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    Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis

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    Author
    Welz, M; Eickhoff, S; Abdullah, Z; Trebicka, J; Gartlan, KH; Spicer, JA; Demetris, AJ; Akhlaghi, H; Anton, M; Manske, K; ...
    Date
    2018-11-15
    Source Title
    Nature Communications
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    Trapani, Joseph
    Affiliation
    Sir Peter MacCallum Department of Oncology
    Metadata
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    Document Type
    Journal Article
    Citations
    Welz, M., Eickhoff, S., Abdullah, Z., Trebicka, J., Gartlan, K. H., Spicer, J. A., Demetris, A. J., Akhlaghi, H., Anton, M., Manske, K., Zehn, D., Nieswandt, B., Kurts, C., Trapani, J. A., Knolle, P., Wohlleber, D. & Kastenmueller, W. (2018). Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis. NATURE COMMUNICATIONS, 9 (1), https://doi.org/10.1038/s41467-018-07213-x.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/253254
    DOI
    10.1038/s41467-018-07213-x
    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.

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