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Chen, Jun

Positions:

Associate Professor of Medicine

Medicine, Cellular Therapy
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1991

M.D. — Sun Yat Sen University (China)

Publications:

Uncommon structural motifs dominate the antigen binding site in human autoantibodies reactive with basement membrane collagen.

Autoantibodies mediate organ destruction in multiple autoimmune diseases, yet their origins in patients remain poorly understood. To probe the genetic origins and structure of disease-associated autoantibodies, we engrafted immunodeficient mice with human CD34+ hematopoietic stem cells and immunized with the non-collagenous-1 (NC1) domain of the alpha3 chain of type IV collagen. This antigen is expressed in lungs and kidneys and is targeted by autoantibodies in anti-glomerular basement membrane (GBM) nephritis and Goodpasture syndrome (GPS), prototypic human organ-specific autoimmune diseases. Using Epstein Barr virus transformation and cell fusion, six human anti-alpha3(IV)NC1 collagen monoclonal autoantibodies (mAb) were recovered, including subsets reactive with human kidney and with epitopes recognized by patients' IgG. Sequence analysis reveals a long to exceptionally long heavy chain complementarity determining region3 (HCDR3), the major site of antigen binding, in all six mAb. Mean HCDR3 length is 25.5 amino acids (range 20-36), generated from inherently long DH and JH genes and extended regions of non-templated N-nucleotides. Long HCDR3 are suited to forming noncontiguous antigen contacts and to binding recessed, immunologically silent epitopes hidden from conventional antibodies, as seen with self-antigen crossreactive broadly neutralizing anti-HIV Ig (bnAb). The anti-alpha3(IV)NC1 collagen mAb also show preferential use of unmutated variable region genes that are enriched among human chronic lymphocytic leukemia antibodies that share features with natural polyreactive Ig. Our findings suggest unexpected relationships between pathogenic anti-collagen Ig, bnAb, and autoreactive Ig associated with malignancy, all of which arise from B cells expressing unconventional structural elements that may require transient escape from tolerance for successful expansion.

Authors
Foster, MH; Buckley, ES; Chen, BJ; Hwang, K-K; Clark, AG
MLA Citation
Foster, MH, Buckley, ES, Chen, BJ, Hwang, K-K, and Clark, AG. "Uncommon structural motifs dominate the antigen binding site in human autoantibodies reactive with basement membrane collagen." Molecular immunology 76 (August 2016): 123-133.
PMID
27450516
Source
epmc
Published In
Molecular Immunology
Volume
76
Publish Date
2016
Start Page
123
End Page
133
DOI
10.1016/j.molimm.2016.07.004

Differential Requirements of TCR Signaling in Homeostatic Maintenance and Function of Dendritic Epidermal T Cells.

Dendritic epidermal T cells (DETCs) are generated exclusively in the fetal thymus and maintained in the skin epithelium throughout postnatal life of the mouse. DETCs have restricted antigenic specificity as a result of their exclusive usage of a canonical TCR. Although the importance of the TCR in DETC development has been well established, the exact role of TCR signaling in DETC homeostasis and function remains incompletely defined. In this study, we investigated TCR signaling in fully matured DETCs by lineage-restricted deletion of the Lat gene, an essential signaling molecule downstream of the TCR. We found that Lat deletion impaired TCR-dependent cytokine gene activation and the ability of DETCs to undergo proliferative expansion. However, linker for activation of T cells-deficient DETCs were able to maintain long-term population homeostasis, although with a reduced proliferation rate. Mice with Lat deletion in DETCs exhibited delayed wound healing accompanied by impaired clonal expansion within the wound area. Our study revealed differential requirements for TCR signaling in homeostatic maintenance of DETCs and in their effector function during wound healing.

Authors
Zhang, B; Wu, J; Jiao, Y; Bock, C; Dai, M; Chen, B; Chao, N; Zhang, W; Zhuang, Y
MLA Citation
Zhang, B, Wu, J, Jiao, Y, Bock, C, Dai, M, Chen, B, Chao, N, Zhang, W, and Zhuang, Y. "Differential Requirements of TCR Signaling in Homeostatic Maintenance and Function of Dendritic Epidermal T Cells." Journal of immunology (Baltimore, Md. : 1950) 195.9 (November 2015): 4282-4291.
PMID
26408667
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
195
Issue
9
Publish Date
2015
Start Page
4282
End Page
4291
DOI
10.4049/jimmunol.1501220

Recovery of a human natural antibody against the noncollagenous-1 domain of type IV collagen using humanized models.

Anti-glomerular basement membrane nephritis and Goodpasture syndrome result from autoantibody (Ab)-mediated destruction of kidney and lung. Ab target the noncollagenous 1 (NC1) domain of alpha3(IV) collagen, but little is known about Ab origins or structure. This ignorance is due in part to the inability to recover monoclonal Ab by transformation of patients' blood cells. The aim of this study was to assess the suitability of two humanized models for this purpose.NOD-scid-gamma immunodeficient mice were engrafted either with human CD34+ hematopoietic stem cells (HSC) (Hu-HSC mice) and immunized with alpha3(IV)NC1 collagen containing the Goodpasture epitopes or with nephritis patients' peripheral blood leukocytes (PBL) (Hu-PBL mice). After in vivo immune cell development and/or expansion, recovered human B cells were Epstein Barr virus (EBV)-transformed, screened for antigen (Ag) binding, electrofused with a mouse-human heterohybridoma, subcloned, and human Ab RNA sequenced by PCR after reverse transcription to cDNA. Flow cytometry was used to assess human B cell markers and differentiation in Hu-PBL mice.Sequence analysis of a human Ab derived from an immunized Hu-HSC mouse and reactive with alpha3(IV)NC1 collagen reveals that it is encoded by unmutated heavy and light chain genes. The heavy chain complementarity determining region 3, a major determinant of Ag binding, contains uncommon motifs, including an N-region somatically-introduced highly hydrophobic tetrapeptide and dual cysteines encoded by a uniquely human IGHD2-2 Ab gene segment that lacks a murine counterpart. Comparison of human and mouse autoantibodies suggests that structurally similar murine Ab may arise by convergent selection. In contrast to the Hu-HSC model, transformed human B cells are rarely recovered from Hu-PBL mice, in which human B cells terminally differentiate and lose expression of EBV receptor CD21, thus precluding their transformation and recovery.Hu-HSC mice reveal that potentially pathogenic B cells bearing unmutated Ig receptors reactive with the NC1 domain on alpha3(IV) collagen can be generated in, and not purged from, the human preimmune repertoire. Uniquely human gene elements are recruited to generate the antigen binding site in at least a subset of these autoantibodies, indicating that humanized models may provide insights inaccessible using conventional mouse models.

Authors
Worni-Schudel, IM; Clark, AG; Chien, T; Hwang, K-K; Chen, BJ; Foster, MH
MLA Citation
Worni-Schudel, IM, Clark, AG, Chien, T, Hwang, K-K, Chen, BJ, and Foster, MH. "Recovery of a human natural antibody against the noncollagenous-1 domain of type IV collagen using humanized models." Journal of translational medicine 13 (June 6, 2015): 185-.
PMID
26048777
Source
epmc
Published In
Journal of Translational Medicine
Volume
13
Publish Date
2015
Start Page
185
DOI
10.1186/s12967-015-0539-4

The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function.

CD4 T cell activation leads to proliferation and differentiation into effector (Teff) or regulatory (Treg) cells that mediate or control immunity. While each subset prefers distinct glycolytic or oxidative metabolic programs in vitro, requirements and mechanisms that control T cell glucose uptake and metabolism in vivo are uncertain. Despite expression of multiple glucose transporters, Glut1 deficiency selectively impaired metabolism and function of thymocytes and Teff. Resting T cells were normal until activated, when Glut1 deficiency prevented increased glucose uptake and glycolysis, growth, proliferation, and decreased Teff survival and differentiation. Importantly, Glut1 deficiency decreased Teff expansion and the ability to induce inflammatory disease in vivo. Treg cells, in contrast, were enriched in vivo and appeared functionally unaffected and able to suppress Teff, irrespective of Glut1 expression. These data show a selective in vivo requirement for Glut1 in metabolic reprogramming of CD4 T cell activation and Teff expansion and survival.

Authors
Macintyre, AN; Gerriets, VA; Nichols, AG; Michalek, RD; Rudolph, MC; Deoliveira, D; Anderson, SM; Abel, ED; Chen, BJ; Hale, LP; Rathmell, JC
MLA Citation
Macintyre, AN, Gerriets, VA, Nichols, AG, Michalek, RD, Rudolph, MC, Deoliveira, D, Anderson, SM, Abel, ED, Chen, BJ, Hale, LP, and Rathmell, JC. "The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function." Cell metabolism 20.1 (July 2014): 61-72.
PMID
24930970
Source
epmc
Published In
Cell Metabolism
Volume
20
Issue
1
Publish Date
2014
Start Page
61
End Page
72
DOI
10.1016/j.cmet.2014.05.004

Toward an organ based dose prescription method for the improved accuracy of murine dose in orthovoltage x-ray irradiators.

Accurate dosimetry is essential when irradiating mice to ensure that functional and molecular endpoints are well understood for the radiation dose delivered. Conventional methods of prescribing dose in mice involve the use of a single dose rate measurement and assume a uniform average dose throughout all organs of the entire mouse. Here, the authors report the individual average organ dose values for the irradiation of a 12, 23, and 33 g mouse on a 320 kVp x-ray irradiator and calculate the resulting error from using conventional dose prescription methods.Organ doses were simulated in the Geant4 application for tomographic emission toolkit using the MOBY mouse whole-body phantom. Dosimetry was performed for three beams utilizing filters A (1.65 mm Al), B (2.0 mm Al), and C (0.1 mm Cu + 2.5 mm Al), respectively. In addition, simulated x-ray spectra were validated with physical half-value layer measurements.Average doses in soft-tissue organs were found to vary by as much as 23%-32% depending on the filter. Compared to filters A and B, filter C provided the hardest beam and had the lowest variation in soft-tissue average organ doses across all mouse sizes, with a difference of 23% for the median mouse size of 23 g.This work suggests a new dose prescription method in small animal dosimetry: it presents a departure from the conventional approach of assigninga single dose value for irradiation of mice to a more comprehensive approach of characterizing individual organ doses to minimize the error and uncertainty. In human radiation therapy, clinical treatment planning establishes the target dose as well as the dose distribution, however, this has generally not been done in small animal research. These results suggest that organ dose errors will be minimized by calibrating the dose rates for all filters, and using different dose rates for different organs.

Authors
Belley, MD; Wang, C; Nguyen, G; Gunasingha, R; Chao, NJ; Chen, BJ; Dewhirst, MW; Yoshizumi, TT
MLA Citation
Belley, MD, Wang, C, Nguyen, G, Gunasingha, R, Chao, NJ, Chen, BJ, Dewhirst, MW, and Yoshizumi, TT. "Toward an organ based dose prescription method for the improved accuracy of murine dose in orthovoltage x-ray irradiators." Medical physics 41.3 (March 2014): 034101-.
PMID
24593746
Source
epmc
Published In
Medical physics
Volume
41
Issue
3
Publish Date
2014
Start Page
034101
DOI
10.1118/1.4864237

The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function

CD4 T cell activation leads to proliferation and differentiation into effector (Teff) or regulatory (Treg) cells that mediate or control immunity. While each subset prefers distinct glycolytic or oxidative metabolic programs in vitro, requirements and mechanisms that control T cell glucose uptake and metabolism in vivo are uncertain. Despite expression of multiple glucose transporters, Glut1 deficiency selectively impaired metabolism and function of thymocytes and Teff. Resting T cells were normal until activated, when Glut1 deficiency prevented increased glucose uptake and glycolysis, growth, proliferation, and decreased Teff survival and differentiation. Importantly, Glut1 deficiency decreased Teff expansion and the ability to induce inflammatory disease in vivo. Treg cells, in contrast, were enriched in vivo and appeared functionally unaffected and able to suppress Teff, irrespective of Glut1 expression. These data show a selective in vivo requirement for Glut1 in metabolic reprogramming of CD4 T cell activation and Teff expansion and survival. © 2014 Elsevier Inc.

