In several specific liver pathologies, including autoimmune hepatitis (AIM) and HCV infection, hepatocellular damage results from T cell mediated attack. Disease progression in patients with these conditions is influenced by the individual's genetic constitution. However, other than the major histocompatibility complex (MHC), the genes that regulate T cell mediated hepatocellular damage have largely eluded identification. The identification of genetic susceptibility loci can be greatly facilitated through the use of robust animal model systems. We recently developed a mouse model of T cell mediated hepatocellular injury. BALB/c mice deficient in TGF-beta1 spontaneously develop early-onset Th1 mediated hepatitis. Hepatocellular damage is strictly dependent upon genetic background. TGF-beta1-/- mice on the BALB/c background are susceptible whereas TGF-beta1-/- mice on the 129/Sv1 background are resistant. This indicates the presence of genetic modifiers with background-specific alleles that influence the development of T cell mediated hepatocellular damage in TGF-beta1-/- mice. In this application, we propose to use linkage analysis to genetically map a locus that regulates the differential development of hepatitis in mice. Preliminary studies from a F2 intercross show that susceptibility is likely determined by a single autosomal recessive locus and analyses of MHC congenic BALB mice indicate that the MHC is not the relevant locus. We propose to use interspecific crosses and microsatellite marker analyses to map a genetic locus, distinct from the MHC, that regulates susceptibility to T cell mediated hepatocellular damage in mice. This will be an important first step in the identification a gene, unlinked to MHC, with allelic variants that differentially determine the development of T cell mediated liver injury. This will have important implications for understanding the genetic basis of autoimmune hepatitis, and of hepatocellular damage in the settings of HCV infection.
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