Delayed Regulation of GVHD with Retained GVL Effect

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Following allogeneic blood and marrow transplantation (BMT), the high inverse correlation between graft-versus-host disease (GVHD) and leukemic relapse necessitates that calculated measures be taken to reduce GVHD pathology while retaining a graft-versus-leukemia (GVL) effect. In this regard, we have recently found that in the MHC-matched, minor histocompatibility antigen (miHA) disparate B10.BR->CBA murine model, freshly isolated donor CD4+CD25+ T cells were effective at suppressing early-ongoing CD8+ T cell-mediated GVHD when injected as late as day 10 post-BMT. Of importance, this early regulation of developing GVHD still permitted a potent GVL effect against a host-type myeloid leukemia (MM.CBA6) challenge. The overall goal of the project outlined here is to optimize the conditions for mediating GVHD regulation while maximizing the GVL effect, and to determine the precise cellular mechanisms involved in the elimination of the leukemia cells in vivo and the requirements for regulatory cell activity in order to stop the developing GVHD response. Our working hypothesis is that donor anti-host miHA cytotoxic T lymphocytes (CTL) are generated early after transplantation and readily encounter leukemia cells before they are able to mediate extensive target cell injury of GVHD. The addition of regulatory cells at day 10 post-BMT would then suppress both the GVHD and GVL responses, but the window for GVL interaction was large enough for prior elimination of the leukemic challenge. To test this hypothesis, we will focus on the following specific aims: 1) To determine the optimum conditions and mechanism for regulatory cell control over developing GVHD responses with the longest window of interactive opportunity; 2) To determine the mechanism of the GVL activity concomitant with CD4+CD25+ T cell regulation of developing GVHD responses in the B10.BR -> CBA and B6 -> BALB.B models; and 3) To determine the effect of anti-CTLA-4 mAb and GVAX treatments on GVL activity in the context of CD4+CD25+ T cell regulation of developing GVHD.