Authors
Macintyre, AN; Gerriets, VA; Nichols, AG; Michalek, RD; Rudolph, MC; Deoliveira, D; Anderson, SM; Abel, ED; Chen, BJ; Hale, LP; Rathmell, JC
MLA Citation
Macintyre, AN, Gerriets, VA, Nichols, AG, Michalek, RD, Rudolph, MC, Deoliveira, D, Anderson, SM, Abel, ED, Chen, BJ, Hale, LP, and Rathmell, JC. "The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function." Cell Metabolism 20.1 (2014): 61-72.
Source
scival
Published In
Cell Metabolism
Volume
20
Issue
1
Publish Date
2014
Start Page
61
End Page
72
DOI
10.1016/j.cmet.2014.05.004

Insulin-like growth factor 1 mitigates hematopoietic toxicity after lethal total body irradiation.

To investigate whether and how insulin-like growth factor 1 (IGF-1) mitigates hematopoietic toxicity after total body irradiation.BALB/c mice were irradiated with a lethal dose of radiation (7.5 Gy) and treated with IGF-1 at a dose of 100 μg/dose intravenously once a day for 5 consecutive days starting within 1 hour after exposure. Survival and hematopoietic recovery were monitored. The mechanisms by which IGF-1 promotes hematopoietic recovery were also studied by use of an in vitro culture system.IGF-1 protected 8 of 20 mice (40%) from lethal irradiation, whereas only 2 of 20 mice (10%) in the saline control group survived for more than 100 days after irradiation. A single dose of IGF-1 (500 μg) was as effective as daily dosing for 5 days. Positive effects were noted even when the initiation of treatment was delayed as long as 6 hours after irradiation. In comparison with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red blood cells in peripheral blood, total cell numbers, hematopoietic stem cells, and progenitor cells in the bone marrow when measured at day 14 after irradiation. IGF-1 protected both hematopoietic stem cells and progenitor cells from radiation-induced apoptosis and cell death. In addition, IGF-1 was able to facilitate the proliferation and differentiation of nonirradiated and irradiated hematopoietic progenitor cells.IGF-1 mitigates radiation-induced hematopoietic toxicity through protecting hematopoietic stem cells and progenitor cells from apoptosis and enhancing proliferation and differentiation of the surviving hematopoietic progenitor cells.

Authors
Zhou, D; Deoliveira, D; Kang, Y; Choi, SS; Li, Z; Chao, NJ; Chen, BJ
MLA Citation
Zhou, D, Deoliveira, D, Kang, Y, Choi, SS, Li, Z, Chao, NJ, and Chen, BJ. "Insulin-like growth factor 1 mitigates hematopoietic toxicity after lethal total body irradiation." International journal of radiation oncology, biology, physics 85.4 (March 2013): 1141-1148.
PMID
23021438
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
85
Issue
4
Publish Date
2013
Start Page
1141
End Page
1148
DOI
10.1016/j.ijrobp.2012.08.014

Long-term in vivo imaging of multiple organs at the single cell level.

Two-photon microscopy has enabled the study of individual cell behavior in live animals. Many organs and tissues cannot be studied, especially longitudinally, because they are located too deep, behind bony structures or too close to the lung and heart. Here we report a novel mouse model that allows long-term single cell imaging of many organs. A wide variety of live tissues were successfully engrafted in the pinna of the mouse ear. Many of these engrafted tissues maintained the normal tissue histology. Using the heart and thymus as models, we further demonstrated that the engrafted tissues functioned as would be expected. Combining two-photon microscopy with fluorescent tracers, we successfully visualized the engrafted tissues at the single cell level in live mice over several months. Four dimensional (three-dimensional (3D) plus time) information of individual cells was obtained from this imaging. This model makes long-term high resolution 4D imaging of multiple organs possible.

Authors
Chen, BJ; Jiao, Y; Zhang, P; Sun, AY; Pitt, GS; Deoliveira, D; Drago, N; Ye, T; Liu, C; Chao, NJ
MLA Citation
Chen, BJ, Jiao, Y, Zhang, P, Sun, AY, Pitt, GS, Deoliveira, D, Drago, N, Ye, T, Liu, C, and Chao, NJ. "Long-term in vivo imaging of multiple organs at the single cell level." PLoS One 8.1 (2013): e52087-.
PMID
23300962
Source
pubmed
Published In
PloS one
Volume
8
Issue
1
Publish Date
2013
Start Page
e52087
DOI
10.1371/journal.pone.0052087

Insulin-like growth factor 1 mitigates hematopoietic toxicity after lethal total body irradiation

Purpose: To investigate whether and how insulin-like growth factor 1 (IGF-1) mitigates hematopoietic toxicity after total body irradiation. Methods and Materials: BALB/c mice were irradiated with a lethal dose of radiation (7.5 Gy) and treated with IGF-1 at a dose of 100 μg/dose intravenously once a day for 5 consecutive days starting within 1 hour after exposure. Survival and hematopoietic recovery were monitored. The mechanisms by which IGF-1 promotes hematopoietic recovery were also studied by use of an in vitro culture system. Results: IGF-1 protected 8 of 20 mice (40%) from lethal irradiation, whereas only 2 of 20 mice (10%) in the saline control group survived for more than 100 days after irradiation. A single dose of IGF-1 (500 μg) was as effective as daily dosing for 5 days. Positive effects were noted even when the initiation of treatment was delayed as long as 6 hours after irradiation. In comparison with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red blood cells in peripheral blood, total cell numbers, hematopoietic stem cells, and progenitor cells in the bone marrow when measured at day 14 after irradiation. IGF-1 protected both hematopoietic stem cells and progenitor cells from radiation-induced apoptosis and cell death. In addition, IGF-1 was able to facilitate the proliferation and differentiation of nonirradiated and irradiated hematopoietic progenitor cells. Conclusions: IGF-1 mitigates radiation-induced hematopoietic toxicity through protecting hematopoietic stem cells and progenitor cells from apoptosis and enhancing proliferation and differentiation of the surviving hematopoietic progenitor cells. © 2013 Elsevier Inc. All rights reserved.

Authors
Zhou, D; Deoliveira, D; Kang, Y; Choi, SS; Li, Z; Chao, NJ; Chen, BJ
MLA Citation
Zhou, D, Deoliveira, D, Kang, Y, Choi, SS, Li, Z, Chao, NJ, and Chen, BJ. "Insulin-like growth factor 1 mitigates hematopoietic toxicity after lethal total body irradiation." International Journal of Radiation Oncology Biology Physics 85.4 (2013): 1141-1148.
Source
scival
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
85
Issue
4
Publish Date
2013
Start Page
1141
End Page
1148
DOI
10.1016/j.ijrobp.2012.08.014

Allospecific CD4(+) effector memory T cells do not induce graft-versus-host disease in mice.

We studied whether allospecific CD4(+) effector memory T cells (T(EM)) could induce graft-versus-host disease (GVHD) using a novel GVHD model induced solely by CD4(+) T cell receptor transgenic TEa cells. Allospecific T(EM) generated in a lymphopenic host bore a typical memory phenotype. Moreover, these cells were able to elicit a faster and more effective proliferative response on challenge with alloantigen in vitro and to mediate "second-set" skin graft rejection in vivo. However, these allospecific T(EM) were unable to induce GVHD. Allospecific T(EM) recipients became tolerant to alloantigen as a result of clonal deletion. Even though allospecific T(EM) were able to respond to alloantigen initially, the expansion of these cells and inflammatory cytokine production during GVHD were dramatically decreased. The inability of allospecific T(EM) to sustain the alloresponse may be a result of enhanced activation-induced cell death. These observations provide insight into how allospecific CD4(+) T(EM) respond to alloantigen during GVHD and underscore the fundamental differences in alloresponses mediated by allospecific T(EM) in graft rejection and GVHD settings.

Authors
Zhang, P; Wu, J; Deoliveira, D; Chao, NJ; Chen, BJ
MLA Citation
Zhang, P, Wu, J, Deoliveira, D, Chao, NJ, and Chen, BJ. "Allospecific CD4(+) effector memory T cells do not induce graft-versus-host disease in mice." Biol Blood Marrow Transplant 18.10 (October 2012): 1488-1499.
PMID
22809867
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
18
Issue
10
Publish Date
2012
Start Page
1488
End Page
1499
DOI
10.1016/j.bbmt.2012.07.009

CD62L - memory T cells enhance T-cell regeneration after allogeneic stem cell transplantation by eliminating host resistance in mice

A major challenge in allogeneic hematopoietic cell transplantation is how to transfer T-cell immunity without causing graftversus- host disease (GVHD). Effector memory T cells (CD62L -) are a cell subset that can potentially address this challenge because they do not induce GVHD. Here, we investigated how CD62L - T cells contributed to phenotypic and functional T-cell reconstitution after transplantation. On transfer into allogeneic recipients, CD62L - T cells were activated and expressed multiple cytokines and cytotoxic molecules. CD62L - T cells were able to deplete host radioresistant T cells and facilitate hematopoietic engraftment, resulting in enhanced de novo T-cell regeneration. Enhanced functional immune reconstitution was demonstrated in CD62L -T-cell recipients using a tumor and an influenza virus challenge model. Even though CD62L - T cells are able to respond to alloantigens and deplete host radioresistant immune cells in GVHD recipients, alloreactive CD62L - T cells lost the reactivity over time and were eventually tolerant to alloantigens as a result of prolonged antigen exposure, suggesting a mechanism by which CD62L - T cells were able to eliminate host resistance without causing GVHD. These data further highlight the unique characteristics of CD62L - T cells and their potential applications in clinical hematopoietic cell transplantation. © 2012 by The American Society of Hematology.

Authors
Zhang, J; Barefoot, BE; Mo, W; Deoliveira, D; Son, J; Cui, X; Ramsburg, E; Chen, BJ
MLA Citation
Zhang, J, Barefoot, BE, Mo, W, Deoliveira, D, Son, J, Cui, X, Ramsburg, E, and Chen, BJ. "CD62L - memory T cells enhance T-cell regeneration after allogeneic stem cell transplantation by eliminating host resistance in mice." Blood 119.26 (2012): 6344-6353.
PMID
22596261
Source
scival
Published In
Blood
Volume
119
Issue
26
Publish Date
2012
Start Page
6344
End Page
6353
DOI
10.1182/blood-2011-03-342055

An ear punch model for studying the effect of radiation on wound healing.

PURPOSE: Radiation and wound combined injury represents a major clinical challenge because of the synergistic interactions that lead to higher morbidity and mortality than either insult would produce singly. The purpose of this study was to develop a mouse ear punch model to study the physiological mechanisms underlying radiation effects on healing wounds. MATERIALS AND METHODS: Surgical wounds were induced by a 2 mm surgical punch in the ear pinnae of MRL/MpJ mice. Photographs of the wounds were taken and the sizes of the ear punch wounds were quantified by image analysis. Local radiation to the ear was delivered by orthovoltage X-ray irradiator using a specially constructed jig that shields the other parts of body. RESULTS: Using this model, we demonstrated that local radiation to the wound area significantly delayed the healing of ear punch wounds in a dose-dependent fashion. The addition of sublethal whole body irradiation (7 Gy) further delayed the healing of ear punch wounds. These results were replicated in C57BL/6 mice; however, wound healing in MRL/MpJ mice was accelerated. CONCLUSIONS: These data indicate that the mouse ear punch model is a valuable model to study radiation and wound combined injury.

