Abstract
CD8 T cells protect the liver against viral infection, but can also cause severe liver damage that may even lead to organ failure. Given the lack of mechanistic insights and specific treatment options in patients with acute fulminant hepatitis, we develop a mouse model reflecting a severe acute virus-induced CD8 T cell-mediated hepatitis. Here we show that antigen-specific CD8 T cells induce liver damage in a perforin-dependent manner, yet liver failure is not caused by effector responses targeting virus-infected hepatocytes alone. Additionally, CD8 T cell mediated elimination of cross-presenting liver sinusoidal endothelial cells causes endothelial damage that leads to a dramatically impaired sinusoidal perfusion and indirectly to hepatocyte death. With the identification of perforin-mediated killing as a critical pathophysiologic mechanism of liver failure and the protective function of a new class of perforin inhibitor, our study opens new potential therapeutic angles for fulminant viral hepatitis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoviridae / genetics
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Adenoviridae / immunology
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Adenoviridae / pathogenicity
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Animals
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Antibodies / administration & dosage
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CD40 Antigens / antagonists & inhibitors
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CD40 Antigens / genetics
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CD40 Antigens / immunology
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / virology
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Capillaries / drug effects
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Capillaries / virology
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Disease Models, Animal
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Endothelial Cells / drug effects*
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Endothelial Cells / immunology
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Endothelial Cells / virology
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Gene Expression
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Genes, Reporter
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Hepatitis, Viral, Animal / drug therapy*
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Hepatitis, Viral, Animal / immunology
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Hepatitis, Viral, Animal / virology
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Hepatocytes / drug effects
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Hepatocytes / immunology
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Hepatocytes / virology
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Humans
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Liver / blood supply
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Liver / drug effects*
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Liver / pathology
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Liver / virology
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Luciferases / genetics
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Luciferases / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Ovalbumin / administration & dosage
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Poly I-C / administration & dosage
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Pore Forming Cytotoxic Proteins / antagonists & inhibitors*
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Pore Forming Cytotoxic Proteins / genetics
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Pore Forming Cytotoxic Proteins / immunology
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Protective Agents / pharmacology*
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Sulfonamides / pharmacology*
Substances
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Antibodies
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CD40 Antigens
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Pore Forming Cytotoxic Proteins
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Protective Agents
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Sulfonamides
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perforin, mouse
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Green Fluorescent Proteins
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Ovalbumin
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Luciferases
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Poly I-C