RRC ID 2275
Author Nakayama Y, Shimizu Y, Hirano K, Ebata K, Minemura M, Watanabe A, Sugiyama T.
Title CTLA-4Ig suppresses liver injury by inhibiting acquired immune responses in a mouse model of fulminant hepatitis.
Journal Hepatology
Abstract Expression of costimulatory molecules is significantly upregulated in various organs in an animal model of severe hepatitis induced by injection of Propionibacterium acnes (P. acnes) and lipopolysaccharide (LPS). In the present study, we examined whether blockade of costimulatory signals by CTLA-4Ig can suppress the liver injury in this model. We injected an adenovirus encoding CTLA-4Ig (AdCTLA-4Ig) into mice 7 days before, on the same day, or 3 days after P. acnes priming. The virus was found to infect the liver preferentially, and CTLA-4Ig was detected in the serum as early as 2 days after viral injection. After injection of LPS, liver injury and survival rates were examined. Most of the mice not injected with AdCTLA-4Ig died within 12 hours after injection of LPS. In contrast, all the AdCTLA-4Ig-injected mice survived when the virus was injected 7 days before or on the same day as P. acnes priming. Importantly, hemorrhagic liver injury and serum alanine aminotransferase levels were significantly reduced after LPS injection even when AdCTLA-4Ig was injected 3 days after P. acnes priming. Immunological analyses showed that CTLA-4Ig inhibited the activation and expansion of P. acnes-specific CD4+ T cells in the hepatic lymph nodes, leading to a reduction in the recruitment of the cells to the liver. The total amounts of interferon-gamma, interleukin-12, and various chemokines in the liver were then decreased, resulting in inhibition of the secondary recruitment of not only T cells but also macrophages. In conclusion, CTLA-4Ig could be useful for treatment of severe liver injury.
Volume 42(4)
Pages 915-24
Published 2005-10-1
DOI 10.1002/hep.20872
PMID 16175605
MeSH Abatacept Adenoviridae / genetics Animals Antigens, CD / metabolism B7-1 Antigen / metabolism B7-2 Antigen CD11b Antigen / metabolism CD4-Positive T-Lymphocytes / metabolism CD4-Positive T-Lymphocytes / pathology Cell Count Cell Division / immunology Dendritic Cells / physiology Disease Models, Animal Female Genetic Therapy / methods* Immunoconjugates / blood Immunoconjugates / genetics* Interferon-gamma / genetics Interferon-gamma / metabolism Lipopolysaccharide Receptors / genetics Lipopolysaccharides Liver / pathology Liver / physiology Liver Failure, Acute / immunology* Liver Failure, Acute / mortality Liver Failure, Acute / therapy* Macrophages / pathology Membrane Glycoproteins / metabolism Mice Mice, Inbred C57BL Propionibacterium acnes Tryptophan Oxygenase / genetics Tumor Necrosis Factor-alpha / genetics
IF 14.679
Times Cited 13
DNA material AxCALacZ (RDB01745)