Mechanisms of liver disease in a mouse model of AIH

Dartmouth College, Hanover NH

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Autoimmune hepatitis (AIH) results from a dysfunction in normal immune homeostasis in the liver. Little is understood, however, about either the normal mechanisms that regulate the hepatic immune system, or about the pathogenesis of AIH. A new mouse model recapitulates the important features of AIH, and is characterized by (1) extensive liver inflammation (2) significant hepatocyte damage (3) spontaneous disease development (4) the strong influence of genetic background and (5) the involvement of T helper type 1 (Th1) cells. Additional features render the model particularly amenable to experimental manipulation, such as predictability of kinetics, genetic homogeneity, and intensity of disease. Balb/c mice with a knockout in the gene encoding the immunoregulatory cytokine transforming growth factor-beta1(TGF-b1) predictably and uniformly develop a lethal Th1-mediated fulminant hepatitis, that is under strict genetic control. Experiments are proposed using this mouse model to understand the mechanisms that regulate the initiation, progression, and effector phases of autoimmune liver disease in BALB/c-TGF-b1 (-/-)mice. The first aim of this project is to determine whether cell compartment-specific expression of TGF-b1 dictates the development of liver disease. The second aim is to determine whether the development of immune mediated hepatocellular damage in BALB/c-TGF-b1 (-/-) mice is antigen-specific or antigen nonspecific. The final aim is to analyze the genetics, mechanisms, and specificity of hepatic BALB/c-TGF-b1(-/-) effector cytotoxic T lymphocytes.