title: Ineffective CD8(+) T-cell immunity to adeno-associated virus can result in prolonged liver injury and fibrogenesis.
abstract: Chronic viral hepatitis depends on the inability of the T-cell immune response to eradicate antigen. This results in a sustained immune response accompanied by tissue injury and fibrogenesis. We have created a mouse model that reproduces these effects, based on the response of CD8(+) T cells to hepatocellular antigen delivered by an adeno-associated virus (AAV) vector. Ten thousand antigen-specific CD8(+) T cells undergo slow expansion in the liver and can precipitate a subacute inflammatory hepatitis with stellate cell activation and fibrosis. Over time, antigen-specific CD8(+) T cells show signs of exhaustion, including high expression of PD-1, and eventually both inflammation and fibrosis resolve. This model allows the investigation of both chronic liver immunopathology and its resolution.
authors.affiliation: David H. Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center, Rochester, New York, USA. spahnj@wudosis.wustl.edu
authors.forename: Jessica
authors.initials: J
authors.lastname: Spahn
authors.forename: Robert H
authors.initials: RH
authors.lastname: Pierce
authors.forename: Ian N
authors.initials: IN
authors.lastname: Crispe
mesh_terms: D000257:Adenoviridae Infections / Q000276:immunology*; D019264:Adoptive Transfer; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D054357:Chemokine CXCL10 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D005822:Genetic Vectors; D006521:Hepatitis, Chronic / Q000276:immunology; D006524:Hepatitis, Viral, Animal / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000502:physiology; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008103:Liver Cirrhosis / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D017710:Lymphocyte Transfusion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D019076:Transgenes / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D012313:RNA; D007371:Interferon-gamma; D000410:Alanine Transaminase