Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis.
Nat Commun
; 9(1): 4805, 2018 11 15.
Article
en En
| MEDLINE
| ID: mdl-30442932
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Sulfonamidas
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Sustancias Protectoras
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Células Endoteliales
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Proteínas Citotóxicas Formadoras de Poros
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Hepatitis Viral Animal
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Tipo de estudio:
Prognostic_studies
Idioma:
En
Año:
2018
Tipo del documento:
Article