RRC ID 41743
Author Matsumoto G, Tsunematsu S, Tsukinoki K, Ohmi Y, Iwamiya M, Oliveira-dos-Santos A, Tone D, Shindo J, Penninger JM.
Title Essential role of the adhesion receptor LFA-1 for T cell-dependent fulminant hepatitis.
Journal J Immunol
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.
Volume 169(12)
Pages 7087-96
Published 2002-12-15
DOI 10.4049/jimmunol.169.12.7087
PMID 12471145
MeSH Adoptive Transfer Animals Antibodies, Monoclonal / administration & dosage Antigens / biosynthesis Antigens, Surface Cell Adhesion / genetics Cell Adhesion / immunology Cell Line Chemical and Drug Induced Liver Injury / etiology Chemical and Drug Induced Liver Injury / genetics Chemical and Drug Induced Liver Injury / immunology* Chemical and Drug Induced Liver Injury / prevention & control Concanavalin A / toxicity Cytotoxicity, Immunologic / genetics Injections, Intravenous Intercellular Adhesion Molecule-1 / immunology Killer Cells, Natural / immunology Killer Cells, Natural / metabolism Killer Cells, Natural / transplantation Lectins, C-Type Liver / immunology Liver / pathology Lymphocyte Activation / genetics Lymphocyte Activation / immunology Lymphocyte Function-Associated Antigen-1 / biosynthesis Lymphocyte Function-Associated Antigen-1 / genetics Lymphocyte Function-Associated Antigen-1 / physiology* Mice Mice, Inbred C57BL Mice, Knockout NK Cell Lectin-Like Receptor Subfamily B Protein Biosynthesis Proteins* Receptors, Antigen, T-Cell, alpha-beta / biosynthesis T-Lymphocyte Subsets / immunology* T-Lymphocyte Subsets / metabolism T-Lymphocyte Subsets / transplantation
IF 4.886
Times Cited 22
Human and Animal Cells