Autoimmune liver disease involves the combined activity of multiple immune cell types in the liver, involving cells of the adaptive immune system, particularly antigen-specific Th1 cells, and cells of the innate immune system. We hypothesize that specific chemokines are critical for coordinating these cells in the autoimmune attack and mediate the progression from initial encounter of T cells with antigen to full-blown hepatocellular damage. The CXCR3 and CCR5 response pathways are important for mediating the chemotactic attraction of Th1 cells and we hypothesize that these pathways are critical for the development of autoimmune necroinflammatory liver disease. We test this hypothesis using a mouse model of spontaneously developing antigen-specific autoimmune T cell mediated hepatocellular damage. The BALB/c-TGF-21-/- mouse is a model of acute fulminant liver disease in a pediatric setting, and provides an excellent model system in which to address important questions relevant to T cell mediated liver damage. In this model system: liver damage develops spontaneously and rapidly;is mediated by antigen-specific Th1 cells;is associated with dramatic over-expression of specific chemokines that bind to CXCR3 and CCR5;and requires the activity of neutrophils. In this proposal, we address the relevance of specific chemokine pathways in liver disease, determine the mechanisms by which neutrophils accumulate in liver, and test whether a deficit in regulatory T cells is responsible for pathology.

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Autoimmune liver disease involves the combined activity of multiple immune cell types particularly Th1 cells and cells of the innate immune system. We hypothesize that small secreted molecules known as chemokines are important for initiating the influx of immune cells and the development of liver damage. In this project, we test the role of specific chemokine pathways, neutrophils, and regulatory T cells in the development of autoimmune hepatitis in mice lacking the protein TGF-21.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Rothermel, Annette L
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Dartmouth College
Schools of Medicine
United States
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