Non-Suppurative Destructive Cholangitis (NSDC), the characteristic histopathological lesion of Primary Biliary Cirrhosis has recently been identified as the principal lesion of human Chronic Graft-Versus-Host Disease (CGVHD) and liver allograft rejection. Although the occurrence of NSDC in the latter diseases indicates that alloimmune mechanisms are capable of bile duct destruction, the mechanism(s) involved have not been identified. Evidence that immunological mechanisms can cause NSDC provides circumstantial support for the unproven hypothesis that NSDC in Primary Biliary Cirrhosis results from T lymphocyte-mediated mechanisms of autoimmunity. The overall objective of this proposal is to utilize a murine model of CGVHD induced by minor histocompatibility antigens to define the mechanism(s) of hepatobiliary injury. This murine model, involving strains that are define the mechanism(s) of hepatobiliary injury. This murine model, involving strains that are identical at both the H-2 and Mis loci, is analogous to the situation of HLA-matched, MLR- unreactive human bone marrow transplantation in which CGVHD frequently occurs. Moreover, this model is associated with a reproducible evolution of hepatic injury characterized by progressive NSDC. The current proposal addresses the hypothesis that NSDC in this murine model of CGVHD results from the alloimmune response of class II MHC restricted donor T cells to host minor histocompatibility antigens expressed on bile duct epithelial cells. This hypothesis predicts that alloactivated donor T cells elaborate lymphokines(e.g., interferon-gamma) that cause aberrant expression of class II MHC antigens by bile duct epithelial cells. This aberrant expression of class II MHC antigens permits presentation of biliary antigens resulting in specific class II MHC restricted sensitization and differentiation into effector cells capable of destroying the bile duct epithelia. To assess the types of cells required for NSDC, we will deplete specific functional classes of donor T and NK cells prior to engraftment using Leu-Leu-OMe cytolysis. To evaluate the capacity of host cells to participate in NSDC, we will deplete specific T and NK populations by injecting monoclonal antibodies into recipients prior to engraftment. To assess the immunogenicity of bile duct epithelial cells (the targets of NSDC), we will isolate and culture bile duct cells from both donor and host strains and transplantation them beneath the kidney capsule before and after stimulation of class II MHC antigen expression by interferon-gamma. Additional experiments will evaluate the capacity of inflammatory cells isolated from the livers of CGVHD mice to mediate in vitro cytotoxicity against bile duct target cells and to secrete potentially toxic cytokines. Finally, we will establish and characterize T cell clones from the livers and spleens of CGVHD mice. Clones will be established both by selection of T cells proliferating in response to IL-2 in vitro and by selection of antigen- specific T cells proliferating in response to simulation with isolated bile duct epithelial cells.
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