Authors
Deoliveira, D; Jiao, Y; Ross, JR; Corbin, K; Xiao, Q; Toncheva, G; Anderson-Evans, C; Yoshizumi, TT; Chen, BJ; Chao, NJ
MLA Citation
Deoliveira, D, Jiao, Y, Ross, JR, Corbin, K, Xiao, Q, Toncheva, G, Anderson-Evans, C, Yoshizumi, TT, Chen, BJ, and Chao, NJ. "An ear punch model for studying the effect of radiation on wound healing." Int J Radiat Biol 87.8 (August 2011): 869-877.
PMID
21480768
Source
pubmed
Published In
International Journal of Radiation Biology (Informa)
Volume
87
Issue
8
Publish Date
2011
Start Page
869
End Page
877
DOI
10.3109/09553002.2011.568575

Prevention of GVHD without losing GVL effect: windows of opportunity.

Allogeneic hematopoietic cell transplantation has developed into a most successful form of immunotherapy for hematologic malignancies in the past 50 years. However, its effectiveness and wider applications have been greatly limited by the development of graft-versus-host disease (GVHD), a potentially lethal side effect associated with this procedure. Since the main effectors for both graft-versus-leukemia (GVL) effect and GVHD are T lymphocytes and these two processes share many similar pathways, it has not been easy to separate GVL from GVHD. Because the clinically used pan immunosuppressive therapy for GVHD prevention also results in decreased GVL effect, the success of allogeneic hematopoietic cell transplantation relies on a small and unpredictable therapeutic window at the present time. This review discusses how we may widen this therapeutic window so that we can reliably prevent GVHD without losing GVL effect.

Authors
Zhang, P; Chen, BJ; Chao, NJ
MLA Citation
Zhang, P, Chen, BJ, and Chao, NJ. "Prevention of GVHD without losing GVL effect: windows of opportunity." Immunol Res 49.1-3 (April 2011): 49-55. (Review)
PMID
21136200
Source
pubmed
Published In
Immunologic Research
Volume
49
Issue
1-3
Publish Date
2011
Start Page
49
End Page
55
DOI
10.1007/s12026-010-8193-7

Progenitor cell dose determines the pace and completeness of engraftment in a xenograft model for cord blood transplantation.

Two critical concerns in clinical cord blood transplantation are the initial time to engraftment and the subsequent restoration of immune function. These studies measured the impact of progenitor cell dose on both the pace and strength of hematopoietic reconstitution by transplanting nonobese diabetic/severe combined immunodeficiency/interleukin-2 receptor-gamma-null (NSγ) mice with lineage-depleted aldehyde dehydrogenase-bright CD34(+) human cord blood progenitors. The progress of each transplant was monitored over an extended time course by repeatedly analyzing the peripheral blood for human hematopoietic cells. In vivo human hematopoietic development was complete. After long-term transplantation assays (≥ 19 weeks), human T-cell development was documented within multiple tissues in 16 of 32 NSγ mice. Human T-cell differentiation was active within NSγ thymuses, as documented by the presence of CD4(+) CD8(+) T-cell progenitors as well as T-cell receptor excision circles. It is important to note that although myeloid and B-cell engraftment was detected as early as 4 weeks after transplantation, human T-cell development was exclusively late onset. High progenitor cell doses were associated with a robust human hematopoietic chimerism that accelerated both initial time to engraftment and subsequent T-cell development. At lower progenitor cell doses, the chimerism was weak and the human hematopoietic lineage development was frequently incomplete.

Authors
Liu, C; Chen, BJ; Deoliveira, D; Sempowski, GD; Chao, NJ; Storms, RW
MLA Citation
Liu, C, Chen, BJ, Deoliveira, D, Sempowski, GD, Chao, NJ, and Storms, RW. "Progenitor cell dose determines the pace and completeness of engraftment in a xenograft model for cord blood transplantation." Blood 116.25 (December 16, 2010): 5518-5527.
PMID
20833978
Source
pubmed
Published In
Blood
Volume
116
Issue
25
Publish Date
2010
Start Page
5518
End Page
5527
DOI
10.1182/blood-2009-12-260810

Selective enhancement of donor hematopoietic cell engraftment by the CXCR4 antagonist AMD3100 in a mouse transplantation model.

The interaction between stromal cell-derived factor-1 (SDF-1) with CXCR4 chemokine receptors plays an important role in hematopoiesis following hematopoietic stem cell transplantation. We examined the efficacy of post transplant administration of a specific CXCR4 antagonist (AMD3100) in improving animal survival and in enhancing donor hematopoietic cell engraftment using a congeneic mouse transplantation model. AMD3100 was administered subcutaneously at 5 mg/kg body weight 3 times a week beginning at day +2 post-transplant. Post-transplant administration of AMD3100 significantly improves animal survival. AMD3100 reduces pro-inflammatory cytokine/chemokine production. Furthermore, post transplant administration of AMD3100 selectively enhances donor cell engraftment and promotes recovery of all donor cell lineages (myeloid cells, T and B lymphocytes, erythrocytes and platelets). This enhancement results from a combined effect of increased marrow niche availability and greater cell division induced by AMD3100. Our studies shed new lights into the biological roles of SDF-1/CXCR4 interaction in hematopoietic stem cell engraftment following transplantation and in transplant-related mortality. Our results indicate that AMD3100 provides a novel approach for enhancing hematological recovery following transplantation, and will likely benefit patients undergoing transplantation.

Authors
Kang, Y; Chen, BJ; Deoliveira, D; Mito, J; Chao, NJ
MLA Citation
Kang, Y, Chen, BJ, Deoliveira, D, Mito, J, and Chao, NJ. "Selective enhancement of donor hematopoietic cell engraftment by the CXCR4 antagonist AMD3100 in a mouse transplantation model." PloS one 5.6 (June 28, 2010): e11316-.
Website
http://hdl.handle.net/10161/5087
PMID
20596257
Source
epmc
Published In
PloS one
Volume
5
Issue
6
Publish Date
2010
Start Page
e11316
DOI
10.1371/journal.pone.0011316

Growth hormone mitigates against lethal irradiation and enhances hematologic and immune recovery in mice and nonhuman primates.

Medications that can mitigate against radiation injury are limited. In this study, we investigated the ability of recombinant human growth hormone (rhGH) to mitigate against radiation injury in mice and nonhuman primates. BALB/c mice were irradiated with 7.5 Gy and treated post-irradiation with rhGH intravenously at a once daily dose of 20 microg/dose for 35 days. rhGH protected 17 out of 28 mice (60.7%) from lethal irradiation while only 3 out of 28 mice (10.7%) survived in the saline control group. A shorter course of 5 days of rhGH post-irradiation produced similar results. Compared with the saline control group, treatment with rhGH on irradiated BALB/c mice significantly accelerated overall hematopoietic recovery. Specifically, the recovery of total white cells, CD4 and CD8 T cell subsets, B cells, NK cells and especially platelets post radiation exposure were significantly accelerated in the rhGH-treated mice. Moreover, treatment with rhGH increased the frequency of hematopoietic stem/progenitor cells as measured by flow cytometry and colony forming unit assays in bone marrow harvested at day 14 after irradiation, suggesting the effects of rhGH are at the hematopoietic stem/progenitor level. rhGH mediated the hematopoietic effects primarily through their niches. Similar data with rhGH were also observed following 2 Gy sublethal irradiation of nonhuman primates. Our data demonstrate that rhGH promotes hematopoietic engraftment and immune recovery post the exposure of ionizing radiation and mitigates against the mortality from lethal irradiation even when administered after exposure.

Authors
Chen, BJ; Deoliveira, D; Spasojevic, I; Sempowski, GD; Jiang, C; Owzar, K; Wang, X; Gesty-Palmer, D; Cline, JM; Bourland, JD; Dugan, G; Meadows, SK; Daher, P; Muramoto, G; Chute, JP; Chao, NJ
MLA Citation
Chen, BJ, Deoliveira, D, Spasojevic, I, Sempowski, GD, Jiang, C, Owzar, K, Wang, X, Gesty-Palmer, D, Cline, JM, Bourland, JD, Dugan, G, Meadows, SK, Daher, P, Muramoto, G, Chute, JP, and Chao, NJ. "Growth hormone mitigates against lethal irradiation and enhances hematologic and immune recovery in mice and nonhuman primates. (Published online)" PLoS One 5.6 (June 16, 2010): e11056-.
Website
http://hdl.handle.net/10161/4547
PMID
20585403
Source
pubmed
Published In
PloS one
Volume
5
Issue
6
Publish Date
2010
Start Page
e11056
DOI
10.1371/journal.pone.0011056

Novel mechanism of rapamycin in GVHD: Increase in interstitial regulatory T cells

Rapamycin (RAPA) is an immunosuppressive drug that prevents and treats graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplant (HCT). One possible mechanism for its efficacy is induction of tolerance, through increased number or enhanced survival of regulatory T cells. In our experiments, B10.D2 BM and splenocytes were injected into lethally irradiated BALB/cJ recipients. The mice received i.p. injections of either RAPA or vehicle control on days 1-28. There was a significant survival advantage in RAPA-treated mice. Evaluation of the skin biopsies showed a dense cellular infiltrate in RAPA-treated mice. Further characterization of these cells revealed a higher percentage of regulatory T cells characterized by FoxP3-positive cells in high-dose RAPA-treated mice as compared with controls on day 30. This effect appears to be dose dependent. When peripheral blood analysis for FoxP3-positive cells was performed, there was no significant difference observed in the RAPA-treated mice as compared with control mice. These data show a novel mechanism of rapamycin in GVHD, accumulation of regulatory T cells in the GVHD target tissue: the skin. © 2010 Macmillan Publishers Limited All rights reserved.

Authors
Palmer, JM; Chen, BJ; Deoliveira, D; Le, N-D; Chao, NJ
MLA Citation
Palmer, JM, Chen, BJ, Deoliveira, D, Le, N-D, and Chao, NJ. "Novel mechanism of rapamycin in GVHD: Increase in interstitial regulatory T cells." Bone Marrow Transplantation 45.2 (2010): 379-384.
PMID
19597415
Source
scival
Published In
Bone Marrow Transplantation
Volume
45
Issue
2
Publish Date
2010
Start Page
379
End Page
384
DOI
10.1038/bmt.2009.140

Increased skin carcinogenesis in caspase-activated DNase knockout mice.

Caspase-activated DNase (CAD), also called DNA fragmentation factor (DFF), is the enzyme responsible for DNA fragmentation during apoptosis, a hallmark of programmed cell death. CAD/DFF has been shown to suppress radiation-induced carcinogenesis by preventing genomic instability in cells. In this study, we have investigated the role of CAD in chemical carcinogenesis using CAD-null mice and two-stage model of skin carcinogenesis. After topical treatment of mouse skin with dimethylbenz[a]anthracene (DMBA) as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoting agent, there was a 4-fold increase in the number of papillomas per mouse and 50.8% increase in the incidence of papilloma formation in the CAD knockout mice compared with wild-type littermates. The papillomas in CAD-null mice grew faster and reached larger sizes. These data indicate that loss of CAD function enhances tumorigenesis induced by a chemical carcinogen in the DMBA/TPA two-stage model of skin carcinogenesis in mice.

Authors
Yan, B; Wang, H; Xie, D; Wakamatsu, N; Anscher, MS; Dewhirst, MW; Mitchel, REJ; Chen, BJ; Li, C-Y
MLA Citation
Yan, B, Wang, H, Xie, D, Wakamatsu, N, Anscher, MS, Dewhirst, MW, Mitchel, REJ, Chen, BJ, and Li, C-Y. "Increased skin carcinogenesis in caspase-activated DNase knockout mice." Carcinogenesis 30.10 (October 2009): 1776-1780.
PMID
19541853
Source
pubmed
Published In
Carcinogenesis
Volume
30
Issue
10
Publish Date
2009
Start Page
1776
End Page
1780
DOI
10.1093/carcin/bgp146

Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis.

