The long-range goal of this study is to develop the capability of providing allogeneic marrow transplantation to patients who lack an HLA genotypically identical sibling donor. Both """"""""partially matched"""""""" related and phenotypically matched unrelated individuals will be considered as alternative donors and the feasibility and efficacy of transplantation in this setting will be evaluated. Although successful HLA incompatible transplants have been performed, it is not clear whether disparity for any given HLA antigen will cause a significant allograft reaction. For this reason, we will continue to analyze the role of HLA in marrow transplantation and will attempt to define the minimal degree of HLA class I and class II compatibility required to reduce the incidence of graft rejection and graft-versus-host disease (GVHD). Further elucidation of the most relevant genetic factors will be especially important in helping to establish practical matching criteria for selecting volunteer unrelated marrow donors. Pilot clinical trials will be undertaken to determine whether additional immunosuppressive therapy, including total lymphoid irradiation (TLI) and monoclonal antibodies, can reduce the risk of rejection. This objective must be successfully addressed before T cell depletion of donor marrow can be safely used for the prevention of GVHD in mismatched transplants. The laboratory components of this project will address three transplanted-related questions. First, we will study T cell reactivity immediately following transplantation by cloning and limiting dilution methods to determine whether variants of conventionally-defined HLA alleles or undetected HLA determinants can induce specific T cell reactivity. Second, we will determine the frequency of recombination within the HLA-D region, and study whether such recombination in putative identical siblings might increase the risk of GVHD. Third, we will study the suppressor T cells that regulate autoreactive and non- HLA-reactive effector cells, and the role that these suppressors play in preventing anti-host responses and induction of tolerance in HLA identical transplants.
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