PATHOGENESIS OF CHRONIC GRAFT VERSUS HOST LIVER DISEASE

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DESCRIPTION: The long-term goal of this project is to define the mechanisms through which T cells mediate bile duct destruction in graft-versus-host disease and primary biliary cirrhosis. The project is based on a mouse model of GVHD and the central hypothesis that bile duct destruction during GVHD is mediated by donor CD4+ and CD8+ T cells that recognize minor histocompatibility alloantigens in the host bile duct epithelial cells. The first specific aim is to determine the in vitro helper and cytotoxic function of donor T cells isolated from livers of mice with GVHD. They will determine whether the donor T cells recognize bile duct restricted miH antigens and define the mechanism by which T cells kill bile duct epithelial cells. Specific aim #2 is to define the immunopathogenicity of purified BALB/c intrahepatic bile duct epithelial (IBDE) cells in vivo and in vitro. They will take the purified bile duct cells, inject them intraperitoneally, and determine the immune response in B10.D2 mice. They will compare the T cell repertoire in this system to their model of GVHD. Lastly, in specific aim #3 they will determine the requirement of proinflammatory cytokines in the genesis of GVHD. They will perform these experiments by using knockout mice and neutralization of IL12 and INF gamma by treatment with cytokines.