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Thomas Wekerle^*, Mohamed H. Sayegh, Joshua Hill^*, Yong Zhao^*, Anil Chandraker, Kirsten G. Swenson^*, Guiling Zhao^*, and Megan Sykes^*

From the ^* Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 02129; and the Laboratory of Immunogenetics and Transplantation, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115

A reliable, nontoxic method of inducing transplantation tolerance is needed to overcome the problems of chronic organ graft rejection and immunosuppression-related toxicity. Treatment of mice with single injections of an anti-CD40 ligand antibody and CTLA4Ig, a low dose (3 Gy) of whole body irradiation, plus fully major histocompatibility complex–mismatched allogeneic bone marrow transplantation (BMT) reliably induced high levels (>40%) of stable (>8 mo) multilineage donor hematopoiesis. Chimeric mice permanently accepted donor skin grafts (>100 d), and rapidly rejected third party grafts. Progressive deletion of donor-reactive host T cells occurred among peripheral CD4⁺ lymphocytes, beginning as early as 1 wk after bone marrow transplantation. Early deletion of peripheral donor-reactive host CD4 cells also occurred in thymectomized, similarly treated marrow recipients, demonstrating a role for peripheral clonal deletion of donor-reactive T cells after allogeneic BMT in the presence of costimulatory blockade. Central intrathymic deletion of newly developing T cells ensued after donor stem cell engraftment had occurred. Thus, we have shown that high levels of chimerism and systemic T cell tolerance can be reliably achieved without myeloablation or T cell depletion of the host. Chronic immunosuppression and rejection are avoided with this powerful, nontoxic approach to inducing tolerance.

Key Words: tolerance • transplantation • costimulation • chimerism • bone marrow

¹ Abbreviations used in this paper: ATX, thymectomized; BM, bone marrow; BMT, bone marrow transplantation; CD40L, CD40 ligand; FCM, flow cytometric analysis; MR1, hamster anti–mouse CD40L mAb; MST, median survival time; WBI, whole body irradiation.

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• Iwakoshi, N. N., Mordes, J. P., Markees, T. G., Phillips, N. E., Rossini, A. A., Greiner, D. L. (2000). Treatment of Allograft Recipients with Donor-Specific Transfusion and Anti-CD154 Antibody Leads to Deletion of Alloreactive CD8+ T Cells and Prolonged Graft Survival in a CTLA4-Dependent Manner. J. Immunol. 164: 512-521 [Abstract] [Full Text]  
• Storb, R., Yu, C., Zaucha, J. M., Deeg, H. J., Georges, G., Kiem, H.-P., Nash, R. A., McSweeney, P. A., Wagner, J. L. (1999). Stable Mixed Hematopoietic Chimerism in Dogs Given Donor Antigen, CTLA4Ig, and 100 cGy Total Body Irradiation Before and Pharmacologic Immunosuppression After Marrow Transplant. Blood 94: 2523-2529 [Abstract] [Full Text]  
• Maxwell, J. R., Campbell, J. D., Kim, C. H., Vella, A. T. (1999). CD40 Activation Boosts T Cell Immunity In Vivo by Enhancing T Cell Clonal Expansion and Delaying Peripheral T Cell Deletion. J. Immunol. 162: 2024-2034 [Abstract] [Full Text]  
• ROSSINI, A. A., GREINER, D. L., MORDES, J. P. (1999). Induction of Immunologic Tolerance for Transplantation. Physiol. Rev. 79: 99-141 [Abstract] [Full Text]  

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