Allogeneic bone marrow transplantation (BMT) has been successfully applied in the treatment of hematological malignancies. The eradication of leukemia following allogeneic BMT is in part due to due to a graft- versus-leukemia (GVL) effect mediated by the donor T cell. Clinically, the GVL effect is associated with a donor T cell-mediated graft-versus- host disease (GVHD), which is commonly fatal. In patients receiving BMT from HLA-matched donors, host antigens responsible for GVHD and GVL effect are functionally defined as the minor histocompatibility antigens (MiHA). The MiHA system is poorly characterized and few MiHA proteins responsible for GVL and/or GVH effects have been identified. Several studies indicated that MiHA may have selective tissue-restricted expression. The current grant will develop leukemia therapy with donor CD4+ and CD8+ T cell subsets specific for host hematopoietic tissue- restricted MiHA in murine models. The hypothesis to be tested is that targeting donor T-cell immunity against MiHA exclusively expressed on host hematopoietic cells may preserve a curative GVL effect without causing GVHD. The functional distinct MiHA-specific donor CD4+ and CD8+ T cell subsets may differentially mediate the processes in GVL effect and GVHD. The insights gained from this study may advance the understanding of the role of donor T cell subsets in mediating GVL and GVH effects and enable us to develop new therapeutic strategies for overcoming the clinical problem currently preventing the successful treatment of leukemia with donor T cells following allogeneic BMT.
The specific aims are: 1. To analyze the therapeutic efficacy, toxicity and mechanisms of donor CD4+Th1 and Th2 subsets specific for host hematopoietic tissue- restricted MiHA. 2. To assess the therapeutic efficacy, toxicity and mechanisms of donor CD8+ Tc1 and Tc2 specific for host hematopoietic tissue-restricted MiHA. 3. To develop methods develops for in vitro induction of MiHA-specific T cells for leukemia therapy.
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