Abstract

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 i s 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 i s to analyze the genetics, mechanisms, and specificity of hepatic BALB/c-TGF-b1(-/-) effector cytotoxic T lymphocytes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI053056-04
Application #
6982776
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Esch, Thomas R
Project Start
2002-12-01
Project End
2007-11-30
Budget Start
2005-12-01
Budget End
2007-11-30
Support Year
4
Fiscal Year
2006
Total Cost
$347,147
Indirect Cost

  Institution

Name
Dartmouth College
Department
Pathology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755

  Publications

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
Robinson, Richard T; French, Margaret A; Kitzmiller, Tamar J et al. (2006) Restriction of the CD4+ T-cell receptor repertoire prevents immune pathology in TGF-beta1 knockout mice. Lab Invest 86:815-28
Lin, Jack T; Martin, Stacey L; Xia, Luxi et al. (2005) TGF-beta 1 uses distinct mechanisms to inhibit IFN-gamma expression in CD4+ T cells at priming and at recall: differential involvement of Stat4 and T-bet. J Immunol 174:5950-8
Park, Il-Kyoo; Shultz, Leonard D; Letterio, John J et al. (2005) TGF-beta1 inhibits T-bet induction by IFN-gamma in murine CD4+ T cells through the protein tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1. J Immunol 175:5666-74
Gorham, James D (2005) Transforming growth factor-beta1, Th1 responses, and autoimmune liver disease. Transfusion 45:51S-59S
Lin, Jack T; Kitzmiller, Tamar J; Cates, Justin M M et al. (2005) MHC-independent genetic regulation of liver damage in a mouse model of autoimmune hepatocellular injury. Lab Invest 85:550-61
Rudner, Lynnie A; Lin, Jack T; Park, Il-Kyoo et al. (2003) Necroinflammatory liver disease in BALB/c background, TGF-beta 1-deficient mice requires CD4+ T cells. J Immunol 170:4785-92

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