| Programmed death-1/B7-H1 negative costimulation protects mouse liver against ischemia and reperfusion injury. | |
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MedLine Citation:
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PMID: 20815020 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Programmed death-1 (PD-1)/B7-H1 costimulation acts as a negative regulator of host alloimmune responses. Although CD4 T cells mediate innate immunity-dominated ischemia and reperfusion injury (IRI) in the liver, the underlying mechanisms remain to be elucidated. This study focused on the role of PD-1/B7-H1 negative signaling in liver IRI. We used an established mouse model of partial liver warm ischemia (90 minutes) followed by reperfusion (6 hours). Although disruption of PD-1 signaling after anti-B7-H1 monoclonal antibody treatment augmented hepatocellular damage, its stimulation following B7-H1 immunoglobulin (B7-H1Ig) fusion protected livers from IRI, as evidenced by low serum alanine aminotransferase levels and well-preserved liver architecture. The therapeutic potential of B7-H1 engagement was evident by diminished intrahepatic T lymphocyte, neutrophil, and macrophage infiltration/activation; reduced cell necrosis/apoptosis but enhanced anti-necrotic/apoptotic Bcl-2/Bcl-xl; and decreased proinflammatory chemokine/cytokine gene expression in parallel with selectively increased interleukin (IL)-10. Neutralization of IL-10 re-created liver IRI and rendered B7-H1Ig-treated hosts susceptible to IRI. These findings were confirmed in T cell-macrophage in vitro coculture in which B7-H1Ig diminished tumor necrosis factor-α/IL-6 levels in an IL-10-dependent manner. Our novel findings document the essential role of the PD-1/B7-H1 pathway in liver IRI. CONCLUSION: This study is the first to demonstrate that stimulating PD-1 signals ameliorated liver IRI by inhibiting T cell activation and Kupffer cell/macrophage function. Harnessing mechanisms of negative costimulation by PD-1 upon T cell-Kupffer cell cross-talk may be instrumental in the maintenance of hepatic homeostasis by minimizing organ damage and promoting IL-10-dependent cytoprotection. |
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Authors:
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Haofeng Ji; Xiuda Shen; Feng Gao; Bibo Ke; Maria Cecilia S Freitas; Yoichiro Uchida; Ronald W Busuttil; Yuan Zhai; Jerzy W Kupiec-Weglinski |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: 52 ISSN: 1527-3350 ISO Abbreviation: Hepatology Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-09-29 Completed Date: 2010-10-18 Revised Date: 2012-05-21 |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: United States |
Other Details:
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Languages: eng Pagination: 1380-9 Citation Subset: IM |
Affiliation:
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Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antibodies, Monoclonal / pharmacology Antigens, CD274 Antigens, CD80 / pharmacology* Antigens, Surface / pharmacology* Apoptosis / drug effects Apoptosis Regulatory Proteins / pharmacology* Cytoprotection / immunology Immunity, Innate Interleukin-10 / immunology Liver / blood supply Liver Diseases / prevention & control* Membrane Glycoproteins / pharmacology* Mice Mice, Inbred C57BL Peptides / pharmacology* Programmed Cell Death 1 Receptor Rats Reperfusion Injury / prevention & control* |
| Grant Support | |
ID/Acronym/Agency:
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AI23847/AI/NIAID NIH HHS; R01 DK062357/DK/NIDDK NIH HHS; R01 DK062357/DK/NIDDK NIH HHS; R01 DK062357-06S1/DK/NIDDK NIH HHS; R01 DK062357-08/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antibodies, Monoclonal; 0/Antigens, CD274; 0/Antigens, CD80; 0/Antigens, Surface; 0/Apoptosis Regulatory Proteins; 0/Cd274 protein, mouse; 0/Membrane Glycoproteins; 0/Pdcd1 protein, mouse; 0/Peptides; 0/Programmed Cell Death 1 Receptor; 130068-27-8/Interleukin-10 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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