Immunologic Mechanism/Destruction/Biliary Artesia

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DESCRIPTION (provided by applicant) My career goals are to become a physician scientist, caring for children with liver disease and making significant research contributions to the field of Pediatric Hepatology. I have been intrigued with biliary atresia (BA) and its possible mechanisms of pathogenesis since my exposure to this disease in pediatric residency. For the past year, I have been studying immunology in the laboratory of Dr. Stephen Miller, PhD, Northwestern University. I plan to remain in the academic setting long-term as a research scientist with the goal of defining clearly the role of the immune system in the pathogenesis of biliary atresia and other pediatric liver diseases. Biliary atresia is a progressive, inflammatory cholangiopathy of infancy that leads to fibrosis and obliteration of both the extrahepatic and intrahepatic bile ducts. The immune response appears to be the key player in the ongoing destruction of the bile ducts. The hypothesis herein is that the pathogenesis of BA involves a viral induced, progressive autoreactive CD4+ Th1 cell mediated destruction of bile ducts. The group A rotavirus murine model will be used to test this hypothesis and entails a virally induced, progressive inflammatory destruction of extrahepatic and intrahepatic bile ducts leading to extrahepatic ductal fibrosis and obliteration. Limited studies on human liver tissue obtained at the time of diagnosis of BA will also be performed. Specific Aim 1 will be to characterize the inflammatory immune response in this murine model through the use of immunohistochemistry and flow cytometric studies. Characterization of the cytokine profile will also be performed. Specific Aim 2 will determine the principal mediator of ductal destruction (virus versus immune response) in the murine model by comparing infected BALB/c pups with infected SCID (immunodeficient) pups. Specific Aim 3 will determine if autoreactive lymphocytes to bile duct antigens are present in the murine model by performing in-vitro T-cell proliferation studies. Specific Aim 4 will characterize the inflammatory immune response in human liver tissue obtained at the time of diagnosis of BA with immunohistochemistry studies. Cytokine profiles will be characterized by cytokine mRNA expression.