Early host @entity405 T-cell recovery and sensitized anti-donor XXXX -producing and cytotoxic T-cell responses associated with marrow graft rejection following nonmyeloablative allogeneic bone marrow transplantation.

@entity1 @entity5 @entity786 @entity1503 @entity2132 @entity1199 @entity405
OBJECTIVE: We developed a nonmyeloablative conditioning regimen for allogeneic bone marrow transplantation (BMT) followed by donor lymphocyte infusions (DLI) for treatment of chemotherapy refractory @entity5 . Although the majority of @entity1 who receive this regimen achieve lasting mixed or full allogeneic chimerism, approximately 30% show initial mixed chimerism followed by loss of the donor graft. These @entity1 recover host hematopoiesis without significant @entity1503 . To assess the role of immunologic rejection in graft loss, we compared T-cell recovery and in vitro alloresponses in six @entity1 who lost their marrow graft to that in 16 concurrent @entity1 with sustained donor chimerism. @entity1 AND METHODS: Conditioning included pretransplant @entity786 (150-200 mg/kg), thymic irradiation (700 cGy), and pre- and post-transplant equine antithymocyte globulin (ATG; ATGAM). HLA-identical related donor BMT was followed by DLI at approximately day 35 in @entity1 without @entity2132 . RESULTS: The group with transient chimerism showed significantly increased circulating host T-cell (median 416 cells/mm(3) vs 10 cells/mm(3), p<0.05) and @entity405 T-cell numbers (354 cells/mm(3) vs 71 cells/mm(3), p<0.05) compared to the group with stable mixed or full donor chimerism within the first 100 days post-BMT. All DLI recipients who lost chimerism following DLI had greater than 80% recipient T cells at the time of DLI, whereas those with persistent chimerism had <60% host T cells. Graft rejection was associated with the development of a sensitized anti-donor bulk cytotoxic T-lymphocyte (CTL) response in 4 of 6 evaluated @entity1 , compared to only 1 of 10 evaluated @entity1 with sustained chimerism (p<0.05). Additionally, 3 of 5 evaluated transient chimeras showed high anti-donor CTL precursor frequencies in limiting dilution assays, and 3 of 4 evaluated transient chimeras showed high anti-donor @entity1199 ( @entity1199 )-producing T-helper (T(H)) cell frequencies. High anti-donor T(H) or cytotoxic T-lymphocyte precursors were not detected in sustained chimeras. CONCLUSION: These data indicate that loss of chimerism in @entity1 receiving this nonmyeloablative regimen is due to immune-mediated rejection. This rejection appears to bemediated by recovering recipient cytolytic @entity405 (+) cells as well as @entity1199 -producing recipient T(H) cells. These data are the first to demonstrate sensitization of recipient anti-donor @entity1199 -producing cells in association with @entity1 marrow allograft rejection.
