The emerging role of t cell immunoglobulin mucin-1 in the mechanism of liver ischemia and reperfusion injury in the mouse

Yoichiro Uchida, Bibo Ke, Maria Cecilia S. Freitas, Haofeng Ji, Danyun Zhao, Elizabeth R. Benjamin, Nader Najafian, Hideo Yagita, Hisaya Akiba, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


The T cell immunoglobulin and mucin domain-containing molecules (TIM) protein family, which is expressed by T cells, plays a crucial role in regulating host adaptive immunity and tolerance. However, its role in local inflammation, such as innate immunity-dominated organ ischemia-reperfusion injury (IRI), remains unknown. Liver IRI occurs frequently after major hepatic resection or liver transplantation. Using an antagonistic anti-TIM-1 antibody (Ab), we studied the role of TIM-1 signaling in the model of partial warm liver ischemia followed by reperfusion. Anti-TIM-1 Ab monotherapy ameliorated the hepatocellular damage and improved liver function due to IR, as compared with controls. Histological examination has revealed that anti-TIM-1 Ab treatment decreased local neutrophil infiltration, inhibited sequestration of T lymphocytes, macrophages, TIM-1 ligand- expressing TIM-4+< cells, and reduced liver cell apoptosis. Intrahepatic neutrophil activity and induction of proinflammatory cytokines/ chemokines were also reduced in the treatment group. In parallel in vitro studies, anti-TIM-1 Ab suppressed interferon-γ (IFN-γ) production in concanavalin A (conA)-stimulated spleen T cells, and diminished tumor necrosis factor α (TNF-α)/interleukin (IL)-6 expression in amacrophage/spleen T cell coculture system. This is the first study to provide evidence for the novel role of TIM-1 signaling in the mechanism of liver IRI. TIM-1 regulates not only T for the role of cell activation but may also affect macrophage function in the local inflammation response. These results provide compelling data for further investigation of TIM-1 pathway in the mechanism of IRI, to improve liver function, expand the organ donor pool, and improve the overall success of liver transplantation.

Original languageEnglish (US)
Pages (from-to)1363-1372
Number of pages10
Issue number4
StatePublished - Apr 2010

ASJC Scopus subject areas

  • Hepatology


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