Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis
| Autor: | Jonel Trebicka, Zeinab Abdullah, Sarah Eickhoff, Dietmar Zehn, K Manske, Meike Welz, Hedieh Akhlaghi, Percy A. Knolle, Anthony J. Demetris, Martina Anton, Joseph A. Trapani, Julie Ann Spicer, Kate H. Gartlan, Christian Kurts, Bernhard Nieswandt, Dirk Wohlleber, Wolfgang Kastenmüller |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Fulminant Gene Expression General Physics and Astronomy CD8-Positive T-Lymphocytes Mice Liver disease 0302 clinical medicine Genes Reporter Cytotoxic T cell Luciferases lcsh:Science Mice Knockout Sulfonamides Multidisciplinary biology food and beverages 3. Good health medicine.anatomical_structure Liver Hepatitis Viral Animal Hepatocyte 030211 gastroenterology & hepatology Viral hepatitis Pore Forming Cytotoxic Proteins Ovalbumin Science Green Fluorescent Proteins Protective Agents Article Antibodies General Biochemistry Genetics and Molecular Biology Adenoviridae 03 medical and health sciences medicine Animals Humans CD40 Antigens Fulminant hepatitis Hepatitis business.industry fungi Endothelial Cells General Chemistry medicine.disease Capillaries Mice Inbred C57BL Disease Models Animal Poly I-C 030104 developmental biology Perforin Hepatocytes biology.protein Cancer research lcsh:Q business |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-13 (2018) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. CD8 T cells can protect the liver from viral infection, but can also result in severe liver damage and organ failure. Here, the authors develop a mouse model reflecting fulminant CD8 T cell mediated viral hepatitis, which occurs in a perforin-dependent manner that is protected by the use of perforin inhibitors. |
| Databáze: | OpenAIRE |
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