Prevention of Chronic Rejection in Murine Cardiac Allografts: A Comparison of Chimerism- and Nonchimerism-Inducing Costimulation Blockade-Based Tolerance Induction Regimens

Journal of Immunology - Tập 169 Số 5 - Trang 2677-2684 - 2002
Nozomu Shirasugi1, Andrew Adams1, Megan M. Durham1, Aron E. Lukacher1, Huaying Xu1, Phyllis A. Rees1, Shannon Cowan1, Matthew A. Williams1, Thomas C. Pearson1, Christian P. Larsen1
1The Carlos and Marguerite Mason Transplantation Biology Research Center, Departments of Surgery, Emory University School of Medicine, Atlanta, GA 30322

Tóm tắt

AbstractWe have previously described a nonirradiation-based regimen combining costimulation blockade, busulfan, and donor bone marrow cells that promotes stable, high level chimerism, deletion of donor-reactive T cells, and indefinite survival of skin allografts in mice. The purpose of the current study is to determine the efficacy of this tolerance regimen in preventing acute and chronic rejection in a vascularized heart graft model and to compare this regimen with other putative tolerance protocols. Mice receiving costimulation blockade (CTLA4-Ig and anti-CD40 ligand) alone or in combination with donor cells enjoyed markedly prolonged heart graft survival and initially preserved histological structure. However, tolerance was not achieved, as evidenced by the eventual onset of chronic rejection characterized by obliterative vasculopathy and the rejection of secondary skin grafts. In contrast, following treatment with costimulation blockade, busulfan, and bone marrow, heart grafts survived indefinitely without detectable signs of chronic rejection or structural damage, even 100 days after placement of a secondary donor skin graft. We detected multilineage chimerism in peripheral blood, spleen, lymph nodes, and thymus, and peripheral deletion of donor-reactive cells was complete by day 90. These findings indicate that only the CD40/CD28 blockade chimerism induction regimen prevents both acute and chronic rejection of vascularized organ transplants. Further testing of these strategies in a preclinical large animal model is warranted.

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Tài liệu tham khảo

Denton, M. D., C. C. Magee, M. H. Sayegh. 1999. Immunosuppressive strategies in transplantation. Lancet 353: 1083

Libby, P., J. S. Pober. 2001. Chronic rejection. Immunity 14: 387

Shimizu, K., U. Schonbeck, F. Mach, P. Libby, R. N. Mitchell. 2000. Host CD40 ligand deficiency induces long-term allograft survival and donor-specific tolerance in mouse cardiac transplantation but does not prevent graft arteriosclerosis. J. Immunol. 165: 3506

Russell, P. S., C. M. Chase, M. Sykes, H. Ito, J. Shaffer, R. B. Colvin. 2001. Tolerance, mixed chimerism, and chronic transplant arteriopathy. J. Immunol. 167: 5731

Larsen, C. P., E. T. Elwood, D. Z. Alexander, S. C. Ritchie, R. Hendrix, C. Tucker-Burden, H. R. Cho, A. Aruffo, D. Hollenbaugh, P. S. Linsley, et al 1996. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 381: 434

Sayegh, M. H., X. G. Zheng, C. Magee, W. W. Hancock, L. A. Turka. 1997. Donor antigen is necessary for the prevention of chronic rejection in CTLA4Ig-treated murine cardiac allograft recipients. Transplantation 64: 1646

Judge, T. A., Z. Wu, X. G. Zheng, A. H. Sharpe, M. H. Sayegh, L. A. Turka. 1999. The role of CD80, CD86, and CTLA4 in alloimmune responses and the induction of long-term allograft survival. J. Immunol. 162: 1947

Markees, T. G., N. E. Phillips, E. J. Gordon, R. J. Noelle, L. D. Shultz, J. P. Mordes, D. L. Greiner, A. A. Rossini. 1998. Long-term survival of skin allografts induced by donor splenocytes and anti-CD154 antibody in thymectomized mice requires CD4+ T cells, interferon-γ, and CTLA4. J. Clin. Invest. 101: 2446