Studies in humans and animal models indicate a key contribution of angiotensin II to the pathogenesis of glomerular diseases. To examine the role of type 1 angiotensin (AT1) receptors in glomerular inflammation associated with autoimmune disease, we generated MRL-Faslpr/lpr (lpr) mice lacking the major murine type 1 angiotensin receptor (AT1A); lpr mice develop a generalized autoimmune disease with glomerulonephritis that resembles SLE. Surprisingly, AT1A deficiency was not protective against disease but instead substantially accelerated mortality, proteinuria, and kidney pathology. Increased disease severity was not a direct effect of immune cells, since transplantation of AT1A-deficient bone marrow did not affect survival. Moreover, autoimmune injury in extrarenal tissues, including skin, heart, and joints, was unaffected by AT1A deficiency. In murine systems, there is a second type 1 angiotensin receptor isoform, AT1B, and its expression is especially prominent in the renal glomerulus within podocytes. Further, expression of renin was enhanced in kidneys of AT1A-deficient lpr mice, and they showed evidence of exaggerated AT1B receptor activation, including substantially increased podocyte injury and expression of inflammatory mediators. Administration of losartan, which blocks all type 1 angiotensin receptors, reduced markers of kidney disease, including proteinuria, glomerular pathology, and cytokine mRNA expression. Since AT1A-deficient lpr mice had low blood pressure, these findings suggest that activation of type 1 angiotensin receptors in the glomerulus is sufficient to accelerate renal injury and inflammation in the absence of hypertension.

Authors
Crowley, SD; Vasievich, MP; Ruiz, P; Gould, SK; Parsons, KK; Pazmino, AK; Facemire, C; Chen, BJ; Kim, H-S; Tran, TT; Pisetsky, DS; Barisoni, L; Prieto-Carrasquero, MC; Jeansson, M; Foster, MH; Coffman, TM
MLA Citation
Crowley, SD, Vasievich, MP, Ruiz, P, Gould, SK, Parsons, KK, Pazmino, AK, Facemire, C, Chen, BJ, Kim, H-S, Tran, TT, Pisetsky, DS, Barisoni, L, Prieto-Carrasquero, MC, Jeansson, M, Foster, MH, and Coffman, TM. "Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis." J Clin Invest 119.4 (April 2009): 943-953.
PMID
19287096
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
119
Issue
4
Publish Date
2009
Start Page
943
End Page
953
DOI
10.1172/JCI34862

Endothelial progenitor cell infusion induces hematopoietic stem cell reconstitution in vivo.

Hematopoietic stem cells (HSCs) reside in association with bone marrow (BM) sinusoidal vessels in vivo, but the function of BM endothelial cells (ECs) in regulating hematopoiesis is unclear. We hypothesized that hematopoietic regeneration following injury is regulated by BM ECs. BALB/c mice were treated with total body irradiation (TBI) and then infused with C57Bl6-derived endothelial progenitor cells (EPCs) to augment endogenous BM EC activity. TBI caused pronounced disruption of the BM vasculature, BM hypocellularity, ablation of HSCs, and pancytopenia in control mice, whereas irradiated, EPC-treated mice displayed accelerated recovery of BM sinusoidal vessels, BM cellularity, peripheral blood white blood cells (WBCs), neutrophils, and platelets, and a 4.4-fold increase in BM HSCs. Systemic administration of anti-VE-cadherin antibody significantly delayed hematologic recovery in both EPC-treated mice and irradiated, non-EPC-treated mice compared with irradiated controls. These data demonstrate that allogeneic EPC infusions can augment hematopoiesis and suggest a relationship between BM microvascular recovery and hematopoietic reconstitution in vivo.

Authors
Salter, AB; Meadows, SK; Muramoto, GG; Himburg, H; Doan, P; Daher, P; Russell, L; Chen, B; Chao, NJ; Chute, JP
MLA Citation
Salter, AB, Meadows, SK, Muramoto, GG, Himburg, H, Doan, P, Daher, P, Russell, L, Chen, B, Chao, NJ, and Chute, JP. "Endothelial progenitor cell infusion induces hematopoietic stem cell reconstitution in vivo." Blood 113.9 (February 26, 2009): 2104-2107.
PMID
19141867
Source
pubmed
Published In
Blood
Volume
113
Issue
9
Publish Date
2009
Start Page
2104
End Page
2107
DOI
10.1182/blood-2008-06-162941

Allogeneic memory T cell response.

Recent data have revealed marked differences in alloresponses mediated by memory T cells during GVH and host-versus-graft (HVG) reactions (summarized in Table 1). Even though the mechanisms are not completely understood, it is clear that all memory T cells including nonallospecific, crossreactive, and allospecific memory T cells have decreased ability to induce GVHD. Selection of memory T cells or removal of naïve T cells will not only prevent GVHD, but could also enhance immune reconstitution, facilitate engraftment, and have the potential to enhance antitumor effects. A clinical trial has been planned. Successful translation of this approach in the clinic will improve the safety, enhance the effectiveness, and broaden the scope of allogeneic hematopoietic stem cell transplantation.

Authors
Chen, BJ
MLA Citation
Chen, BJ. "Allogeneic memory T cell response." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 14.1 Suppl 1 (2008): 20-22.
PMID
19418623
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
14
Issue
1 Suppl 1
Publish Date
2008
Start Page
20
End Page
22

Alloimmune lung injury induced by local innate immune activation through inhaled lipopolysaccharide.

BACKGROUND: Alloimmune lung injury, characterized by perivascular lymphocytic inflammation, lymphocytic bronchiolitis (LB), and obliterative bronchiolitis (OB), causes substantial morbidity and mortality after lung transplantation and bone marrow transplantation (BMT), but little is known regarding its pathogenesis. We have developed and pursued the hypothesis that local activation of pulmonary innate immunity through toll-like receptor (TLR)-4 is critical to the development of posttransplant alloimmune lung injury. METHODS: We developed a fully major histocompatibility complex-mismatched murine BMT model without systemic graft-versus-host disease, and challenged mice with aerosolized lipopolysaccharide (LPS), a prototypic TLR4 agonist, to determine the effect upon pulmonary alloimmune lung injury. RESULTS: LPS-exposed allogeneic BMT recipient mice developed histological and biological features of LB and OB, which were not observed in non-LPS-exposed allogeneic controls or syngeneic LPS-exposed mice. LPS-induced lymphocytic lung inflammation was dependent upon intact TLR4 signaling in donor-derived hematopoietic cells but not recipient structural lung cells, demonstrating a distinct function for TLR4 on hematopoietic cells in mediating alloimmunity. CONCLUSIONS: We demonstrate a critical role for localized, environmentally induced innate immune activation in promoting alloimmune lung injury. Local inhibition of TLR4 signaling in pulmonary resident hematopoietic cells represents a novel and potentially important therapeutic target to prevent posttransplant rejection.

Authors
Garantziotis, S; Palmer, SM; Snyder, LD; Ganous, T; Chen, BJ; Wang, T; Cook, DN; Schwartz, DA
MLA Citation
Garantziotis, S, Palmer, SM, Snyder, LD, Ganous, T, Chen, BJ, Wang, T, Cook, DN, and Schwartz, DA. "Alloimmune lung injury induced by local innate immune activation through inhaled lipopolysaccharide." Transplantation 84.8 (October 27, 2007): 1012-1019.
PMID
17989607
Source
pubmed
Published In
Transplantation
Volume
84
Issue
8
Publish Date
2007
Start Page
1012
End Page
1019
DOI
10.1097/01.tp.0000286040.85007.89

Inability of memory T cells to induce graft-versus-host disease is a result of an abortive alloresponse.

Several groups, including our own, have independently demonstrated that effector memory T cells from non-alloantigen-primed donors do not cause graft-versus-host disease (GVHD). In the current study, we further investigated whether this approach could be extended to all memory T cells, and we studied the underlying mechanisms. Neither total memory T cells nor purified central memory T cells were able to induce GVHD. Memory T cells were at least 3-log less potent than bulk T cells in mediating GVHD. As expected, memory T cells failed to elicit cytotoxicity and proliferated poorly against alloantigens in standard 5-day mixed-lymphocyte cultures. However, the proliferative responses of memory T cells were more comparable with those of bulk and naive T cells when the culture time was shortened. Moreover, the frequencies of IL-2-secreting cells measured by 42-hour enzyme-linked immunosorbent spot (ELISPOT) assay were similar among naive, memory, and bulk T cells. These data indicated that memory T cells are able to respond to alloantigens initially but fail to develop to full potential. The abortive immune response, which was mediated by non-alloantigen-specific memory T cells in response to alloantigens, may explain why memory T cells from unprimed and non-alloantigen-primed donors could not induce GVHD.

Authors
Chen, BJ; Deoliveira, D; Cui, X; Le, NT; Son, J; Whitesides, JF; Chao, NJ
MLA Citation
Chen, BJ, Deoliveira, D, Cui, X, Le, NT, Son, J, Whitesides, JF, and Chao, NJ. "Inability of memory T cells to induce graft-versus-host disease is a result of an abortive alloresponse." Blood 109.7 (April 1, 2007): 3115-3123.
PMID
17148592
Source
pubmed
Published In
Blood
Volume
109
Issue
7
Publish Date
2007
Start Page
3115
End Page
3123
DOI
10.1182/blood-2006-04-016410

Transplantation of vascular endothelial cells mediates the hematopoietic recovery and survival of lethally irradiated mice.

Flk-1(+) endothelial progenitors contribute critically to the definitive onset of hematopoiesis during embryogenesis. Recent studies have suggested that adult sources of endothelial cells also possess hematopoietic activity. In this study, we sought to determine whether transplantation of primary vascular endothelial cells (ECs) could enhance the hematopoietic recovery and survival of irradiated mice. C57Bl6 mice were exposed to sublethal and lethal doses of irradiation and were subsequently given transplants of either primary murine brain-derived ECs (MBECs) or fetal blood-derived ECs (FBECs). Mice that received a transplant with MBECs alone demonstrated accelerated BM cellular recovery, radioprotection of BM c-kit(+)sca-1(-)lin(-) progenitors and enhanced regeneration of c-kit(+)sca-1(+)lin(-) (KSL) stem/progenitor cells following irradiation compared with controls. MBEC transplantation also facilitated the recovery of circulating white blood cell and platelet counts following radiation exposure. Remarkably, 57% of mice that received a transplant with MBECs alone survived long term following 1050 cGy exposure, which was 100% lethal in control mice. FBEC transplantation was also associated with increased survival compared with controls, although these mice did not survive in the long term. These data suggest that reestablishment of endothelial cell activity can improve the hematopoietic recovery and survival of irradiated mice.

Authors
Chute, JP; Muramoto, GG; Salter, AB; Meadows, SK; Rickman, DW; Chen, B; Himburg, HA; Chao, NJ
MLA Citation
Chute, JP, Muramoto, GG, Salter, AB, Meadows, SK, Rickman, DW, Chen, B, Himburg, HA, and Chao, NJ. "Transplantation of vascular endothelial cells mediates the hematopoietic recovery and survival of lethally irradiated mice." Blood 109.6 (March 15, 2007): 2365-2372.
PMID
17095624
Source
pubmed
Published In
Blood
Volume
109
Issue
6
Publish Date
2007
Start Page
2365
End Page
2372
DOI
10.1182/blood-2006-05-022640

High-resolution in vivo imaging of blood vessels without labeling

We demonstrate that both oxyhemoglobin and deoxyhemoglobin have sequential two-color, two-photon absorption properties that can serve as endogenous contrasts in microvasculature imaging. Using a sensitive modulation transfer technique, we are able to image hemoglobin in red blood cells with micrometer resolution, both in vitro and in vivo. We show that excellent contrast from hemoglobin without any labeling can be obtained in tissue. © 2007 Optical Society of America.

