PATHOGENESIS OF CHRONIC GRAFT-VS-HOST DISEASE

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This work will examine the pathogenesis of chronic graft-versus-host (GVHD) in the rat. Bone marrow transplantation between the inbred AUG.2b (PVG) and AUG strains is associated with the appearance of a chronic, prolonged GVHD 4-6 months following transplantation. These two strains are congenic for a blood group antigen, RT2, and apparently differ for a histocompatibility locus identical to or closely linked to RT2. The experiments are designed to achieve three specific aims. The first is to characterize the cellular and humoral immunopathological changes present in the animals undergoing a chronic GVHD. The onset of clinical disease follows a period of stable chimerism and we are particularly interested in the immunological events that occur during the onset of the GVHD. Second, we intend to examine the pathogenesis of the cell-mediated lesions of the chronic GVHD by adoptive transfer, in vitro modification of the transplanted marrow, and the generation of alloreactive T-cell clones. The T-cell clones will be particularly useful for reconstitution experiments to establish the cell subpopulations and target specificity required to produce the GVHD. Third, the use of the congenic donor-recipient strain combination provides the opportunity to characterize the antigen(s) responsible for stimulating a chronic GVHD. We intend to use donor antihost antibody and T-cell clones to establish the tissue distribution, degree of polymorphism and structural characteristics of the target antigen. The importance of the proposed work is the opportunity to study an experimental model of chronic graft-versus-host disease that closely mimics the disease seen following bone marrow transplantation between HLA-identical siblings. The chronic GVHD seen in man and in our experimental model share important clinical and pathological features that allow for experimental investigation not possible in other experimental animals. The unique feature of the RT2 congenic model is a chronic GVHD in MHC matched animals directed against a single non-MHC background gene. The results obtained from these studies will greatly improve our understanding of the pathogenesis of chronic GVHD and should have direct application for donor-recipient selections and therapeutic applications of bone marrow transplantation in man. (TT)