconsin

After a decade of rapid development, simultaneous pancreas - kidney (SPK) transplantation has become routine at the University of Wisconsin (UW). Since developing the concept of direct drainage of pancreas allograft exocrine secretions into the urinary bladder at UW in 1982, we performed 381 SPK transplantations in this technique. Patient and graft survival following SPK transplantation has increased significantly from our early experience to the recent time. The one- and five-year patient survival rates for the entire series of 381 SPK transplantations were 96% and 88%, respectively. The actuarial one- and five-year kidney allograft survival rates in these patients were 87% and 78%. The pancreas allograft survival rates were similar at 86% and 74%. Several changes are responsible for our current high level of success: UW preservation solution, improved surgical technique, advances in immunosuppression, and expeditious diagnosis and treatment of complications.

Authors
Rayhill, SC; Heimes, M; Kirk, AD; Sollinger, HW
MLA Citation
Rayhill, SC, Heimes, M, Kirk, AD, and Sollinger, HW. "Simultaneous pancreas - kidney transplantation: Recent experience at the University of Wisconsin." Experimental and Clinical Endocrinology and Diabetes 104.5 (1996): 353-359.
Source
scival
Published In
Experimental and Clinical Endocrinology & Diabetes
Volume
104
Issue
5
Publish Date
1996
Start Page
353
End Page
359

Rapid, comprehensive analysis of human cytokine mRNA and its application to the study of acute renal allograft rejection.

Cytokine mRNA analysis was performed on human renal allograft needle core biopsies by a PCR-based assay. The assay was specifically developed to be capable of simultaneous analysis of multiple interleukin transcripts (IL-1-IL-12), as well as those of other relevant cytokines, by one person in less than 1 day from cultured cells or directly from tissue samples. It was initially used on preparations containing known amounts of plasmid DNA encoding individual cytokine cDNA sequences, confirming that the sensitivity of this technique was both well defined and comparable for all target sequences tested. Analysis of human PBLs prior to stimulation, after polyclonal stimulation with PHA and after simultaneous treatment with PHA and MP or CyA, was also performed to show a proportional relationship between mRNA levels measured by PCR and protein release measured by ELISA (R2 = 0.86). This correlation was not adversely altered by pharmacologic immunosuppression by MP or CyA. Thus, this method of PCR primer design and usage was appropriate for the clinical study of cytokine mRNA levels during allograft rejection. Direct study of cytokine mRNA in allograft biopsy tissue showed that IL-2 was specifically and significantly (p = 0.006) elevated during ACR when compared to other causes of graft dysfunction. Transcripts from the IFN-gamma and IL-6 genes were also increased in ACR (p = 0.001 and 0.017, respectively), whereas increased IL-8 mRNA was correlated with irreversible loss of graft function (p = 0.02). TNF-alpha, IL-1 beta, and IL-10 gene transcripts were also detected during ACR, but were not quantitatively increased compared to other forms of graft injury (p > 0.2). We conclude that acute cellular rejection is associated with intragraft mRNA from the IL-2 gene. Other transcripts, including those from the IFN-gamma, IL-6, and IL-8 genes, are detected in increased amounts during this process. Messenger RNA from the TNF-alpha, IL-1 beta and IL-10 genes is also detected during ACR, but the presence of these transcripts is not exclusive to this process.

Authors
Kirk, AD; Bollinger, RR; Finn, OJ
MLA Citation
Kirk, AD, Bollinger, RR, and Finn, OJ. "Rapid, comprehensive analysis of human cytokine mRNA and its application to the study of acute renal allograft rejection." Hum Immunol 43.2 (June 1995): 113-128.
PMID
7591871
Source
pubmed
Published In
Human Immunology
Volume
43
Issue
2
Publish Date
1995
Start Page
113
End Page
128

Simultaneous pancreas-kidney transplantation at the University of Wisconsin.

After a decade of rapid development, SPK transplantation has become routine at our center. There are several developments responsible for the current high level of success: UW preservation solution, improved surgical technique, advances in immunosuppression, and expeditious diagnosis and treatment of complications. The critical modifications in surgical technique have included the avoidance of systemic heparinization, complete mobilization of the iliac vein for a tension-free anastomosis between an unmodified donor portal vein and the recipient iliac vein, oversewing of the revised duodenal staple lines and meticulous hemostasis. The most important recent improvement in immunosuppression is the use of mycophenolate mofetil, which has dramatically reduced rejection. Finally, PDC leaks, the principal and potentially most devastating complication of SPK transplantation, are rapidly diagnosed and treated expeditiously.

