Chambers, FD

Fu, F

Fung, JJ

Li, Y

Lu, L

Qian, S

Starzl, TE

Thomson, AW

English

PubMed

Name not available

Costimulatory molecule-deficient dendritic cell progenitors induce T cell hyporesponsiveness in vitro and prolong the survival of vascularized cardiac allografts

D-Scholarship@Pitt

f, 1; I J I ELSEVIER Costimulatory Molecule-Deficient Dendritic Cell Progenitors Induce T Cell Hyporesponsiveness In Vitro and Prolong the Survival of Vascularized Cardiac Allografts F. Fu, Y. Li, S. Qian, L. Lu, F.D. Chambers, T.E. Starzl, J.J. Fung, and A.W. Thomson D endritic cells (DC) are specialized antigen-presenting cells for the induction of cell-mediated immunity, including graft rejection. l Evidence also exists, however, for their tolerogenicity.2.3 We have previously shown that GM-CSF-stimulated mouse bone marrow (BM)-derived DC progenitors that express cell surface MHC class II antigens but are deficient in expression of the costimulatory mole-cules B7-1 (CD80) and B7-2 (CD86) can induce alloanti-gen-specific T cell anergy in vitro.4 In the present study. we tested the in vivo relevance of these findings in a vascular-ized cardiac allograft model. MATERIALS AND METHODS C57BL/1O (BlO; Hi'), C3H (H2k), or BALB/c (H2d ) mouse BM-derived DC progenitors. propagated in GM-CSF as described previously,5 were injected intravenously into normal C3H (H2k) recipients. Seven days later. the mice received abdominal heart transplants from normal BlO donors." No immunosuppressive treatment was given. Spleen T cells from the C3H mice seven days after the injection of DC progenitors of B10 donors were used as responder/effector cells in mixed leukocyte reaction (MLR) and cytotoxic T lymphocyte (CTL) assays. Cell surface phenotype was analyzed hy flow cytometry with a panel of monoclonal antihodies. RESULTS AND DISCUSSION As we reported previously, BIO mouse BM-derived DC progenitors (DEC20S T • MHC class II+, B7_1dim, B7-r) induced allogeneic-specific T cell hyporesponsiveness in C3H T cells in vitro.-' In addition, however, we found that B IO heart grafts were prolonged significantly in C3H mice that were injected intravenously with 2 x 10" of these BIO DC progenitors 7 days hefore transplantation [median survival time (MST) 22 days vs 9.S days in control group). MST was also prolonged although to a lesser extent (l6.S days) in miee that received third-party (BALB/C: H2d ) DC progenitors cultured under the same conditions and ex-0041-1315/97/$17.00 PII S0041-1345(96)00532-5 1310 pressing the same phenotype. However, C3H recipients injected with "mature" GM-CSF + IL-4 stimulated B10 DC (DEC20S+, MHC class nbright, B7-1+, B7_2bright) 7 days before transplant rejected BlO heart grafts in an acceler-ated fashion (MST 7 days). T cells from C3H mice given BI0 B7-r DC progenitors seven days earlier showed very low MLR responses to donor stimulators, but those from C3H mice injected with B7_2hright BlO DC showed marked proliferative responses to donor stimulators. T cells from C3H mice injected with B10 B7-r DC progenitors gener-ated lower CTL activity than animals given B7_2bright BlO DC. Amongst the injected donor MHC class 11+ DC progenitors that migrated to recipient secondary lymphoid tissue were cells that appeared to have unregulated cell surface B7-1 and B7-2 molecule expression. This observa-tion may at least in part explain the temporary or unstable nature of the hyporesponsiveness induced by donor-derived DC progenitors in non-immunosuppressed recipients. REFERENCES 1. Steinman RM: Annu Rev Immunol 9:271, 1991 2. Matzinger p, Guerder S: Nature 33R:74, 1989 3. Rastellini C. Lu L. Ricordi C. ct al: Transplantation 60:1366, 1995 4. Lu L. McCaslin D. Starzl TE, ct al: Transplantation 60:1539. 1995 5. Lu L. Woo j, Rao AS, et al: j Exp Mcd 179:1823, 1994 6. Ono K & Lindsey ES: J Thorac Cardiovasc Surg 7:225, 1969 From the Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania. Supported by NIH grants OK 29961-14 and DK 49745-01A 1. Address reprint requests to Dr Angus W. Thomson, W1 544 Biomedical Science Tower, Thomas E. Starzl Transplantation Institute, Univ of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213. © 1997 by Elsevier Science Inc. 655 Avenue of the Americas. New York, NY 10010 Transplantation Proceedings, 29. 1310 (1997) 

F. Fu

Y. Li

S. Qian

L. Lu

F.D. Chambers

T.E. Starzl

J.J. Fung

A.W. Thomson

Crossref

Transplantation Proceedings

Costimulatory molecule-deficient dendritic cell progenitors induce T cell hyporesponsiveness in vitro prolong the survival of vascularized cardiac allografts

http://d-scholarship.pitt.edu/5284/1/31735062133636.pdf

Costimulatory molecule-deficient dendritic cell progenitors induce T cell hyporesponsiveness in vitro and prolong the survival of vascularized cardiac allografts

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