Clinical bone marrow transplantation has become an important therapeutic treatment for several diseases including high risk leukemia, aplastic anemia, and severe combined immunodeficiency. However, graft-versus-host disease (GVHD) remains a major complication following a high proportion of transplants. The general aim of this proposal is to continue our study of the immunobiology of lethal GVHD in murine models. In recent years we have clearly defined the relative etiological roles of both Lyt-2+ and L3T4+ T cell subsets in GVHD directed across both MHC class I and II, and non-MHC (multiple minor H) genetic barriers. We now intend to focus on the characteristics of GVHD pathogenesis mediated by each of these subsets and to define involved mechanisms. In this regard we will concentrate our efforts specifically on the following areas: (1) the role of individual T cell subsets in the etiology and pathogenesis of GVHD across class I and class II MHC genetic barriers with emphasis on the functional activity and related differences in development of GVHD mediated by either Lyt-2+ or L3T4+ cells, the importance of target tissue expression of MHC antigens in development of GVHD, and the effect of non-MHC background genes on the GVHD potential of T cell subsets: (2) the features of T cell subsets mediating GVHD directed to minor H antigens including the role of exogenous """"""""help"""""""" GVHD mediated by purified Lyt-Z+ T cells, the functional characteristics and related differences in pathogenesis of T cell subsets Involved in anti-minor H GVHD, the value of in vitro assays for predicting L3T4+ cell GVHD potential, the importance of target tissue expression of minor H antigens for development of GVHD, the ability of single minor H antigens to induce lethal GVHD, and the role of immunodominance in GVHD responses to multiple minor H antigens; (3) the use of selective Lyt-2+ T cell depletion of allogeneic donor inoculum to avoid GVHD directed to minor H antigens in irradiated recipients and allow for graft-versus-leukemia effects to be mediated by remaining donor L3T4+ cells; and (4) the use of selective Lyt-2+ T cell depletion of allogeneic donor inoculum to avoid GVHD directed to minor H antigens and allow for protection of recipients to infectious virus challenge by presensitized donor L3T4+ T and B cells.
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