Authors
Rayhill, SC; Kirk, AD; Odorico, JS; Heisey, DM; Cangro, CB; Pirsch, JD; D'Alessandro, AM; Knechtle, SJ; Sollinger, HW
MLA Citation
Rayhill, SC, Kirk, AD, Odorico, JS, Heisey, DM, Cangro, CB, Pirsch, JD, D'Alessandro, AM, Knechtle, SJ, and Sollinger, HW. "Simultaneous pancreas-kidney transplantation at the University of Wisconsin." Clinical transplants (January 1995): 261-269.
PMID
8794272
Source
epmc
Published In
Clinical transplants
Publish Date
1995
Start Page
261
End Page
269

Brief report: treatment of hepatic failure with ex vivo pig-liver perfusion followed by liver transplantation.

Authors
Chari, RS; Collins, BH; Magee, JC; DiMaio, JM; Kirk, AD; Harland, RC; McCann, RL; Platt, JL; Meyers, WC
MLA Citation
Chari, RS, Collins, BH, Magee, JC, DiMaio, JM, Kirk, AD, Harland, RC, McCann, RL, Platt, JL, and Meyers, WC. "Brief report: treatment of hepatic failure with ex vivo pig-liver perfusion followed by liver transplantation." N Engl J Med 331.4 (July 28, 1994): 234-237.
PMID
8015570
Source
pubmed
Published In
The New England journal of medicine
Volume
331
Issue
4
Publish Date
1994
Start Page
234
End Page
237
DOI
10.1056/NEJM199407283310404

The effect of soluble complement receptor type 1 on hyperacute rejection of porcine xenografts.

The use of xenografts (Xgs) from distantly related species to relieve the increasing shortage of organs for clinical transplantation is prevented by the occurrence of hyperacute rejection (HAR). This process, in which C activation plays a central role, cannot be inhibited with currently available immunosuppressants. In two clinically relevant xenotransplantation models, this study evaluated the effect of C inhibition using recombinant soluble complement receptor type 1 (sCR1) on HAR. In an ex vivo model in which porcine cardiac Xgs were perfused with human blood, cardiac function ceased within 34 min when the perfusate blood was untreated (n = 3). When the perfusate blood was treated with sCR1 (300 micrograms/ml), cardiac Xg function was maintained for up to 4 hr (n = 3). Immunohistologic examination of these Xgs demonstrated deposition of C3b/iC3b and C3d in Xgs perfused with untreated human blood but only C3d deposition in those Xgs perfused with sCR1-treated human blood. These findings are consistent with the cofactor activity of sCR1 for factor I-mediated degradation of deposited C3b/iC3b to C3d. Treatment with sCR1 also prevented the histopathologic changes of HAR observed when untreated blood was used as the perfusate. In an in vivo pig-to-primate heterotopic cardiac xenotransplantation model, in which porcine Xgs transplanted into untreated cynomolgus monkey recipients underwent HAR in 1 hr or less (n = 3), a single intravenous bolus of sCR1 (15 mg/kg) administered to the recipient immediately before Xg reperfusion markedly inhibited total and alternative pathway serum C activity and prolonged Xg survival to between 48 and 90 hr (n = 5). These studies confirm the important role of C activation in HAR of porcine cardiac Xgs by primates and indicate that sCR1 may be a useful agent for xenotransplantation.

Authors
Pruitt, SK; Kirk, AD; Bollinger, RR; Marsh, HC; Collins, BH; Levin, JL; Mault, JR; Heinle, JS; Ibrahim, S; Rudolph, AR
MLA Citation
Pruitt, SK, Kirk, AD, Bollinger, RR, Marsh, HC, Collins, BH, Levin, JL, Mault, JR, Heinle, JS, Ibrahim, S, and Rudolph, AR. "The effect of soluble complement receptor type 1 on hyperacute rejection of porcine xenografts." Transplantation 57.3 (February 1994): 363-370.
PMID
8108871
Source
pubmed
Published In
Transplantation
Volume
57
Issue
3
Publish Date
1994
Start Page
363
End Page
370

Ex vivo characterization of human anti-porcine hyperacute cardiac rejection.

