Clinical bone marrow transplantation is an important therapeutic treatment for several diseases including high risk leukemia, aplastic anemia, and severe combined immunodeficiency. In addition there is a wide range of metabolic and genetic disorders that can potentially be corrected by this approach. Recently, based on preliminary data, it has also been suggested that marrow transplantation may be a very effective tool in acquired immunodeficiency syndrome (AIDS) therapy. However, the usefulness of marrow transplantation is currently limited by several important risk factors, the principal one being graft-versus-host disease (GVHD), an oftentimes lethal complication which occurs in 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 CD4+ and CD8+ T cell subsets in GVHD directed across both major histocompatibility complex (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, particularly across multiple minor H antigen differences. In this regard we will concentrate our efforts specifically on the following areas: 1) the features of T cell subsets mediating GVHD directed to minor H antigens including the functional characteristics and related differences in pathogenesis of the T cell subsets involved, the tissue expression of minor H antigens and recognition sites for T cell subsets, and the role of tumor necrosis factor (TNF) in development of GVHD; (2) the role of immunodominance in GVHD responses to multiple minor H antigens by which responses are directed to only a few select antigens, why in vivo results differ from in vitro, tissue distribution of minor H antigens, and mechanisms of immunodominance; and (3) the use of selective CD8+ T cell depletion of allogeneic donor inoculum to avoid GVHD directed to minor H antigens in irradiated recipients and allow for either enhanced resistance to cytomegalovirus (CMV) challenge or graft-versus-leukemia effects. In all, we feel that the projects designed in this proposal will add significant understanding to the mechanism and pathogenesis of GVHD as mediated by T cell subsets in MHC-matched transplantation situations. Insights generated from these studies will hopefully lead to new approaches for overcoming some of the major obstacles for improved and expanded use of clinical bone marrow transplantation.
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