Authors
Fu, D; Ye, T; Matthews, TE; Chen, BJ; Yurtserver, G; Warren, WS
MLA Citation
Fu, D, Ye, T, Matthews, TE, Chen, BJ, Yurtserver, G, and Warren, WS. "High-resolution in vivo imaging of blood vessels without labeling." Optics Letters 32.18 (2007): 2641-2643.
PMID
17873920
Source
scival
Published In
Optics Letters
Volume
32
Issue
18
Publish Date
2007
Start Page
2641
End Page
2643
DOI
10.1364/OL.32.002641

Vascular endothelial cells produce soluble factors that mediate the recovery of human hematopoietic stem cells after radiation injury.

The risk of terrorism with nuclear or radiologic weapons is considered to be high over the coming decade. Ionizing radiation can cause a spectrum of hematologic toxicities, from mild myelosuppression to myeloablation and death. However, the potential regenerative capacity of human hematopoietic stem cells (HSCs) after radiation injury has not been well characterized. In this study, we sought to characterize the effects of ionizing radiation on human HSCs and to determine whether signals from vascular endothelial cells could promote the repair of irradiated HSCs. Exposure of human bone marrow CD34+ cells to 400 cGy caused a precipitous decline in hematopoietic progenitor cell content and primitive cells capable of repopulating nonobese diabetic/severe combined immunodeficient mice (SCID-repopulating cells), which was not retrievable via treatment with cytokines. Conversely, culture of 400 cGy-irradiated bone marrow CD34+ cells with endothelial cells under noncontact conditions supported the differential recovery of both viable progenitor cells and primitive SCID-repopulating cells. These data illustrate that vascular endothelial cells produce soluble factors that promote the repair and functional recovery of HSCs after radiation injury and suggest that novel factors with radiotherapeutic potential can be identified within this milieu.

Authors
Muramoto, GG; Chen, B; Cui, X; Chao, NJ; Chute, JP
MLA Citation
Muramoto, GG, Chen, B, Cui, X, Chao, NJ, and Chute, JP. "Vascular endothelial cells produce soluble factors that mediate the recovery of human hematopoietic stem cells after radiation injury." Biol Blood Marrow Transplant 12.5 (May 2006): 530-540.
PMID
16635788
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
12
Issue
5
Publish Date
2006
Start Page
530
End Page
540
DOI
10.1016/j.bbmt.2005.12.039

Prophylaxis and treatment of acute graft-versus-host disease.

Acute graft-versus-host disease (GVHD) remains a major obstacle to successful allogeneic hematopoietic stem cell transplantation (HSCT). The ability to prevent GVHD--the application of successful prophylaxis--is crucial as treatment when prophylaxis fails or remains suboptimal. A calcineurin inhibitor in combination with methotrexate is still the mainstream regimen for prophylaxis of GVHD. Despite a steady increase in the repertoire of available drugs, corticosteroids remain the first-line therapy for patients who fail prevention and develop GVHD. Pan T-cell depletion studies suggest that success in prophylaxis and treatment of GVHD will depend on whether GVHD can be prevented without losing anti-malignancy and anti-infectious effects. Better understanding of the allogeneic response that is responsible for GVHD will facilitate the development of such an approach.

Authors
Chao, NJ; Chen, BJ
MLA Citation
Chao, NJ, and Chen, BJ. "Prophylaxis and treatment of acute graft-versus-host disease." Semin Hematol 43.1 (January 2006): 32-41. (Review)
PMID
16412787
Source
pubmed
Published In
Seminars in Hematology
Volume
43
Issue
1
Publish Date
2006
Start Page
32
End Page
41
DOI
10.1053/j.seminhematol.2005.09.007

Treg-cell expansion: Better to be "naive"

Authors
Chen, BJ
MLA Citation
Chen, BJ. "Treg-cell expansion: Better to be "naive"." Blood 108.13 (2006): 3963-3964.
Source
scival
Published In
Blood
Volume
108
Issue
13
Publish Date
2006
Start Page
3963
End Page
3964
DOI
10.1182/blood-2006-09-048447

The critical role of hematopoietic cells in lipopolysaccharide-induced airway inflammation.

Rapid and selective recruitment of neutrophils into the airspace in response to LPS facilitates the clearance of bacterial pathogens. However, neutrophil infiltration can also participate in the development and progression of environmental airway disease. Previous data have revealed that Toll-like receptor 4 (tlr4) is required for neutrophil recruitment to the lung after either inhaled or systemically administrated LPS from Escherichia coli. Although many cell types express tlr4, endothelial cell expression of tlr4 is specifically required to sequester neutrophils in the lung in response to systemic endotoxin. To identify the cell types requiring trl4 expression for neutrophil recruitment after inhaled LPS, we generated chimeric mice separately expressing tlr4 on either hematopoietic cells or on structural lung cells. Neutrophil recruitment into the airspace was completely restored in tlr4-deficient mice receiving wild-type bone marrow. By contrast, wild-type animals receiving tlr4-deficient marrow had dramatically reduced neutrophil recruitment. Moreover, adoptive transfer of wild-type alveolar macrophages also restored the ability of tlr4-deficient recipient mice to recruit neutrophils to the lung. These data demonstrate the critical role of hematopoietic cells and alveolar macrophages in initiating LPS-induced neutrophil recruitment from the vascular space to the airspace.

Authors
Hollingsworth, JW; Chen, BJ; Brass, DM; Berman, K; Gunn, MD; Cook, DN; Schwartz, DA
MLA Citation
Hollingsworth, JW, Chen, BJ, Brass, DM, Berman, K, Gunn, MD, Cook, DN, and Schwartz, DA. "The critical role of hematopoietic cells in lipopolysaccharide-induced airway inflammation." Am J Respir Crit Care Med 171.8 (April 15, 2005): 806-813.
PMID
15618460
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
171
Issue
8
Publish Date
2005
Start Page
806
End Page
813
DOI
10.1164/rccm.200407-953OC

Selective elimination of alloreactivity from immunotherapeutic T cells by photodynamic cell purging and memory T-cell sorting.

Allogeneic stem cell transplantation (alloSCT), especially in the mismatched setting, carries a high risk of life-threatening GvHD because of activation of donor T cells by Ag present on host cells. Removal of mature donor T cells can prevent GvHD but leads to delayed immune reconstitution, and an increased incidence of opportunistic infections and disease relapse. These findings demonstrate the vital role of donor T cells in providing graft-versus-tumor (GvT) and anti-pathogen effects as well as facilitating immune reconstitution. It has been well documented that GvHD can be separated from GvT effects, making it possible potentially to eliminate GvHD while preserving the immunotherapeutic benefits of donor T cells. Over the past decade, major attempts have been made to reduce GvHD incidence without loss of GvT effect, especially in the haplo-identical setting. Novel techniques to deplete host-reactive donor T cells selectively have been explored. This review focuses on the use of the photodynamic cell purging (PDP) process and of sorting memory T cells for the selective elimination of alloreactivity. Minimizing the threat of GvHD while maximizing the beneficial GvT effect would broaden the scope and effectiveness of alloSCT.

Authors
Le, NT; Chen, BJ; Chao, NJ
MLA Citation
Le, NT, Chen, BJ, and Chao, NJ. "Selective elimination of alloreactivity from immunotherapeutic T cells by photodynamic cell purging and memory T-cell sorting." Cytotherapy 7.2 (2005): 126-133. (Review)
PMID
16040391
Source
pubmed
Published In
Cytotherapy (Informa)
Volume
7
Issue
2
Publish Date
2005
Start Page
126
End Page
133
DOI
10.1080/14653240510018163

Hematopoietic stem cell dose correlates with the speed of immune reconstitution after stem cell transplantation.

In the current study, we tested whether higher numbers of hematopoietic stem cells correlate with the speed of immune reconstitution in a congenic transplantation model (C57BL/Ka, CD45.1, Thy1.1-->C57BL/6, CD45.2, Thy1.2) using purified hematopoietic stem cells (c-Kit(+)Thy1.1(low)Lin(-/low)Sca-1(+)). There were 3 different doses of stem cells used (400, 1000, and 5000). Phenotypic analyses in peripheral blood and spleen demonstrated that higher numbers of infused stem cells are associated with more rapid regeneration of T cells (CD4(+), CD8(+), naive CD4(+), naive CD8(+)) and B cells at early time points. The numbers of T and B cells eventually became equivalent between different dose groups at late time points. Production of interleukin-2 and inter-feron-gamma per T cell was similar regardless of stem cell dose even when tested at the time when there were significant differences in peripheral T-cell counts. The improved immune recovery was attributed to a more rapid regeneration of donor-type immune cells. Higher numbers of total thymocytes and signal joint T-cell receptor excision circles were observed in the higher dose stem cell recipients, suggesting that accelerated regeneration of T cells was due to enhanced thymopoiesis.

Authors
Chen, BJ; Cui, X; Sempowski, GD; Domen, J; Chao, NJ
MLA Citation
Chen, BJ, Cui, X, Sempowski, GD, Domen, J, and Chao, NJ. "Hematopoietic stem cell dose correlates with the speed of immune reconstitution after stem cell transplantation." Blood 103.11 (June 1, 2004): 4344-4352.
PMID
14976038
Source
pubmed
Published In
Blood
Volume
103
Issue
11
Publish Date
2004
Start Page
4344
End Page
4352
DOI
10.1182/blood-2003-07-2534

Transfer of allogeneic CD62L- memory T cells without graft-versus-host disease.

The major challenge in allogeneic hematopoietic cell transplantation is how to transfer allogeneic T-cell immunity without causing graft-versus-host disease (GVHD). Here we report a novel strategy to selectively prevent GVHD by depleting CD62L(+) T cells (naive and a subset of memory T cells). In unprimed mice, CD62L(-) T cells (a subset of memory T cells) failed to proliferate in response to alloantigens (which the mice have never previously encountered) and were unable to induce GVHD in allogeneic hosts. CD62L(-) T cells contributed to T-cell reconstitution by peripheral expansion as well as by promoting T-cell regeneration from bone marrow stem/progenitor cells. CD62L(-) T cells from the animals previously primed with a tumor cell line (BCL1) were able to inhibit the tumor growth in vivo but were unable to induce GVHD in the third-party recipients. This novel technology may allow transfer of allogeneic recall antitumor and antimicrobial immunity without causing GVHD.

Authors
Chen, BJ; Cui, X; Sempowski, GD; Liu, C; Chao, NJ
MLA Citation
Chen, BJ, Cui, X, Sempowski, GD, Liu, C, and Chao, NJ. "Transfer of allogeneic CD62L- memory T cells without graft-versus-host disease." Blood 103.4 (February 15, 2004): 1534-1541.
PMID
14551132
Source
pubmed
Published In
Blood
Volume
103
Issue
4
Publish Date
2004
Start Page
1534
End Page
1541
DOI
10.1182/blood-2003-08-2987

Growth hormone accelerates immune recovery following allogeneic T-cell-depleted bone marrow transplantation in mice.

