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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Karp, Robert W
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Dartmouth College
Schools of Medicine
United States
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Milks, Michael W; Cripps, James G; Lin, Heping et al. (2009) The role of Ifng in alterations in liver gene expression in a mouse model of fulminant autoimmune hepatitis. Liver Int 29:1307-15
Robinson, Richard T; Wang, Jing; Cripps, James G et al. (2009) End-organ damage in a mouse model of fulminant liver inflammation requires CD4+ T cell production of IFN-gamma but is independent of Fas. J Immunol 182:3278-84
Park, Il-Kyoo; Letterio, John J; Gorham, James D (2007) TGF-beta 1 inhibition of IFN-gamma-induced signaling and Th1 gene expression in CD4+ T cells is Smad3 independent but MAP kinase dependent. Mol Immunol 44:3283-90
Robinson, Richard T; Gorham, James D (2007) TGF-beta 1 regulates antigen-specific CD4+ T cell responses in the periphery. J Immunol 179:71-9