The hepatitis C virus and immune evasion:: nonstructural 3/4A transgenic mice are resistant to lethal tumour necrosis factor α mediated liver disease

被引:44
作者
Frelin, L.
Brenndorfer, E. D.
Ahlen, G.
Weiland, M.
Hultgren, C.
Alheim, M.
Glaumann, H.
Rozell, B.
Milich, D. R.
Bode, J. G.
Sallberg, M.
机构
[1] Karolinska Univ Hosp, Karolinska Inst, Div Clin Virol, S-14186 Huddinge, Sweden
[2] Univ Dusseldorf, Dept Gastroenterol Hepatol & Infect Dis, D-4000 Dusseldorf, Germany
[3] Karolinska Univ Hosp, Karolinska Inst, Div Infect Dis, Huddinge, Sweden
[4] Karolinska Univ Hosp, Karolinska Inst, Div Pathol, Huddinge, Sweden
[5] Karolinska Univ Hosp, Karolinska Inst, Clin Res Ctr, Huddinge, Sweden
[6] Vaccine Res Inst, San Diego, CA USA
关键词
D O I
10.1136/gut.2005.085050
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background: The hepatitis C virus (HCV) establishes chronic infection by incompletely understood mechanisms. The non-structural (NS) 3/4A protease/helicase has been proposed as a key complex in modulating the infected hepatocyte, although nothing is known about the effects this complex exerts in vivo. Aim: To generate mice with stable and transient hepatocyte expression of the HCV NS3/4A proteins to study its effects in vivo. Methods: NS3/4A expression was determined by western blot and immunohistochemistry. Two independent pathologists determined the liver histology. Hepatic immunity was characterised by quantifying intrahepatic immune cell subsets. Liver damage was induced using carbon tetrachloride (CCl4), lipopolysaccaride (LPS), tumour necrosis factor alpha (TNF alpha), and anti-Fas antibody. Results: Expression of NS3/4A was restricted to the cytoplasm of hepatocytes, and did not cause liver cancer or any spontaneous liver pathology. However, the presence of NS3/4A modulated the intrahepatic immunity, as follows: first, the CD4+ T cell and type I/II dendritic cell subsets were reduced in transgenic livers; second, NS3/4A protected hepatocytes from liver damage mediated in vivo by CCl4, LPS, TNFa, but not FAS; and third, both stable and transiently NS3/4A transgenic mice were resistant to lethal doses of liver targeted TNFa, and the resistance could be reverted by treatment with a p38 mitogen activated protein kinase inhibitor (MAPK). Conclusions: Hepatic expression of NS3/4A does not induce spontaneous liver disease. NS3/4A does, however, alter the intrahepatic immune cell subsets and protects hepatocytes against TNF alpha induced liver damage in vivo. The TNFa resistance can be reverted by treatment with a p38 MAPK inhibitor. This represents a new immune evasion strategy conferred by NS3/4A.
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页码:1475 / 1483
页数:9
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