ovalbumin and Hepatitis--Viral--Animal

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.

Topics: Adenoviridae; Animals; Antibodies; Capillaries; CD40 Antigens; CD8-Positive T-Lymphocytes; Disease Models, Animal; Endothelial Cells; Gene Expression; Genes, Reporter; Green Fluorescent Proteins; Hepatitis, Viral, Animal; Hepatocytes; Humans; Liver; Luciferases; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; Poly I-C; Pore Forming Cytotoxic Proteins; Protective Agents; Sulfonamides

Infection of BALB/c mice with mouse hepatitis virus, strain JHM (MHV-JHM), at any of several intervals relative to ovalbumin (OVA) administration resulted in elevated OVA-specific IgG 2 a titers. Since gamma interferon (IFN) has been implicated as an up-regulator of IgG 2 a production, attempts were made to determine whether levels of this cytokine were modified in sera of infected mice. Serum IFN-gamma was not detected, but treatment of MHV-JHM-infected mice with monoclonal anti-IFN-gamma antibody resulted in high mortality with decreased survival times, enhanced virus titers in liver and spleen, and more severe virus-associated pathology, compared to mock-treated, infected mice. Immunotherapy with recombinant IFN-gamma ameliorated disease as reflected by mortality rates and virus titers in target organs.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Viral; Disease Susceptibility; Female; Hepatitis, Viral, Animal; Interferon-gamma; Mice; Mice, Inbred BALB C; Murine hepatitis virus; Ovalbumin; Recombinant Proteins; Virus Replication