Indispensable role for TNF-alpha and IFN-gamma at the effector phase of liver injury mediated by Th1 cells specific to hepatitis B virus surface antigen.
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-alpha mAb prevented liver injury, whereas severe liver injury was induced in TNF-alpha-/- mice. Moreover, IFN-gamma receptor-deficient mice were resistant to Th1-mediated liver injury. Therefore, TNF-alpha and IFN-gamma, which were produced by HBsAg-specific Th1 cells during the effector phase, appeared to be indispensable in the pathogenesis of fulminant hepatitis.
Ohta
A
A
Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, and Division of Biological Sciences, Graduate School of Science, Hokkaido University, Sapporo, Japan.
Sekimoto
M
M
Sato
M
M
Koda
T
T
Nishimura
S
S
Iwakura
Y
Y
Sekikawa
K
K
Nishimura
T
T
D000818:Animals; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D053222:Fas Ligand Protein; D005260:Female; D006509:Hepatitis B / Q000209:etiology / Q000276:immunology / Q000473:pathology; D006514:Hepatitis B Surface Antigens / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism / Q000633:toxicity; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000502:physiology*; D008024:Ligands; D008099:Liver / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D009928:Organ Specificity / Q000276:immunology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012995:Solubility; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D019014:fas Receptor / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006514:Hepatitis B Surface Antigens; D008024:Ligands; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D054353:Perforin; D007371:Interferon-gamma