OBJECTIVE: To test in a murine model whether recombinant human growth hormone can promote immune recovery after allogeneic T-cell-depleted bone marrow transplantation. MATERIALS AND METHODS: Lethally irradiated (8.5 Gy) BALB/c mice (H2(d)) were transplanted with 5 x 10(6) T cell-depleted bone marrow cells from C57BL/6 mice (H2(b)). Recipient mice were injected intraperitoneally with recombinant human growth hormone (20 microg/dose/day) or saline for the first 4 weeks after transplantation. These animals were followed for phenotypic and functional immune recovery. RESULTS: Administration of human recombinant growth hormone improved the CD4(+) T-cell counts in peripheral blood on day +14 (44+/-14 vs 33+/-7/microL blood, p<0.05) and day +21 (281+/-109 vs 187+/-76/microL blood, p<0.01) compared with the saline control. These differences were no longer significant by day +28 despite continued growth hormone administration. Similar effects were also observed on CD8(+) T cells and B220(+) B cells. The improvements in peripheral T-cell counts were at least partially as a result of enhanced thymopoiesis because there was an increase in total thymocytes after treatment with growth hormone. T-cell-depleted bone marrow recipients treated with growth hormone rejected the third-party grafts faster than those treated with saline control (median survival time: 20 days vs 26 days, p<0.05). CONCLUSIONS: These data demonstrated that recombinant human growth hormone can accelerate phenotypic and functional immune reconstitution following allogeneic T-cell-depleted bone marrow transplantation in mice.

Authors
Chen, BJ; Cui, X; Sempowski, GD; Chao, NJ
MLA Citation
Chen, BJ, Cui, X, Sempowski, GD, and Chao, NJ. "Growth hormone accelerates immune recovery following allogeneic T-cell-depleted bone marrow transplantation in mice." Exp Hematol 31.10 (October 2003): 953-958.
PMID
14550811
Source
pubmed
Published In
Experimental Hematology
Volume
31
Issue
10
Publish Date
2003
Start Page
953
End Page
958

Prevention of graft-versus-host disease while preserving graft-versus-leukemia effect after selective depletion of host-reactive T cells by photodynamic cell purging process.

In this study, we investigated the possibility of selective depletion of donor alloantigen-specific T cells from C57BL/6 (H-2(b)) mice to prevent graft-versus-host disease (GVHD). These cells were first activated with irradiated BALB/c (H-2(d)) host spleen cells in a 5-day mixed lymphocyte culture. Following this activation, a photoactive rhodamine derivative called 4,5-dibromorhodamine 123 (TH9402), was added. This compound is selectively retained in the mitochondria of activated host-reactive cells but not tumor- or third-party-specific resting cells. The treated cells were subsequently exposed to visible light (514 nm) to deplete the TH9402-enriched activated host-reactive cells. Treatment with photodynamic cell purging process (PDP) inhibited antihost responses measured by cytotoxic T lymphocytes (CTL) by 93%, and interferon-gamma production by 66%. By contrast, anti-BCL1 (BALB/c-origin leukemia/lymphoma) and anti-third-party C3H/HeJ (H-2(k)) responses were preserved. PDP-treated primed C57BL/6 cells were further tested in vivo. All lethally irradiated BALB/c mice inoculated with BCL1 cells and T-cell-depleted bone marrow cells developed leukemia by day +30, with 50% mortality by 100 days. All mice died of GVHD after addition of 5 x 10(6) untreated primed C57BL/6 cells. However, addition of same numbers of PDP-treated cells allowed 90% of the recipients to survive more than 100 days without detectable BCL1 tumor cells and free of GVHD. Moreover, PDP-treated primed C57BL/6 cells retained the ability to induce GVHD in the third-party C3H/HeJ mice. These data suggest that PDP can selectively deplete host alloantigen-specific T cells for GVHD prevention and immune and antileukemia function preserve.

Authors
Chen, BJ; Cui, X; Liu, C; Chao, NJ
MLA Citation
Chen, BJ, Cui, X, Liu, C, and Chao, NJ. "Prevention of graft-versus-host disease while preserving graft-versus-leukemia effect after selective depletion of host-reactive T cells by photodynamic cell purging process." Blood 99.9 (May 1, 2002): 3083-3088.
PMID
11964269
Source
pubmed
Published In
Blood
Volume
99
Issue
9
Publish Date
2002
Start Page
3083
End Page
3088

Addition of a second, different allogeneic graft accelerates white cell and platelet engraftment after T-cell-depleted bone marrow transplantation.

Significant delays in engraftment and lymphoid recovery are the 2 major challenges in cord blood transplantation. The cause for this delay is presumed to be the low numbers of hematopoietic precursors found in one unit of cord blood. One approach to increase the stem cell doses could be to combine cord blood units from different donors differing at the major histocompatibility complex (MHC). As a first step toward this goal, the kinetics of hematologic engraftment and immune reconstitution were compared between 1 unit (2.5 x 10(6) cells) of T-cell-depleted bone marrow cells from a single donor (C57BL/6 [H2(b)] or SJL/J [H2(s)]) and 2 units from different donors (C57BL/6 + SJL/J) after transplantation into lethally irradiated (8.5 Gy) BALB/c recipients (H2(d)). Addition of T-cell-depleted bone marrow from an MHC-mismatched allogeneic donor doubled the white blood counts compared with recipients of one single unit on days +10 and +14. Similar effects were also observed on platelets. The beneficial effect of additional cells on peripheral T-cell counts were first observed on day +14. Cells both from donors (C57BL/6 and/or SJL/J) and recipients (BALB/c) contributed to myeloid and lymphoid reconstitution. The chimeras containing cells from 3 strains of mice were able to mount a recall immune response. Our data suggest that combining stem cells from MHC-mismatched allogeneic donors is feasible, that it has beneficial effects on myeloid engraftment and T-cell phenotypic recovery, and that the long-term stable mixed chimeras are immunologically normal following T-cell-depleted bone marrow transplantation.

Authors
Chen, BJ; Cui, X; Chao, NJ
MLA Citation
Chen, BJ, Cui, X, and Chao, NJ. "Addition of a second, different allogeneic graft accelerates white cell and platelet engraftment after T-cell-depleted bone marrow transplantation." Blood 99.6 (March 15, 2002): 2235-2240.
PMID
11877303
Source
pubmed
Published In
Blood
Volume
99
Issue
6
Publish Date
2002
Start Page
2235
End Page
2240

Mechanisms of tolerance induced by PG490-88 in a bone marrow transplantation model.

BACKGROUND: PG490-88, a semisynthetic derivative of a novel compound PG490 (triptolide) purified from a Chinese herb (Tripterygium wilfordii Hook F), is effective in prevention of murine graft-versus-host disease (GVHD). METHODS: PG490-88 was administrated into recipients in a model (B10.D2 [H2d, Mls-2b, Mls-3b]-->BALB/c [H2d, Mls-2a, Mls-3a]) of lethal GVHD. Tolerance was evaluated by transplantation of neonatal hearts. The mechanisms of tolerance were studied. RESULTS: Host-specific tolerance was established in PG490-88-treated BALB/c recipients. Significant numbers of host reactive Vbeta3+ T cells (3.56+/-1.66% among CD4, 4.06+/-1.62% among CD8, P<0.0001 vs. normal BALB/c mice, P>0.05 vs. normal B10.D2 mice) were present in PG490-88-treated mice, suggesting that clonal deletion was not responsible for the observed tolerance. Spleen cells from PG490-88-treated mice could not respond to the host antigens measured by a popliteal lymph node weight gain assay. The unresponsiveness was unable to be overcome by supplementation of exogenous interleukin (IL)-2. Tolerant Vbeta3+ T cells obtained from PG490-88-treated mice proliferated normally to nonantigen-specific T cell receptor cross-linking. Neither antigen-specific nor nonantigen-specific suppressor cells were found in PG490-88-treated mice. The tolerant mice produced IL-4 rather than IL-2 and interferon (IFN)-gamma. CONCLUSIONS: Host-specific tolerance induced by PG490-88 in a murine bone marrow transplantation model is not due to deletion of alloreactive cells. Moreover, suppressor cells are not involved in the maintenance of tolerance. Rather, PG490-88 seems to lead to allogeneic tolerance either through the induction of a state of antigen-specific anergy of the responding T cells or through the induction of T-helper cell, type II (TH2) responses.

Authors
Chen, BJ; Chen, Y; Cui, X; Fidler, JM; Chao, NJ
MLA Citation
Chen, BJ, Chen, Y, Cui, X, Fidler, JM, and Chao, NJ. "Mechanisms of tolerance induced by PG490-88 in a bone marrow transplantation model." Transplantation 73.1 (January 15, 2002): 115-121.
PMID
11792990
Source
pubmed
Published In
Transplantation
Volume
73
Issue
1
Publish Date
2002
Start Page
115
End Page
121

A comparison of murine T-cell-depleted adult bone marrow and full-term fetal blood cells in hematopoietic engraftment and immune reconstitution.

Umbilical cord blood has been increasingly used as a source of hematopoietic stem cells. A major area of concern for the use of cord blood transplantation is the delay in myeloid and lymphoid recovery. To directly compare myeloid and lymphoid recovery using an animal model of bone marrow and cord blood as sources of stem cells, hematopoietic engraftment and immune recovery were studied following infusion of T-cell-depleted adult bone marrow or full-term fetal blood cells, as a model of cord blood in a murine allogeneic transplantation model (C57BL/6 [H-2(b)] --> BALB/c [H-2(d)]). Allogeneic full-term fetal blood has poorer radioprotective capacity but greater long-term engraftment potential on a cell-to-cell basis compared with T-cell-depleted bone marrow. Allogeneic full-term fetal blood recipients had decreased absolute numbers of T, B, and dendritic cells compared with bone marrow recipients. Splenic T cells in allogeneic full-term fetal blood recipients proliferated poorly, were unable to generate cytotoxic effectors against third-party alloantigens in vitro, and failed to generate alloantigen-specific cytotoxic antibodies in vivo. In addition, reconstituting T cells in fetal blood recipients had decreased mouse T-cell receptor delta single-joint excision circles compared with bone marrow recipients. At a per-cell level, B cells from fetal blood recipients did not proliferate as well as those found in bone marrow recipients. These results suggest that full-term fetal blood can engraft allogeneic hosts across the major histocompatibility barrier with slower hematopoietic engraftment and impaired immune reconstitution.

Authors
Chen, BJ; Cui, X; Sempowski, GD; Gooding, ME; Liu, C; Haynes, BF; Chao, NJ
MLA Citation
Chen, BJ, Cui, X, Sempowski, GD, Gooding, ME, Liu, C, Haynes, BF, and Chao, NJ. "A comparison of murine T-cell-depleted adult bone marrow and full-term fetal blood cells in hematopoietic engraftment and immune reconstitution." Blood 99.1 (January 1, 2002): 364-371.
PMID
11756193
Source
pubmed
Published In
Blood
Volume
99
Issue
1
Publish Date
2002
Start Page
364
End Page
371

Nonmyeloablative regimen preserves "niches" allowing for peripheral expansion of donor T-cells.

T-cell recovery following myeloablative preparatory regimens and cord blood transplantation in adult patients gen erally occurs between 1 and 3 years following allogeneic bone marrow transplantation. T-cell reconstitution may involve thymic education of donor-derived precursors or peripheral expansion of mature T-cells transferred in the graft. We measured quantitative and qualitative immunologic reconstitution, T-cell receptor spectratyping, and T-cell receptor excision circle (TREC) levels in adult recipients of umbilical cord blood transplants following a novel nonmyeloablative regimen. These results were compared to previously published results of similar patients receiving a myeloablative regimen and cord blood stem cells. With small numbers of patients treated so far, T-cells (CD3+) reached normal levels in adults 6 to 12 months following nonmyeloablative transplantation compared with 24 months in adults receiving a myeloablative regimen. At 12 months after transplantation, the numbers of phenotypically naive (CD45RA) T-cells were higher in those receiving the nonmyeloablative regimen. The T-cell repertoire in cord blood recipients treated with a nonmyeloablative regimen was markedly more diverse and robust compared with the repertoire in those receiving the myeloablative regimen at similar time points. TRECs (which are generated within the thymus and identify new thymic emigrants and those that have not divided) were detected 12 months after transplantation in the nonmyeloablative recipients, whereas TRECs were not detected in adults until 18 to 24 months in those receiving myeloablative regimens. Thus, in adults receiving a nonmyeloablative preparatory regimen, the quantitative and qualitative recovery of T-cells occurs through rapid peripheral expansion. The ability of patients receiving a nonmyeloablative regimen to recover within a few months suggests that the peripheral niches in which T-cells can proliferate are preserved in these patients compared to those receiving ablative regimens. Moreover, the presence of TREC-positive cells within 1 year suggests that thymic recovery is likewise accelerated in non myeloablative compared to myeloablative regimens.

