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T Cell-Mediated Mechanisms of Autoimmunity in Murine and Human Biliary Atresia

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Project Summary. Biliary atresia (BA) is a progressive, inflammatory, sclerosing extrahepatic and intrahepatic cholangiopathy which presents in infancy and leads to bile duct obstruction and biliary cirrhosis. Intrahepatic biliary inflammation and sclerosis progresses in most patients with the resulting need for liver transplantation in 80% of patients, accounting for half of all pediatric liver transplants. Current therapy for BA is inadequate because the etiology and pathogenesis of BA is not understood, however the role of perinatal infection and autoimmune-mediated bile duct injury have been proposed to be involved. The hypothesis to be tested in this proposal is that BA is a viral-induced autoimmune disease of the biliary system, in which T cell-mediated autoimmune responses target bile duct epithelia. Due to the rarity of BA and the limited accessibility to human tissue, the Rhesus rotavirus (RRV)-induced murine model of BA will be utilized in these investigations. We will examine two distinct mechanisms by which infections are known to trigger autoimmune disease: molecular mimicry and bystander activation. Preliminary data for this application demonstrate that autoreactive bile duct epithelial-specific T cells infiltrate the livers of RRV-induced BA mice, and that adoptive transfer of these T cells into naTve SCID recipients leads to bile duct targeted inflammation. Complementary studies will also be performed with human BA tissue. In human BA, the periductal inflammation is composed of Th1 cells and macrophages. We have recently determined that the T cells are oligoclonal in nature, suggesting specific antigen-driven T cell activation. Thus, the specific aims of this proposal are to investigate in detail the role of T cell-mediated autoimmune mechanisms in bile duct injury in both murine and human BA. Specific Aim I is to determine the antigen specificity of liver T cell hybridomas generated from BA mice. Hybridoma technology is a powerful tool used to study the fine specificity of antigen recognition by the T cell receptor. Specific Aim II is to identify the bile duct epithelial peptide that is the target of T cell activation by molecular cloning from a bile duct epithelial cDNA expression library. In Specific Aim III we will analyze the T cells from human BA livers and extrahepatic bile duct remnants and determine the stimulating protein (virus or bile duct epithelia) responsible for the T cell activation and proliferation. Relevance. The significance of this proposal lies in carefully defining the immunopathogenesis of BA in the murine model which will then be translated into investigations in tissues from infants with BA. Delineating the pathways of autoimmune mediated injury in the murine model of BA should stimulate development of novel medical interventions for humans aimed at suppressing the immune response and decreasing bile duct injury. The overall goal of this research program is to use these molecular and immunological insights as a basis for development of future therapeutic and preventative strategies for this important disease.

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