IMMUNE-MEDIATED BILE DUCT INJURY IN BILIARY ATRESIA

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DESCRIPTION (adapted from the application) Biliary atresia is a very serious disease of the newborn in which there is an obliteration or discontinuity of the biliary system. The incidence of this neonatal cholestatic disorder is 1 in 10,000 live births worldwide. If left untreated biliary atresia leads to end-stage liver disease with a median survival of eight months after birth. Thus, biliary atresia is the most common indication for pediatric liver transplantation. The etiology remains unknown and there is little information on disease progression. We have obtained preliminary data to explain the localization of specific lymphocyte subsets to biliary atresia liver. Furthermore, we have identified candidate mediators of cholangiocyte cell death. The objective of this research is to elucidate the immune mediated events which lead to lymphocyte accumulation in the liver and destruction of the bile ducts. In Specific Aim 1 we propose to establish the expression pattern of the chemokines in biliary atresia liver and confirm that lymphocytes with receptors for these chemokines traffic to the liver. Liver tissue from patients with biliary atresia will be analyzed by ribonuclease protection assays and immunohistochemical staining to identify specific chemokines as well as their cellular source and the T cell subsets bearing receptors for these chemokines. Specific Aim 2 will establish if apoptosis is involved in the bile duct obliteration in biliary atresia. Specifically, we will determine the extent and localization of apoptotic cells in biliary atresia liver. In addition, we will examine biliary atresia liver for the presence of well-defined mediators of apoptosis and determine the subsets of infiltrating cells which express these mediators. In Specific Aim 3 we will utilize cDNA microarray strategies to compare gene expression patterns in biliary atresia at early and late stages of disease as well as to other cholestatic liver pathologies. This approach will offer opportunities to identify known and novel genes which participate in the pathogenesis of biliary atresia. We anticipate that these studies will provide unique insights into the pathogenesis of biliary atresia and form the groundwork for future studies related to this severe and enigmatic liver disease.