Authors
Chao, NJ; Liu, CX; Rooney, B; Chen, BJ; Long, GD; Vredenburgh, JJ; Morris, A; Gasparetto, C; Rizzieri, DA
MLA Citation
Chao, NJ, Liu, CX, Rooney, B, Chen, BJ, Long, GD, Vredenburgh, JJ, Morris, A, Gasparetto, C, and Rizzieri, DA. "Nonmyeloablative regimen preserves "niches" allowing for peripheral expansion of donor T-cells." Biol Blood Marrow Transplant 8.5 (2002): 249-256.
PMID
12064361
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
8
Issue
5
Publish Date
2002
Start Page
249
End Page
256

Immunosuppressive and antiinflammatory effects of triptolide and its prodrug PG-490-88

Triptolide is a diterpenoid triepoxide purified from Tripterygium wilfordii Hook F, an herb found in China. Triptolide inhibits T cell activation mainly through inhibition of interleukin-2 production. In contrast to the target of ciclosporin and FK506, the target of triptolide is at the purine-box/ARRE/NF-AT and NF-κB target sequences after specific binding to DNA. Triptolide also induces apoptosis of T cells by activating the caspase cascade. Moreover, triptolide can suppress the expression of multiple proinflammatory cytokines and mediators, which play important roles in the pathogenesis of autoimmune diseases, transplantation rejection and GVHD. Although data in humans is very limited, triptolide has been successfully used to treat rheumatoid arthritis in humans and prevent bleomycin-induced lung fibrosis in mice. Triptolide significantly prolongs the survival of allogeneic grafts in rats and completely prevents lethal GVHD in mice. Despite its narrow therapeutic window, triptolide is a very potent immunosuppressant and antiinflammatory agent with unique mechanisms of action.

Authors
Chen, BJ; Chao, NJ
MLA Citation
Chen, BJ, and Chao, NJ. "Immunosuppressive and antiinflammatory effects of triptolide and its prodrug PG-490-88." Drugs of the Future 27.1 (2002): 57-60.
Source
scival
Published In
Drugs of the Future
Volume
27
Issue
1
Publish Date
2002
Start Page
57
End Page
60
DOI
10.1358/dof.2002.027.01.647608

Triptolide, a novel immunosuppressive and anti-inflammatory agent purified from a Chinese herb Tripterygium wilfordii Hook F.

Triptolide is a diterpenoid triepoxide purified from a Chinese herb Tripterygium Wilfordii Hook F (TWHF). TWHF has been used in traditional Chinese medicine for more than two thousand years. However, its potential value was recognized by the western medicine only after investigators observed the effectiveness of TWHF in the treatment of leprosy and rheumatoid arthritis. Triptolide has been identified as the major component responsible for the immunosuppressive and anti-inflammatory effects of TWHF. Triptolide inhibits both Ca(2+)-dependent and Ca(2+)-independent pathways and affects T cell activation through inhibition of interleukin-2 transcription at a site different from the target of cyclosporin A. Triptolide also has inhibitory effects on a variety of proinflammatory cytokines and mediators and on the expression of adhesion molecules by endothelial cells. Triptolide is effective for the treatment of a variety of autoimmune diseases and in prevention of allograft rejection and graft-versus-host disease in both animals and humans. Moreover, triptolide possesses antitumor and male anti-fertility effect. However, the toxicities of triptolide may be associated with renal, cardiac, hematopoietic and reproductive systems. Currently available data suggest that triptolide is a promising immunosuppressive and anti-inflammatory agent and should be explored further in autoimmune diseases and transplantation.

Authors
Chen, BJ
MLA Citation
Chen, BJ. "Triptolide, a novel immunosuppressive and anti-inflammatory agent purified from a Chinese herb Tripterygium wilfordii Hook F." Leuk Lymphoma 42.3 (July 2001): 253-265. (Review)
PMID
11699390
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
42
Issue
3
Publish Date
2001
Start Page
253
End Page
265
DOI
10.3109/10428190109064582

T-Cell recovery in adults and children following umbilical cord blood transplantation.

T-cell reconstitution following allogeneic stem cell transplantation may involve thymic education of donor-derived precursors or peripheral expansion of mature T cells transferred in the graft. T cell-receptor excision circles (sjTRECs) are generated within the thymus and identify new thymic emigrants and those that have not divided. We measured quantitative and qualitative immunologic reconstitution and sjTREC levels in adult and pediatric recipients of umbilical cord blood transplants (UCBTs). sjTRECs were detected at normal levels in all children, starting 12 months after transplantation. sjTRECs were not detected until 18 months after transplantation in adults, and then only at a 3-fold lower level than expected for age. We used complementarity-determining region 3 (CDR3) spectratyping to measure changes in T cell-receptor diversity occurring with restoration of thymic function. T-cell repertoires were skewed in adults and children at 12 to 18 months after transplantation but recovered to near-normal diversity at 2 to 3 years post-UCBT. T-cell repertoires appeared more diverse earlier in children (at 1 to 2 years post-UCBT) than in adults (at 3 to 4 years post-UCBT). We conclude that early T-cell recovery after UCBT occurs primarily through peripheral expansion of adoptively transferred donor T cells and results in skewing of the T-cell repertoire. The reappearance of sjTREC-containing cells after UCBT is associated with increasing numbers of phenotypicaly naive T cells, improved mitogen and recall antigen responses, and diversification of the T-cell repertoire. The delay in central T-cell recovery in adults relative to children may be due to differences in thymic function resulting from age-related atrophy, graft-versus-host disease, or the pharmacologic effects of prophylaxis and treatment of graft-versus-host disease.

Authors
Klein, AK; Patel, DD; Gooding, ME; Sempowski, GD; Chen, BJ; Liu, C; Kurtzberg, J; Haynes, BF; Chao, NJ
MLA Citation
Klein, AK, Patel, DD, Gooding, ME, Sempowski, GD, Chen, BJ, Liu, C, Kurtzberg, J, Haynes, BF, and Chao, NJ. "T-Cell recovery in adults and children following umbilical cord blood transplantation." Biol Blood Marrow Transplant 7.8 (2001): 454-466.
PMID
11569891
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
7
Issue
8
Publish Date
2001
Start Page
454
End Page
466

Prevention of graft-versus-host disease by a novel immunosuppressant, PG490-88, through inhibition of alloreactive T cell expansion.

BACKGROUND: PG490-88 is a water soluble, semisynthetic derivative of a novel compound PG490 (triptolide) purified from the Chinese herb Tripterygium Wilfordii Hook F. METHODS: PG490-88 was administrated into recipient mice in a model (B10.D2-->BALB/c) of lethal graft-versus-host disease (GVHD) to study the effects of PG490-88 on GVHD and on the various steps involved in the pathological course of GVHD. RESULTS: Injection of PG490-88 i.p. at a dose of 0.535 mg/kg/day for the first 3 weeks after transplantation protected all the recipients from developing GVHD up to 100 days after transplantation. PG490-88 inhibited in vivo both CD4+Vbeta3+ and CD8+Vbeta3+ T cell (alloreactive T cells in this model) expansion in the spleen by 64.09 and 34.02%, respectively, at the time when Vbeta3+ cell expansion was in the logarithmic phase (day 3 after transplantation). Intracellular cytokine staining without further in vitro activation demonstrated 47.42% inhibition of IL-2 production among CD4+ spleen cells in PG490-88-treated mice as compared to GVHD control on day 3 after transplantation. In contrast, CD25 (alpha chain of interleukin-2 receptor) expression did not differ. CONCLUSIONS: PG490-88 is highly effective in prevention of murine GVHD. The immunosuppressive effect of PG490-88 is mediated by inhibition of alloreactive T cell expansion through interleukin-2 production.

Authors
Chen, BJ; Liu, C; Cui, X; Fidler, JM; Chao, NJ
MLA Citation
Chen, BJ, Liu, C, Cui, X, Fidler, JM, and Chao, NJ. "Prevention of graft-versus-host disease by a novel immunosuppressant, PG490-88, through inhibition of alloreactive T cell expansion." Transplantation 70.10 (November 27, 2000): 1442-1447.
PMID
11118087
Source
pubmed
Published In
Transplantation
Volume
70
Issue
10
Publish Date
2000
Start Page
1442
End Page
1447

Graft-versus-host disease prevention by rapamycin: cellular mechanisms.

Understanding the cellular mechanisms that lead to graft-versus-host disease (GVHD) may lead to alternative approaches in the prevention or therapy of this disease process. In this manuscript, we investigated the mechanisms of action of the immunosuppressive drug rapamycin for the prevention of GVHD. GVHD-free long-term survival was achieved in BALB/c (H2d, Mls-2a, Mls-3a) recipients of B10.D2/nSnJ (H-2d, Mls-2a, Mls-3a) bone marrow and spleen cells after a 30-day course of high-dose rapamycin (5 mg/kg per day). Low responses to recipient and third-party cells in a mixed lymphocyte reaction (MLR) were observed as well as decreased mature T-cell numbers in the spleen. This low response was not due to defective interleukin (IL)-2 production, because exogenous IL-2 did not improve the responses in the MLR. However, GVHD-free long-term survival was associated with a large number of infiltrating mononuclear cells in the target organs of GVHD. This observation suggested the possibility that these cells were responsible for suppressing the immune response. Regulatory cells, which could suppress both antirecipient and third-party responses in vitro, were demonstrated to be present in the spleens of these GVHD-free long-term survivors. These results suggest that in addition to impaired cellular immune function, the presence of non-specific regulatory cells (ie, suppression) may contribute to maintenance of GVHD-free long-term survival induced by short-course rapamycin.

Authors
Chen, BJ; Morris, RE; Chao, NJ
MLA Citation
Chen, BJ, Morris, RE, and Chao, NJ. "Graft-versus-host disease prevention by rapamycin: cellular mechanisms." Biol Blood Marrow Transplant 6.5A (2000): 529-536.
PMID
11071258
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
6
Issue
5A
Publish Date
2000
Start Page
529
End Page
536

Mechanisms of tolerance induced by PG490-88 in a bone marrow transplantation model

PG490-88 is a semisyntheüc derivative of a novel compound PG490 (triptolide) purified from a Chinese herb (Tripterygium Wilfordii Hook F). Host specific tolerance in vivo was demonstrated in PG490-88-treated BALB/c recipients (H2d, Mls-21, Mls-3") of bone marrow and spleen cells from B10.D2 mice (H2d, Mls-2", Mls-3") by transplantation of recipient or third party neonatal hearts into the pinna of the ears of recipients. The mechanisms of tolerance were studied further in this model. Since all Vβ3 T cells, which recognize the superantigens Mls-2 and Mls-3 and are present in donor B l O.D2 mice but not in recipient BALB/c mice, are activated and cause GVHD in BALB/c recipients, all Vβ3+ T cells are considered host reactive T cells in this model. Therefore, the roles of clonal deletion/anergy can be studied by following the fate of Vβ3 T cells. As shown in the figure, significant numbers of host reactive Vβ3 CD4+ T cells (3.56+1.66 %), which were significant higher than those in normal BALB/c mice (0.27±0.12, P<0.0001) and were comparable with those in normal B l O.D2 mice (6.18±0.51, P>0.05), were present in PG490-88-treated mice. Simulât results were obtained on CD8 T cells. t r(Figure Presented) 6 NomulBALWc 5 OT-d«plet»d bone marrow T 4 OPG49M8 I I 3 ONwrnil BIO D2 BH These results suggest that clonal deletion was not responsible for the observed tolerance induced by PG490-88, In contrast, Vβ3- T cells were completely deleted in the control Tdepleted bone marrow recipients. Vβ3 T cells obtained from PG490-88-treated recipients which were demonstrated to be tolerant to host antigens proliferated normally in response to T cell receptor crosslinking mediated by anti-CD3 antibody. Neither antigen specific nor antigen nonspecific suppressor cells were found in PG490-88-treated mice. Taken together, the host specific tolerance induced by PG490-88 in a murine BMT model is not due to deletion of alloreactive cells. Moreover, suppressor cells are not involved in the maintenance of tolerance. Rather, PG490-88 appears to lead to allotolerance through the induction of a state of antigen specific anergy of the responding T cells.