Hyperacute rejection (HAR) currently precludes the use of discordant organs for human transplantation. In order to comprehensively evaluate HAR in a clinically applicable species combination, we have developed an ex vivo perfusion model utilizing a neonatal extracorporeal membrane oxygenator circuit; this model allows for functional and sequential biopsy studies of working piglet hearts sustained by human, single donor AB+ type blood. A detailed description of the methods employed is included. Hearts perfused by allogeneic pig blood sustained normal function throughout the study period, while those perfused with human blood lost organized ventricular contraction in 25-34 min with markedly attenuated function. Compared with biopsies from piglet hearts perfused with allogeneic blood and biopsies taken prior to human blood perfusion (t = 0), biopsies of hearts perfused with human blood at t = 15 and 30 min demonstrated significant inflammatory changes involving vessels (endothelial and myointimal swelling and reaction) as well as myocardium (injury and necrosis). By immunohistology, significant vascular deposition of IgM, IgG, fibrinogen, C3, and C1q was seen, along with infiltrates of human leukocytes consisting predominantly of neutrophils, macrophages, and T cells, with occasional B cells and NK cells. Sequential studies of circulating blood demonstrated the progressive consumption of human leukocytes and human anti-porcine antibodies, but no decrease in complement activity as measured by CH50. These findings indicate that the rapid loss of function seen in human anti-porcine cardiac HAR is associated with deposition of IgM and IgG xenoreactive antibody and early complement components and that extensive infiltration by inflammatory cells occurs within 15-30 min. This model provides a useful system for the study of human anti-porcine HAR.

Authors
Kirk, AD; Heinle, JS; Mault, JR; Sanfilippo, F
MLA Citation
Kirk, AD, Heinle, JS, Mault, JR, and Sanfilippo, F. "Ex vivo characterization of human anti-porcine hyperacute cardiac rejection." Transplantation 56.4 (October 1993): 785-793.
PMID
8212196
Source
epmc
Published In
Transplantation
Volume
56
Issue
4
Publish Date
1993
Start Page
785
End Page
793

Characterization of human anti-porcine "natural antibodies" recovered from ex vivo perfused hearts--predominance of IgM and IgG2.

Hyperacute rejection is a major obstacle to successful transplantation of vascularized xenogeneic organs and is believed to be mediated at least in part by performed xenoreactive "natural antibodies" (NAb). In this study, human NAb that could be involved in hyperacute rejection of pig heart xenografts were identified and characterized using an ex vivo model in which pig hearts were perfused with whole blood from individual human or pig donors. This ex vivo perfusion model allows for the continuous monitoring of physiologic parameters of cardiac function as well as sequential sampling of tissue and blood. Pig hearts perfused with allogeneic pig blood maintained normal function for at least 4 hr, whereas those perfused with xenogeneic AB+ human blood never achieved normal function and rejected completely after 30 min. In three separate experiments involving different human blood donors and pig hearts, sequential samples of perfused blood revealed a progressive depletion of anti-porcine NAb. Samples of all three rejected cardiac xenografts were homogenized, and the specifically bound human anti-porcine antibodies were eluted with citric acid. The eluted antibodies were enriched approximately 50-120-fold for anti-porcine reactivity compared with serum from the corresponding donor. Eluates contained NAb of predominantly IgM and IgG2 isotypes. Immunofluorescence histology confirmed the deposition of IgM and IgG2 but not other IgG subclasses in the rejected pig hearts. Since IgG2 utilized predominantly in response to bacterial polysaccharide antigens, our findings are consistent with the possibility that some NAb arise via crossreactivity with microbial antigens and are predominantly directed against carbohydrate rather than protein antigens.

Authors
Ross, JR; Kirk, AD; Ibrahim, SE; Howell, DN; Baldwin, WM; Sanfilippo, FP
MLA Citation
Ross, JR, Kirk, AD, Ibrahim, SE, Howell, DN, Baldwin, WM, and Sanfilippo, FP. "Characterization of human anti-porcine "natural antibodies" recovered from ex vivo perfused hearts--predominance of IgM and IgG2." Transplantation 55.5 (May 1993): 1144-1150.
PMID
8497896
Source
pubmed
Published In
Transplantation
Volume
55
Issue
5
Publish Date
1993
Start Page
1144
End Page
1150

The human antiporcine cellular repertoire. In vitro studies of acquired and innate cellular responsiveness.

