A novel inbred mouse model of autoimmune hepatitis

Dartmouth College, Hanover NH

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Abstract

DESCRIPTION (provided by applicant): Inflammation of the liver is responsible for substantial morbidity and mortality worldwide and is caused by a variety of etiologies including viral infection, alcohol use, toxin exposure, and autoimmune hepatitis (AIH). AIH results when normal immune self-tolerance mechanisms in the liver go awry, but its underlying etiology, and mechanisms of pathogenesis, remain largely unknown. Spontaneous development, genetic pre-disposition, and the involvement of Th1 cells, are prominent features of AIH. The understanding of AIH has advanced slowly, however, largely because of the lack of a suitable animal model. A new inbred mouse model system of AIH is described that recapitulates many of its important features, including (1) extensive inflammation in the liver (2) significant loss of hepatocytes (3) the spontaneous development of the pathology (4) the dependence of the disease upon genetic background and (5) the presence of Th1 cells. Additional features of the model system render it particularly amenable to experimental manipulation, such as predictability: 100% of mice develop AIH with uniform kinetics; genetic homogeneity: susceptible mice are in-bred (genetically identical); and intensity: mice develop an overwhelming fulminant hepatitis. Balb/c mice deficient in the immunosuppressive cytokine transforming growth factor-B1 (TGF-B1) predictably and uniformly develop a lethal IFN-gamma-dependent, fulminant hepatitis, that is under strict genetic control. The hypothesis is put forth that hepatitis in this mouse model is mediated by liver-infiltrating T helper cells. To test this hypothesis, liver-infiltrating lymphocytes will be extensively studied and genetic and adoptive transfer approaches used to determine whether and which lymphocyte subsets are necessary and sufficient for the development of hepatitis. The proposal seeks to understand mechanisms that regulate the development of inflammation in the liver, so as to gain insights into the pathogenic mechanisms of AIH and other hepatic inflammatory diseases.