Primary biliary cirrhosis (PBC) is an enigmatic, liver specific, autoimmune disease characterized by antimitochondrial antibodies and progressive destruction of intrahepatic bile ducts. There has not been an animal model of PBC and studies are dependent on human clinical specimens, a problem compounded by the cryptic nature of disease onset that prevents identification of patients in early stages. In other autoimmune diseases, the dissection of the immune process has been facilitated by informative animal models. We propose a consortium approach utilizing the strengths of 3 campuses to study 2 novel murine models of autoimmune biliary disease, the NOD.c3c4 congenic mouse with B6/B10 derived regions on chromosomes 3 and 4 as well as a new strain, called 2445. Line 2445 has significantly reduced B6/B10 intervals on chromosome 3 and 4 compared to NOD.c3c4, which will facilitate positional cloning of genes integral to disease. Both strains of mice develop progressive portal tract lymphocytic infiltrates, granulomas, anti-mitochondrial antibodies and terminal biliary disease. Our objectives are to perform a detailed ontogenetic analysis of the immune system to define the kinetics by which specific lineages contribute to disease process utilizing NOD.c3c4, strain 2445, and controls. The studies to be performed are those which mirror human PBC, including analysis of the innate, humoral and cellular immune systems, including liver lymphoid subpopulations and immunohistochemistry to identify the developmental stage each component contributes to disease pathogenesis. We will also positionally clone the genes critical for causing liver disease using currently available congenic strains as well as novel congenic strains that will be generated. Based upon this data, adoptive transfer strategies using NOD.c3c4- and 2445-scid recipients will define the pathogenic effector cells required for the development of liver disease. We submit that this model offers significant potential for not only enhancing our understanding of PBC, but also autoimmunity in general. PBC is the prototypic autoimmune disease with a tissue specific impact, but a constant non-tissue specific autoreactivity, features closely reproduced in this model. Finally, because this murine model of PBC is pathologically and immunologically similar to human PBC, it opens the possibility of discriminative analysis of initiating events and eventually study of therapeutic interventions. ? ? ?
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