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Role of Cytokines and Autoimmunity in Murine BA

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Biliary atresia (BA) appears to result from a chronic, progressive inflammatory mediated destruction of extrahepatic and intrahepatic bile ducts, leading some to call it "infantile obliterative cholangiopathy". It has been proposed that the pathogenesis of BA is due to a virus-induced, subsequent immune mediated destruction of bile ducts. The majority of children with BA require liver transplantation for survival. It is of utmost importance to understand the immunopathology of this disease in order to provide treatment options which may delay or eliminate the need for transplantation. The rotavirus (RRV)-induced murine model of BA is being used as a tool to study the early events in the pathogenesis of BA. The hypotheses to be examined in this study are that persistent CD4+ Th1-cell mediated inflammation is responsible for bile duct epithelial death and extrahepatic bile duct obstruction. Furthermore, chronic T cell mediated ductal inflammation and injury may be secondary to autoreactive bile duct epithelial antigen-specific T cells. The role of key players in Th1 cell mediated immunity (IP-10, IFN-gamma and TNF-alpha) will be investigated. Prevention of disease onset will be sought through the use of knockout mice which are deficient in the cytokine or chemokine of interest. Abrogation or amelioration of the biliary disease after the onset of jaundice will be determined by the use of cytokine or chemokine neutralizing antibodies. Determination of the presence of autoreactive T cells specific to bile duct epithelium will be performed through adoptive transfer studies utilizing donor liver T cells from RRV-diseased mice and recipient T cell deficient SCID mice. Defining the immunopathology in biliary atresia will lead to a better understanding of the etiopathogenesis and provide insight into future therapeutic options.
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