EXTRATHYMIC T-CELL DELETION AND ALLOGENEIC STEM-CELL ENGRAFTMENT INDUCED WITH COSTIMULATORY BLOCKADE IS FOLLOWED BY CENTRAL T-CELL TOLERANCE

A reliable, nontoxic method of inducing transplantation tolerance is n eeded to overcome the problems of chronic organ graft rejection and im munosuppression-related toxicity. Treatment of mice with single inject ions of an anti-CD40 ligand antibody and CTLA4Ig, a low dose (3 Gy) of whole body irradiation, plus fully major histocompatibility complex-m ismatched allogeneic bone marrow transplantation (BMT) reliably induce d high levels (>40%) of stable (>8 mo) multilineage donor hematopoiesi s. Chimeric mice permanently accepted donor skin grafts (>100 d), and rapidly rejected third party grafts. Progressive deletion of donor-rea ctive host T cells occurred among peripheral CD4+ lymphocytes, beginni ng as early as 1 wk after bone marrow transplantation. Early deletion of peripheral donor-reactive host CD4 cells also occurred in thymectom ized, similarly treated marrow recipients, demonstrating a role for pe ripheral clonal deletion of donor-reactive T cells after allogeneic BM T in the presence of costimulatory blockade. Central intrathymic delet ion of newly developing T cells ensued after donor stem cell engraftme nt had occurred. Thus, we have shown that high levels of chimerism and systemic T cell tolerance can be reliably achieved without myeloablat ion or T cell depletion of the host. Chronic immunosuppression and rej ection are avoided with this powerful, nontoxic approach to inducing t olerance.