Authors
Chen, BJ; Cui, X; Fidler, JM; Chao, NJ
MLA Citation
Chen, BJ, Cui, X, Fidler, JM, and Chao, NJ. "Mechanisms of tolerance induced by PG490-88 in a bone marrow transplantation model." Blood 96.11 PART II (2000): 309b-.
Source
scival
Published In
Blood
Volume
96
Issue
11 PART II
Publish Date
2000
Start Page
309b

Addition of stem cells from allogeneic donors accelerates engraftment and immune reconstitution after stem cell transplantation

Umbilical cord blood is a valuable source of hematopoietic stem cells. However, stem cell numbers are limited and there are significant delays in engraftment and immune reconstitution. Since full matching at the major histocompatibility complex (MHC) appears to be less critical in cord blood transplantation, one approach to increase the stem cell doses may be to combine cord blood units from different donors. The kinetics of hématologie engraftment and immune reconstitution were compared between one unit (2.5xlO')of T-depleted bone marrow cells from one single donor (C57BL/6 [H2b] or SJL/ J [H2s) and two units from different donors (C57BL/6+SJL/J) after transplantation into lethally irradiated (8.5Gy) BALB/c recipients (H2d). The dose of 2.5xl06 is the minimum required for rescuing the majority of the recipients. As shown in the figure, addition of one unit of stem cells from MHC mismatched allogeneic donor doubled the white blood counts on day+10 and +14. The differences were no longer significant on day +21, with the white counts only half of the pre-transplantation level. Similar effects were also observed on platelet count and hematocrit. The differences on peripheral T and B cell counts were first observed on day +21 and were not significant on day +60. Kinetics of chimerism demonstrated that cells from both donor (C57BL/6 and/or SJL/J) or recipient (BALB/c) contributed to myeloid and lymphoid reconstitution. However, when the stem cell doses in one single unit were increased to 1 x 107, the beneficial effects were not observed. The chimeras, containing cells from all three strains of mice survived in good health for more than 200 days after transplantation and were able to mount a recall immune response upon the challenge of ovalbumin in vivo. Our data suggest that addition of stem cells from MHC mismatched allogeneic donors is feasible and has beneficial effects on engraftment and immune reconstitution in a murine model of stem cell transplantation.

Authors
Chen, BJ; Cui, X; Chao, NJ
MLA Citation
Chen, BJ, Cui, X, and Chao, NJ. "Addition of stem cells from allogeneic donors accelerates engraftment and immune reconstitution after stem cell transplantation." Blood 96.11 PART I (2000): 171a-.
Source
scival
Published In
Blood
Volume
96
Issue
11 PART I
Publish Date
2000
Start Page
171a

Graft-Versus-Host Disease Prevention by Rapamycin: Cellular Mechanisms

Understanding the cellular mechanisms that lead to graft-versus-host disease (GVHD) may lead to alternative approaches in the prevention or therapy of this disease process. In this manuscript, we investigated the mechanisms of action of the immunosuppressive drug rapamycin for the prevention of GVHD. GVHD-free long-term survival was achieved in BALB/c (H2d, Mls-2a, Mls-3a) recipients of B10.D2/nSnJ (H-2d, Mls-2a, Mls-3a) bone marrow and spleen cells after a 30-day course of high-dose rapamycin (5 mg/kg per day). Low responses to recipient and third-party cells in a mixed lymphocyte reaction (MLR) were observed as well as decreased mature T-cell numbers in the spleen. This low response was not due to defective interleukin (IL)-2 production, because exogenous IL-2 did not improve the responses in the MLR. However, GVHD-free long-term survival was associated with a large number of infiltrating mononuclear cells in the target organs of GVHD. This observation suggested the possibility that these cells were responsible for suppressing the immune response. Regulatory cells, which could suppress both antirecipient and third-party responses in vitro, were demonstrated to be present in the spleens of these GVHD-free long-term survivors. These results suggest that in addition to impaired cellular immune function, the presence of non-specific regulatory cells (ie, suppression) may contribute to maintenance of GVHD-free long-term survival induced by short-course rapamycin.

Authors
Chen, BJ; Morris, RE; Chao, NJ
MLA Citation
Chen, BJ, Morris, RE, and Chao, NJ. "Graft-Versus-Host Disease Prevention by Rapamycin: Cellular Mechanisms." Biology of Blood and Marrow Transplantation 6.5 A (2000): 529-536.
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
6
Issue
5 A
Publish Date
2000
Start Page
529
End Page
536

A synthetic random basic copolymer with promiscuous binding to class II major histocompatibility complex molecules inhibits T-cell proliferative responses to major and minor histocompatibility antigens in vitro and confers the capacity to prevent murine graft-versus-host disease in vivo.

Graft-versus-host disease (GVHD) is a T-cell-mediated disease of transplanted donor T cells recognizing host alloantigens. Data presented in this report show, to our knowledge, for the first time that a synthetic copolymer of the amino acids L-Glu, L-Lys, L-Ala, and L-Tyr (molecular ratio, 1.9:6.0:4.7:1.0; Mr, 6000-8500) [corrected], termed GLAT, with promiscuous binding to multiple major histocompatibility complex class II alleles is capable of preventing lethal GVHD in the B10.D2 --> BALB/c model (both H-2d) across minor histocompatibility barriers. Administration of GLAT over a limited time after transplant significantly reduced the incidence, onset, and severity of disease. GLAT also improved long-term survival from lethal GVHD: 14/25 (56%) of experimental mice survived > 140 days after transplant compared to 2/26 of saline-treated or to 1/10 of hen egg lysozyme-treated control mice (P < 0.01). Long-term survivors were documented to be fully chimeric by PCR analysis of a polymorphic microsatellite region in the interleukin 1beta gene. In vitro, GLAT inhibited the mixed lymphocyte culture in a dose-dependent fashion across a variety of major barriers tested. Furthermore, GLAT inhibited the response of nylon wool-enriched T cells to syngeneic antigen-presenting cells presenting minor histocompatibility antigens. Prepulsing of the antigen-presenting cells with GLAT reduced the proliferative response, suggesting that GLAT inhibits antigen presentation.

Authors
Schlegel, PG; Aharoni, R; Chen, Y; Chen, J; Teitelbaum, D; Arnon, R; Sela, M; Chao, NJ
MLA Citation
Schlegel, PG, Aharoni, R, Chen, Y, Chen, J, Teitelbaum, D, Arnon, R, Sela, M, and Chao, NJ. "A synthetic random basic copolymer with promiscuous binding to class II major histocompatibility complex molecules inhibits T-cell proliferative responses to major and minor histocompatibility antigens in vitro and confers the capacity to prevent murine graft-versus-host disease in vivo." Proc Natl Acad Sci U S A 93.10 (May 14, 1996): 5061-5066.
PMID
8643529
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
93
Issue
10
Publish Date
1996
Start Page
5061
End Page
5066

Erratum: A synthetic random basic copolymer with promiscuous binding to class II major histocompatibility complex molecules (Proceedings of the National Academy of Science of the United States of America (May 14, 1996) 93:10 (5061-5066))

Authors
Schlegel, PG; Aharoni, R; Chen, Y; Chen, J; Teitelbaum, D; Arnon, R; Sela, M; Chao, NJ
MLA Citation
Schlegel, PG, Aharoni, R, Chen, Y, Chen, J, Teitelbaum, D, Arnon, R, Sela, M, and Chao, NJ. "Erratum: A synthetic random basic copolymer with promiscuous binding to class II major histocompatibility complex molecules (Proceedings of the National Academy of Science of the United States of America (May 14, 1996) 93:10 (5061-5066))." Proceedings of the National Academy of Sciences of the United States of America 93.16 (1996): 8796--.
Source
scival
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
93
Issue
16
Publish Date
1996
Start Page
8796-
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Research Areas:

  • Administration, Inhalation
  • Adoptive Transfer
  • Adult
  • Airway Resistance
  • Algorithms
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents, Alkylating
  • Apoptosis
  • Autoimmune Diseases
  • B-Lymphocytes
  • Blood Cell Count
  • Blood Platelets
  • Bone Marrow
  • Bone Marrow Cells
  • Bone Marrow Purging
  • Bone Marrow Transplantation
  • CD4-Positive T-Lymphocytes
  • Calibration
  • Cell Count
  • Cell Death
  • Cell Differentiation
  • Cell Division
  • Cell Separation
  • Cell Survival
  • Cell Transplantation
  • Cells, Cultured
  • Chemokines
  • Chimera
  • Chimerism
  • Clonal Anergy
  • Clonal Deletion
  • Coculture Techniques
  • Colony-Forming Units Assay
  • Computer Simulation
  • Cytokines
  • DNA
  • Dendritic Cells
  • Disease Models, Animal
  • Diterpenes
  • Drugs, Chinese Herbal
  • Ear
  • Endothelial Cells
  • Endothelium, Vascular
  • Epoxy Compounds
  • Erythrocytes
  • Escherichia coli
  • Female
  • Fetal Blood
  • Flow Cytometry
  • Graft Rejection
  • Graft Survival
  • Graft vs Host Disease
  • Graft vs Leukemia Effect
  • Graft vs Tumor Effect
  • Growth Hormone
  • Heart
  • Hematologic Neoplasms
  • Hematopoiesis
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells
  • Humans
  • Immune System
  • Immunity
  • Immunity, Innate
  • Immunologic Memory
  • Immunosuppression
  • Immunosuppressive Agents
  • Infant
  • Isoantigens
  • Kidney
  • Light
  • Lipopolysaccharides
  • Lung
  • Lymph Nodes
  • Lymphocyte Activation
  • Lymphocyte Count
  • Lymphocyte Depletion
  • Macrophages, Alveolar
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Inbred MRL lpr
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Animal
  • Myocardium
  • Neoplasm Staging
  • Nephritis
  • Neutrophil Infiltration
  • Peptides
  • Peroxidase
  • Phantoms, Imaging
  • Phenanthrenes
  • Photochemotherapy
  • Phytotherapy
  • Pneumonia
  • Pneumonia, Bacterial
  • Polymers
  • Primates
  • Prodrugs
  • Pulmonary Alveoli
  • RNA, Messenger
  • Radiation Chimera
  • Radiation Dosage
  • Radiation Injuries
  • Radiation Injuries, Experimental
  • Radiometry
  • Rats
  • Receptor, Angiotensin, Type 1
  • Receptors, Antigen, T-Cell
  • Recombinant Proteins
  • Recovery of Function
  • Reproducibility of Results
  • Skin
  • Skin Neoplasms
  • Skin Transplantation
  • Specific Pathogen-Free Organisms
  • Spleen
  • Stem Cell Transplantation
  • Stem Cells
  • Survival Rate
  • T-Lymphocyte Subsets
  • T-Lymphocytes
  • Thymus Gland
  • Toll-Like Receptor 4
  • Transplantation Chimera
  • Transplantation Immunology
  • Transplantation, Heterologous
  • Transplantation, Homologous
  • Tumor Cells, Cultured
  • Whole-Body Irradiation
  • Wounds, Penetrating