title: Essential role of the adhesion receptor LFA-1 for T cell-dependent fulminant hepatitis.
abstract: Viral hepatitis affects more than 2 billion people worldwide. In particular, no effective treatment exists to abrogate death and liver damage in fulminant hepatitis. Activation of T cells is an initial and critical event in the pathogenesis of liver damage in autoimmune and viral hepatitis. The precise molecular mechanisms that induce T cell-mediated hepatocyte injury remain largely unclear. In mice, T cell-dependent hepatitis and acute liver damage can be modeled using ConA. In this study, we examined the role of the adhesion receptor LFA-1 in ConA-induced acute hepatic damage using LFA-1(-/-) (CD11a) mice. Massive liver cell apoptosis and metabolic liver damage were observed in LFA-1(+/+) mice following ConA injection. By contrast, LFA-1(-/-) mice were completely resistant to ConA-induced hepatitis and none of the LFA-1(-/-) mice showed any hepatic damage. Whereas activated hepatic T cells remained in the liver in LFA-1(+/+) mice, activated T cells were rapidly cleared from the livers of LFA-1(-/-) mice. Mechanistically, T cells from LFA-1(-/-) mice showed markedly reduced cytotoxicity toward liver cells as a result of impaired, activation-dependent adhesion. Importantly, adoptive transfer of hepatic T cells from LFA-1(+/+) mice, but not from LFA-1(-/-) mice, sensitized LFA-1(-/-) mice to ConA-induced hepatitis. Thus, LFA-1 expression on T cells is necessary and sufficient for T cell-mediated liver damage in vivo. These results provide the first genetic evidence on an adhesion receptor, LFA-1, that has a crucial role in fulminant hepatitis. These genetic data identify LFA-1 as a potential key target for the treatment of T cell-mediated hepatitis and the prevention of liver damage.
authors.affiliation: First Department of Oral and Maxillofacial Surgery, Kanagawa Dental College, Kanagawa, Japan.
authors.forename: Goichi
authors.initials: G
authors.lastname: Matsumoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tsunematsu
authors.forename: Kei-ichi
authors.initials: K
authors.lastname: Tsukinoki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ohmi
authors.forename: Mariko
authors.initials: M
authors.lastname: Iwamiya
authors.forename: Antonio
authors.initials: A
authors.lastname: Oliveira-dos-Santos
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tone
authors.forename: Junichi
authors.initials: J
authors.lastname: Shindo
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000941:Antigens / Q000096:biosynthesis; D000954:Antigens, Surface; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D003208:Concanavalin A / Q000633:toxicity; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D007275:Injections, Intravenous; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D037181:Lectins, C-Type; D008099:Liver / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055651:NK Cell Lectin-Like Receptor Subfamily B; D014176:Protein Biosynthesis; D011506:Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D000954:Antigens, Surface; D037181:Lectins, C-Type; D016169:Lymphocyte Function-Associated Antigen-1; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D003208:Concanavalin A; D018799:Intercellular Adhesion Molecule-1