Kirk, A. D., D. M. Harlan, N. N. Armstrong, T. A. Davis, Y. Dong, G. S. Gray, X. Hong, D. Thomas, J. H. Fechner, Jr, S. J. Knechtle. 1997. CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc. Natl. Acad. Sci. USA 94: 8789

Hamano, K., M. A. Rawsthorne, A. R. Bushell, P. J. Morris, K. J. Wood. 1996. Evidence that the continued presence of the organ graft and not peripheral donor microchimerism is essential for maintenance of tolerance to alloantigen in vivo in anti-CD4 treated recipients. Transplantation 62: 856

Billingham, R. E., L. Brent, P. B. Medawar. 1953. Actively acquired tolerance of foreign cells. Nature 172: 603

Owen, R. D.. 1945. Immunogenetic consequence of vascular anastomosis between bovine twins. Science 102: 400

Ildstad, S. T., D. H. Sachs. 1984. Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts. Nature 307: 168

Sharabi, Y., D. H. Sachs. 1989. Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen. J. Exp. Med. 169: 493

Tomita, Y., A. Khan, M. Sykes. 1994. Role of intrathymic clonal deletion and peripheral anergy in transplantation tolerance induced by bone marrow transplantation in mice conditioned with a nonmyeloablative regimen. J. Immunol. 153: 1087

Wekerle, T., M. H. Sayegh, J. Hill, Y. Zhao, A. Chandraker, K. G. Swenson, G. Zhao, M. Sykes. 1998. Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is followed by central T cell tolerance. J. Exp. Med. 187: 2037

Quesenberry, P. J., S. Zhong, H. Wang, M. Stewart. 2001. Allogeneic chimerism with low-dose irradiation, antigen presensitization, and costimulator blockade in H-2 mismatched mice. Blood 97: 557

Durham, M. M., A. W. Bingaman, A. B. Adams, J. Ha, S. Y. Waitze, T. C. Pearson, C. P. Larsen. 2000. Cutting edge: administration of anti-CD40 ligand and donor bone marrow leads to hemopoietic chimerism and donor-specific tolerance without cytoreductive conditioning. J. Immunol. 165: 1

Wekerle, T., J. Kurtz, H. Ito, J. V. Ronquillo, V. Dong, G. Zhao, J. Shaffer, M. H. Sayegh, M. Sykes. 2000. Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment. Nat. Med. 6: 464

Adams, A. B., M. M. Durham, L. Kean, N. Shirasugi, J. Ha, M. A. Williams, P. A. Rees, M. C. Cheung, S. Mittelstaedt, A. W. Bingaman, et al 2001. Costimulation blockade, busulfan, and bone marrow promote titratable macrochimerism, induce transplantation tolerance, and correct genetic hemoglobinopathies with minimal myelosuppression. J. Immunol. 167: 1103

Shirasugi, N., Y. Ikeda, Y. Akiyama, K. Matsumoto, K. Hamano, K. Esato, H. Bashuda, H. Yagita, K. Okumura, H. Takami, et al 2001. Induction of hyporesponsiveness to fully allogeneic cardiac grafts by intratracheal delivery of alloantigen. Transplantation 71: 561

Banchereau, J., R. M. Steinman. 1998. Dendritic cells and the control of immunity. Nature 392: 245

Fukao, T., S. Matsuda, S. Koyasu. 2000. Synergistic effects of IL-4 and IL-18 on IL-12-dependent IFN-γ production by dendritic cells. J. Immunol. 164: 64

Larsen, C. P., S. C. Ritchie, R. Hendrix, P. S. Linsley, K. S. Hathcock, R. J. Hodes, R. P. Lowry, T. C. Pearson. 1994. Regulation of immunostimulatory function and costimulatory molecule (B7-1 and B7-2) expression on murine dendritic cells. J. Immunol. 152: 5208

Bill, J., O. Kanagawa, D. L. Woodland, E. Palmer. 1989. The MHC molecule I-E is necessary but not sufficient for the clonal deletion of Vβ11-bearing T cells. J. Exp. Med. 169: 1405

Dyson, P. J., A. M. Knight, S. Fairchild, E. Simpson, K. Tomonari. 1991. Genes encoding ligands for deletion of Vβ11 T cells cosegregate with mammary tumor virus genomes. Nature 349: 531

