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and IFN-
at the Effector Phase of Liver Injury Mediated by Th1 Cells Specific to Hepatitis B Virus Surface Antigen1
*
Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, and
Division of Biological Sciences, Graduate School of Science, Hokkaido University, Sapporo, Japan;
Section of Genetic Engineering, Research Center for Genetic Engineering and Cell Transplantation, Tokai University School of Medicine, Isehara, Japan;
§
Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan; and
¶
Department of Immunology, National Institute of Animal Health, Tsukuba, Japan
We report the development and characterization of a novel model of
severe hepatitis induced against hepatitis B virus surface Ag (HBsAg).
HBsAg was successfully targeted into the liver in soluble form. Using
this unique property of HBsAg, we established a liver injury model
induced by HBsAg-specific Th1 cells. Severe liver injury was induced in
C57BL/6 mice by injection of HBsAg together with HBsAg-specific Th1
cells. Histochemical examination demonstrated extensive
necroinflammatory hepatic lesions in these animals. Application of this
liver injury model to mutant or gene knockout mice enabled us to define
the effector mechanisms of Th1 cells in fulminant hepatitis. When
Fas-deficient lpr mice were used as recipients, a
similar degree of liver injury was induced as in wild-type mice.
Moreover, HBsAg-specific Th1 cells obtained from
perforin-/- mice could induce severe liver
injury in both wild-type and lpr mice. These results
indicated that neither Fas ligand nor perforin are essential for
Th1-mediated liver injury in this model. Pretreatment with
anti-TNF-
mAb prevented liver injury, whereas severe liver
injury was induced in TNF--/- mice.
Moreover, IFN-
receptor-deficient mice were resistant to
Th1-mediated liver injury. Therefore, TNF- and IFN-, which were
produced by HBsAg-specific Th1 cells during the effector phase,
appeared to be indispensable in the pathogenesis of fulminant
hepatitis.
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