Bone marrow transplantation is an important clinical procedure for the cure of such diseases as aplastic anemia, leukemia, and severe combined immunodeficiency. Its potential application for numerous other hematologic disorders is obvious, if the risk factors associated with the technique could be significantly reduced. In this regard, the major complication developing after marrow transfer is graft-versus-host disease (GVHD), which occurs when there is a genetic histoincompatibility between the marrow donor and recipient. Mature T cells contaminating the donor marrow inoculum were first shown to be the cause of the disease in animal models and since then have been strongly implicated as the cause in man. However, the etiological role of particular T-cell subsets (helper or cytotoxic) and the mechanisms that are involved in the pathogenesis of GVHD are still obscure. Murine models for GVHD have been chosen to study these questions, largely because of the availability of both genetically well-defined inbred strains and reagents for characterizing lymphoid subpopulations. Preliminary data in these models suggest that different T-cell subsets may be responsible for GVHD when directed to either non-MHC, class I, or class II MHC-type antigens, i.e., Lyt 2+ cells appear to be involved in anti-minor H and H-2K GVHD whereas Lyt 1+2- cells may be responsible for anti-full MHC or I region GVHD. Our principal aim is to clearly define the participation of these T-cell subsets in GVHD across various genetic barriers. This will be approached by both negative and positive selection techniques of cell subsets in donor inoculum and by sequential histopathologic examination of mice undergoing GVHD. Models for two other major sources of complication in bone marrow transplantation, that of immunodeficiency associated with GVHD and host-versus-marrow graft rejection, will also be investigated. Focus will be placed on the lack of CTL antiviral responses in mice with ongoing GVHD and the cause of host resistance across a non-MHC genetic barrier. The projects presented in this proposal should add significant basic understanding of these major obstacles to clinical marrow transplantation and provide new insights towards possible approaches to surmount them. (TT)
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