O’Connell, P. J., A. Mba-Jonas, G. E. Leverson, D. M. Heisey, K. C. Meyer, R. B. Love, W. J. Burlingham. 1998. Stable lung allograft outcome correlates with the presence of intragraft donor-derived leukocytes. Transplantation 66: 1167

Welsh, R. M., T. G. Markees, B. A. Woda, K. A. Daniels, M. A. Brehm, J. P. Mordes, D. L. Greiner, A. A. Rossini. 2000. Virus-induced abrogation of transplantation tolerance induced by donor-specific transfusion and anti-CD154 antibody. J. Virol. 74: 2210

Burrows, S. R., S. L. Silins, R. Khanna, J. M. Burrows, M. Rischmueller, J. McCluskey, D. J. Moss. 1997. Cross-reactive memory T cells for Epstein-Barr virus augment the alloresponse to common human leukocyte antigens: degenerate recognition of major histocompatibility complex-bound peptide by T cells and its role in alloreactivity. Eur. J. Immunol. 27: 1726

Williams, M. A., J. T. Tan, A. B. Adams, M. M. Durham, N. Shirasugi, J. K. Whitmire, L. E. Harrington, R. Ahmed, T. C. Pearson, C. P. Larsen. 2001. Characterization of virus-mediated inhibition of mixed chimerism and allospecific tolerance. J. Immunol. 167: 4987

Sun, H., V. Subbotin, C. Chen, A. Aitouche, L. A. Valdivia, M. H. Sayegh, P. S. Linsley, J. J. Fung, T. E. Starzl, A. S. Rao. 1997. Prevention of chronic rejection in mouse aortic allografts by combined treatment with CTLA4-Ig and anti-CD40 ligand monoclonal antibody. Transplantation 64: 1838

Chandraker, A., H. Azuma, K. Nadeau, C. B. Carpenter, N. L. Tilney, W. W. Hancock, M. H. Sayegh. 1998. Late blockade of T cell costimulation interrupts progression of experimental chronic allograft rejection. J. Clin. Invest. 101: 2309

Kim, K. S., M. D. Denton, A. Chandraker, A. Knoflach, R. Milord, A. M. Waaga, L. A. Turka, M. E. Russell, R. Peach, M. H. Sayegh. 2001. CD28–B7-mediated T cell costimulation in chronic cardiac allograft rejection: differential role of B7-1 in initiation versus progression of graft arteriosclerosis. Am. J. Pathol. 158: 977

Trambley, J., A. W. Bingaman, A. Lin, E. T. Elwood, S. Y. Waitze, J. Ha, M. M. Durham, M. Corbascio, S. R. Cowan, T. C. Pearson, C. P. Larsen. 1999. Asialo GM1+ CD8+ T cells play a critical role in costimulation blockade-resistant allograft rejection. J. Clin. Invest. 104: 1715

Williams, M. A., J. Trambley, J. Ha, A. B. Adams, M. M. Durham, P. Rees, S. R. Cowan, T. C. Pearson, C. P. Larsen. 2000. Genetic characterization of strain differences in the ability to mediate CD40/CD28-independent rejection of skin allografts. J. Immunol. 165: 6849

Tullius, S. G., N. L. Tilney. 1995. Both alloantigen-dependent and -independent factors influence chronic allograft rejection. Transplantation 59: 313

Takada, M., A. Chandraker, K. C. Nadeau, M. H. Sayegh, N. L. Tilney. 1997. The role of the B7 costimulatory pathway in experimental cold ischemia/reperfusion injury. J. Clin. Invest. 100: 1199

Chandraker, A., M. Takada, K. C. Nadeau, R. Peach, N. L. Tilney, M. H. Sayegh. 1997. CD28–B7 blockade in organ dysfunction secondary to cold ischemia/reperfusion injury. Kidney Int. 52: 1678

Carbone, E., G. Ruggiero, G. Terrazano, C. Palomba, C. Manzo, S. Fontana, H. Spits, K. Karre, S. Zappacosta. 1997. A new mechanism of NK cell cytotoxicity activation: the CD40-CD40 ligand interaction. J. Exp. Med. 185: 2053

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Journal of Immunology

Tập 169 Số 5

2677-2684

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