Discordant xenogeneic transplantation offers a potentially unlimited source of donor organs from easily bred, nonendangered, physiologically compatible animals, but has been limited by the inevitable occurrence of hyperacute rejection (HAR). The potential existence of cell-mediated discordant graft rejection has remained obscured by HAR, and hence is incompletely understood. To define the cellular elements capable of recognition of and subsequent response against discordant tissue in a clinically applicable species combination, we have studied the in vitro interaction of human peripheral blood lymphocytes against 3 porcine B lymphoblastoid cell lines and 6 primary porcine endothelial cell populations. PBL from all individuals tested (n = 10) proliferated in response to culture for 72 hr in xenogeneic mixed lymphocyte culture (XMLC) with cell lines expressing porcine MHC (SLA) class II antigens, while endothelial cultures lacking SLA class II generally failed to evoke a response. The proliferative response to class II-positive cells was attenuated by addition of anti-SLA class II antibody but not by anti-SLA class I antibody. Two endothelial populations expressing class II stimulated an inhibitable proliferative response. The magnitude of the short-term proliferative xenogeneic response was similar to that evoked by fully mismatched allogeneic human B lymphoblastoid stimulators. Additionally, extended XMLC was performed with PBL from 3 individuals. All populations responded with continued proliferation when repeatedly stimulated by porcine cells. This was characterized not only by T cell growth, but by prominent NK cell growth as well. Elucidation of the TCR V beta chain usage patterns by semiquantitative PCR documented selection of TCR transcripts from gene family V beta 2 in each group, complemented by a heterogeneous mixture of other transcripts including V beta 17.1, 20.1, and 6.1, suggesting that direct human TCR binding of porcine cells occurs, and that it is likely to be an individualistic response complemented by a more homogeneous NK response. A 51Cr release assay was utilized to demonstrate that unprimed PBL could also lyse porcine target cells. This cytotoxic response was maintained despite the complete removal of T cells, suggesting that porcine-directed NK cell activity is present prior to the maturation of any T cell response. Cytolysis was also demonstrated in serum-free medium and thus was not mediated solely by antibody-dependent cellular cytotoxicity. Chinese hamster ovary cells transfected with the human T cell receptor accessory molecule CD4 were used to study the ability of this molecule to stabilize the interaction between the human TCR and SLA class II.(ABSTRACT TRUNCATED AT 400 WORDS)

Authors
Kirk, AD; Li, RA; Kinch, MS; Abernethy, KA; Doyle, C; Bollinger, RR
MLA Citation
Kirk, AD, Li, RA, Kinch, MS, Abernethy, KA, Doyle, C, and Bollinger, RR. "The human antiporcine cellular repertoire. In vitro studies of acquired and innate cellular responsiveness." Transplantation 55.4 (April 1993): 924-931.
PMID
8475569
Source
pubmed
Published In
Transplantation
Volume
55
Issue
4
Publish Date
1993
Start Page
924
End Page
931

Human antiporcine mixed lymphocyte reaction.

Authors
Li, RA; Kirk, AD; Abernathy, KA; Bollinger, RR
MLA Citation
Li, RA, Kirk, AD, Abernathy, KA, and Bollinger, RR. "Human antiporcine mixed lymphocyte reaction." Transplant Proc 25.1 Pt 1 (February 1993): 442-443.
PMID
8438370
Source
pubmed
Published In
Transplantation Proceedings
Volume
25
Issue
1 Pt 1
Publish Date
1993
Start Page
442
End Page
443

Characterization of T cells expressing the gamma/delta antigen receptor in human renal allografts.

