Essential pathogenetic role for interferon (IFN-)gamma in concanavalin A-induced T cell-dependent hepatitis: exacerbation by exogenous IFN-gamma and prevention by IFN-gamma receptor-immunoglobulin fusion protein.
We have studied the effects of either exogenously-administered interferon (IFN-)gamma or of a nonimmunogenic mouse IFN-gamma receptor-Immunoglobulin (IFN-gamma R-Ig) fusion protein on the development of Concanavalin (Con)A-induced hepatitis in NMRI mice. PBS-treated control mice injected with 20 mg/kg ConA developed classical serological and histological signs of hepatitis with elevation of transaminases in the blood and infiltration of the liver by mononuclear cells and neutrophils. Treating the mice with rat IFN-gamma 24 h prior to and 1 h after ConA-challenge markedly exacerbated these signs of hepatitis in a dose-dependent fashion. Moreover, mice injected with lower, non hepatitogenic, doses of ConA (10, 5 mg/kg) became fully susceptible to develop hepatitis upon similar treatment with IFN-gamma. Concordantly, ConA-induced hepatitis was abrogated by either IFN-gamma R-Ig fusion protein or anti-IFN-gamma mAb. These data provide further evidence for the central pathogenetic role of endogenous IFN-gamma in ConA-induced hepatitis and demonstrate the feasibility to prevent disease development by means of a non immunogenic IFN-gamma R-Ig fusion protein.
Nicoletti
F
F
Institute of Microbiology, University of Milan, Italy. ferdinic@ctonline.it
Zaccone
P
P
Xiang
M
M
Magro
G
G
Di Mauro
M
M
Di Marco
R
R
Garotta
G
G
Meroni
P
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D016466:CHO Cells; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000276:immunology* / Q000473:pathology; D003208:Concanavalin A / Q000008:administration & dosage; D006224:Cricetinae; D016207:Cytokines / Q000097:blood / Q000276:immunology; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology* / Q000494:pharmacology; D015847:Interleukin-4 / Q000276:immunology; D008099:Liver / Q000276:immunology* / Q000293:injuries / Q000473:pathology; D008297:Male; D051379:Mice; D051381:Rats; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D000096743:Interferon gamma Receptor
D000911:Antibodies, Monoclonal; D003208:Concanavalin A; D016207:Cytokines; D007136:Immunoglobulins; D007371:Interferon-gamma; D015847:Interleukin-4; D017471:Receptors, Interferon; D011993:Recombinant Fusion Proteins; D000096743:Interferon gamma Receptor