Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis

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Welz, M; Eickhoff, S; Abdullah, Z; Trebicka, J; Gartlan, KH; Spicer, JA; Demetris, AJ; Akhlaghi, H; Anton, M; Manske, K; ...Date
2018-11-15Source Title
Nature CommunicationsPublisher
NATURE PUBLISHING GROUPUniversity of Melbourne Author/s
Trapani, JosephAffiliation
Sir Peter MacCallum Department of OncologyMetadata
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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 AccessAbstract
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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