To investigate the role of gamma/delta+ T cells in allograft rejection, we have studied the TCR phenotype and function of lymphocytes infiltrating rejecting, rejected, and nonrejecting human renal allografts. Two-color immunohistologic staining showed that 19% of rejecting biopsies and 40% of rejected nephrectomies had significant infiltration (> 10% of the total T-cell population) with gamma/delta+ T cells. No biopsies from nonrejecting kidneys showed > 10% gamma/delta+ T cells. Flow-cytometry analysis of T-cell populations expanded from rejecting and rejected allografts demonstrated that 33% of biopsy- and 40% of nephrectomy-derived populations had significant percentages (> 10%) of gamma/delta+ T cells. Six cell lines with increased numbers of gamma/delta+ T cells were tested for cytolytic activity against the NK target cell line K562 and compared with cytotoxic activity of exclusively alpha/beta T-cell populations. Lysis was noted by all gamma/delta+, but no gamma/delta-, populations. To confirm that the cytotoxicity of these gamma/delta+ T-cell populations was not MHC directed, one nephrectomy-derived population with 69% gamma/delta+ T cells by cytometry and > 50% by immunohistology was studied extensively. High levels of killing were seen against the NK targets K562 and Daudi as well as other malignant, benign, and third-party renal cell lines, but relevant alloantigen-expressing targets were not killed. Sterile cell sorting was used to isolate the gamma/delta+ T cells. The gamma/delta+ cells displayed enhanced killing of K562 while the gamma/delta- cells showed no cytolytic activity. Cytotoxicity mediated by gamma/delta+ T cells was also demonstrated against donor-derived, untransformed renal cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Kirk, AD; Ibrahim, S; Dawson, DV; Sanfilippo, F; Finn, OJ
MLA Citation
Kirk, AD, Ibrahim, S, Dawson, DV, Sanfilippo, F, and Finn, OJ. "Characterization of T cells expressing the gamma/delta antigen receptor in human renal allografts." Human immunology 36.1 (January 1993): 11-19.
PMID
8458734
Source
epmc
Published In
Human Immunology
Volume
36
Issue
1
Publish Date
1993
Start Page
11
End Page
19
DOI
10.1016/0198-8859(93)90003-j

Variables affecting the T cell receptor V beta repertoire heterogeneity of T cells infiltrating human renal allografts.

Donor-specific, alloreactive T cell lines may be grown from cells infiltrating human renal allografts. These T cell lines utilize restricted T cell receptor (TCR) beta-chain variable (V beta) gene repertoires, although long-term culture appears to be necessary for restriction to be observed. This study was undertaken to determine the effects of potential selective pressures on the TCR repertoires of allograft-infiltrating cells. TCR V beta repertoires of 30 allograft-derived T cell populations, cultured for defined, short time periods, were examined using polymerase chain reaction. When first derived, V beta repertoires of graft-infiltrating T cells were as heterogeneous as those of peripheral blood lymphocytes (PBL). There was no relationship between the length of time an allograft was in situ or the extent of HLA mismatch and repertoire heterogeneity. Repertoire restriction was positively correlated with the length of time cells were cultured in vitro. Long-term, alloreactive mixed lymphocyte reactions (MLR), established from normal, unsensitized PBL, also demonstrated V beta repertoire restriction during expansion in vitro. Restricted alloreactive populations emerged much more slowly from the MLR than from the allograft-derived cultures, however, implying that graft infiltrates contain previously activated populations of T cells. This observation, taken together with the fact that long-term, graft-derived cell lines maintain donor specificity, suggests that functional subsets must be allowed to emerge from heterogeneous infiltrates before TCR repertoire may be correlated with alloreactivity and/or graft rejection.

Authors
Hall, BL; Hand, SL; Alter, MD; Kirk, AD; Finn, OJ
MLA Citation
Hall, BL, Hand, SL, Alter, MD, Kirk, AD, and Finn, OJ. "Variables affecting the T cell receptor V beta repertoire heterogeneity of T cells infiltrating human renal allografts." Transplant immunology 1.3 (January 1993): 217-227.
PMID
8081778
Source
epmc
Published In
Transplant Immunology
Volume
1
Issue
3
Publish Date
1993
Start Page
217
End Page
227
DOI
10.1016/0966-3274(93)90050-i

In vitro analysis of the human antiporcine T-cell repertoire.

Authors
Kirk, AD; Hall, BL; Finn, OJ; Bollinger, RR
MLA Citation
Kirk, AD, Hall, BL, Finn, OJ, and Bollinger, RR. "In vitro analysis of the human antiporcine T-cell repertoire." Transplant Proc 24.2 (April 1992): 602-603.
PMID
1533074
Source
pubmed
Published In
Transplantation Proceedings
Volume
24
Issue
2
Publish Date
1992
Start Page
602
End Page
603

Renal allograft-infiltrating lymphocytes. A prospective analysis of in vitro growth characteristics and clinical relevance.

