Experimental hepatitis and role of cytokines.
Activated T lymphocytes appear to be responsible for liver damage in chronic active hepatitis and autoimmune liver disease. We described three experimental mouse models of T cell dependent liver injury. D-galactosamine (GalN)-sensitized mice challenged with either T cell activating anti-CD3 monoclonal antibody (mAb) or with the superantigen staphylococcal enterotoxin B (SEB) developed severe liver injury characterized by internucleosomal DNA fragmentation as well as by histological hallmarks of hepatocyte apoptosis, both preceding the increase of plasma transaminases. Administration of the T cell mitogen concanavalin A (Con A) to unsensitized mice also resulted in hepatic apoptosis and the ensuing necrosis. Anti-CD3 mAb as well as SEB or Con A induced the release of systemic tumor necrosis factor (TNF), interferon gamma (IFN gamma), and various other cytokines. Passive immunization against TNF or pretreatment with immunosuppressive drugs such as cyclosporin A, FK 506 or dexamethasone protected mice from liver injury. T lymphocytes were identified as effector cells of Con A in vivo i) by proof of resistance of athyrnic nude mice against Con A and ii) by restoration of susceptibility in nude by lymphocyte transfer from control mice. Moreover, antibody-dependent depletion of CD4+ T cells fully protected against Con A, whereas depletion of CD8+ T cells failed to prevent liver injury. These results indicated that cytokines released following T helper cell activation rather than cytotoxic T cells mediated liver injury. We recently found that IFN gamma is also a critical mediator of Con A-induced hepatic damage. In conclusion, these T cell-dependent models of inflammatory liver injury allow the investigation of basic principles of hepatic disorders associated with T cell activation and infiltration as well as pharmacological in vivo studies for the development of hepatoprotective drugs.
Tiegs
G
G
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Germany.
D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000276:immunology*; D003208:Concanavalin A; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D005688:Galactosamine; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000276:immunology*; D006521:Hepatitis, Chronic / Q000276:immunology*; D051379:Mice; D016853:Muromonab-CD3; D013601:T-Lymphocytes / Q000276:immunology
D016207:Cytokines; D016853:Muromonab-CD3; D003208:Concanavalin A; D005688:Galactosamine