One-hundred consecutive human renal allograft Tru-cut needle biopsies were studied for in vitro proliferation of T lymphocytes under restrictive culture conditions containing low-dose recombinant interleukin 2. Each biopsy was entered into a blinded code and evaluated prospectively for visual evidence of growth at 24 hr and for sustained growth. Those T cell populations exhibiting sustained growth were then evaluated for cell surface phenotype by FACS; for allospecific cytotoxicity by 51Cr release; for a proliferative response to alloantigen by incorporation of [3H]-thymidine; and for secretion of IL-2, IL-4, IFN-gamma, and TNF-alpha in response to alloantigenic stimulation by ELISA. All results were compared with clinical diagnosis, immunosuppression at time of biopsy, diagnosis and phenotype by immunopathology, short-term outcome and long-term graft survival. Growth at 24 hr was predictive of acute cellular rejection (P less than 0.0005), unrelated to chronic rejection (P = 0.663) or maintenance immunosuppression (P = 0.911), and inversely correlated with cyclosporine toxicity (P = 0.051) and treatment with OKT3 (P = 0.014). The CD4/CD8 ratio of the sustained T cell populations was unrelated to that seen on histological examination (correlation coefficient = -0.098 and 0.044 for diffuse and aggregate infiltrates, respectively). Cytotoxic specificity for HLA class II was mediated by CD4+ cells and for HLA class I by CD8+ cells. Enhanced secretion of IL-2 in response to alloantigen distinguished those cells associated with irreversible allograft damage from those associated with complete functional recovery (P = 0.01). This study demonstrates that early evaluation of T cell proliferation in vitro identifies activated T cell infiltrates mediating acute cellular allograft rejection in a time frame suitable for clinical diagnostic application. It strengthens the concept that donor-specific cytotoxicity is governed by the stabilization of the alloantigen-T-cell receptor interaction by the accessory molecules CD4 and CD8, but either interaction is equally able to participate in an episode of acute rejection. Irreversible graft injury is associated with infiltrating cells that are capable of amplifying their responsiveness through secretion of IL-2.

Authors
Kirk, AD; Ibrahim, MA; Bollinger, RR; Dawson, DV; Finn, OJ
MLA Citation
Kirk, AD, Ibrahim, MA, Bollinger, RR, Dawson, DV, and Finn, OJ. "Renal allograft-infiltrating lymphocytes. A prospective analysis of in vitro growth characteristics and clinical relevance." Transplantation 53.2 (February 1992): 329-338.
PMID
1371194
Source
pubmed
Published In
Transplantation
Volume
53
Issue
2
Publish Date
1992
Start Page
329
End Page
338

T cells expressing the antigen receptor mediate non-MHC directed human renal allograft cytotoxicity

Authors
Kirk, AD; Finn, OJ
MLA Citation
Kirk, AD, and Finn, OJ. "T cells expressing the antigen receptor mediate non-MHC directed human renal allograft cytotoxicity." Surgical Forum 52 (1991): 384-386. (Academic Article)
Source
manual
Published In
Surgical Forum
Volume
52
Publish Date
1991
Start Page
384
End Page
386

Toothbrush swallowing.

We encountered four cases of toothbrush swallowing and reviewed the literature on this subject. A total of 31 toothbrushes within the gastrointestinal tract have been reported. None have passed spontaneously. Several have caused significant complications related to pressure necrosis, including gastritis, mucosal tears, and perforation. The recommended treatment is endoscopic retrieval and postoperative monitoring for 24 hours in case of esophageal or gastric injury.

Authors
Kirk, AD; Bowers, BA; Moylan, JA; Meyers, WC
MLA Citation
Kirk, AD, Bowers, BA, Moylan, JA, and Meyers, WC. "Toothbrush swallowing." Archives of surgery (Chicago, Ill. : 1960) 123.3 (March 1988): 382-384. (Review)
PMID
3277591
Source
epmc
Published In
Archives of Surgery
Volume
123
Issue
3
Publish Date
1988
Start Page
382
End Page
384
DOI
10.1001/archsurg.1988.01400270122020

The appearance of major histocompatibilit y complex class II antigens in rat small bowel allograft-induced graft-versus-host disease

Authors
Weiss, EA; Kirk, AD; Wolfe, JA
MLA Citation
Weiss, EA, Kirk, AD, and Wolfe, JA. "The appearance of major histocompatibilit y complex class II antigens in rat small bowel allograft-induced graft-versus-host disease." Transplantation Proceedings 19.3 (January 1, 1987): 3019-3021.
Source
scopus
Published In
Transplantation Proceedings
Volume
19
Issue
3
Publish Date
1987
Start Page
3019
End Page
3021
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