title: Programmed death-1/B7-H1 negative costimulation protects mouse liver against ischemia and reperfusion injury.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Haofeng
authors.initials: H
authors.lastname: Ji
authors.forename: Xiuda
authors.initials: X
authors.lastname: Shen
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Bibo
authors.initials: B
authors.lastname: Ke
authors.forename: Maria Cecilia S
authors.initials: MC
authors.lastname: Freitas
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Uchida
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhai
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000954:Antigens, Surface / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology*; D018122:B7-1 Antigen / Q000494:pharmacology*; D060890:B7-H1 Antigen; D019610:Cytoprotection / Q000276:immunology; D007113:Immunity, Innate; D016753:Interleukin-10 / Q000276:immunology; D008099:Liver / Q000098:blood supply; D008107:Liver Diseases / Q000517:prevention & control*; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000494:pharmacology*; D061026:Programmed Cell Death 1 Receptor; D051381:Rats; D015427:Reperfusion Injury / Q000517:prevention & control*
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D016753:Interleukin-10
references.citation: Gastroenterology. 2008 Sep;135(3):980-8
references.pmid: 18621049
references.citation: Exp Mol Pathol. 2003 Apr;74(2):86-93
references.pmid: 12710939
references.citation: J Exp Med. 2000 Oct 2;192(7):1027-34
references.pmid: 11015443
references.citation: Hum Gene Ther. 2007 Apr;18(4):355-66
references.pmid: 17439357
references.citation: Hepatology. 2006 Nov;44(5):1171-81
references.pmid: 17058227
references.citation: Transplantation. 2002 Oct 15;74(7):905-12
references.pmid: 12394829
references.citation: Nat Med. 1999 Dec;5(12):1365-9
references.pmid: 10581077
references.citation: Transplantation. 2003 Sep 27;76(6):994-9
references.pmid: 14508368
references.citation: Hepatology. 2003 Feb;37(2):296-303
references.pmid: 12540779
references.citation: J Immunol. 2006 Nov 1;177(9):5928-35
references.pmid: 17056517
references.citation: Nat Med. 2010 Apr;16(4):452-9
references.pmid: 20208540
references.citation: Hepatology. 2009 Nov;50(5):1537-46
references.pmid: 19670423
references.citation: J Hepatol. 2006 Oct;45(4):520-8
references.pmid: 16876901
references.citation: Annu Rev Immunol. 2008;26:677-704
references.pmid: 18173375
references.citation: Transplantation. 2002 Aug 15;74(3):315-9
references.pmid: 12177608
references.citation: Eur J Immunol. 2007 Oct;37(10):2983-90
references.pmid: 17899549
references.citation: J Exp Med. 2006 Apr 17;203(4):883-95
references.pmid: 16606670
references.citation: Hepatology. 2008 Jan;47(1):199-206
references.pmid: 17935177
references.citation: Am J Transplant. 2010 Jan;10(1):40-6
references.pmid: 19889124
references.citation: Gastroenterology. 2003 Oct;125(4):1246-57
references.pmid: 14517806
references.citation: J Immunol. 2006 Oct 1;177(7):4749-57
references.pmid: 16982915
references.citation: Cancer Res. 2009 Oct 15;69(20):8067-75
references.pmid: 19826049
references.citation: J Clin Invest. 1997 Jul 15;100(2):279-89
references.pmid: 9218504
references.citation: Leukemia. 1997 Apr;11 Suppl 3:380-2
references.pmid: 9209397
references.citation: J Immunol. 2002 Dec 1;169(11):6546-53
references.pmid: 12444166
references.citation: Hepatology. 2008 Jan;47(1):207-14
references.pmid: 18041715
references.citation: Hepatology. 2010 Apr;51(4):1363-72
references.pmid: 20091883
references.citation: Transplantation. 2008 Sep 15;86(5):710-8
references.pmid: 18791453
references.citation: Transplantation. 2005 May 15;79(9):1078-83
references.pmid: 15880047
references.citation: J Immunol. 2004 Dec 15;173(12):7115-9
references.pmid: 15585830
references.citation: J Clin Invest. 2010 Feb;120(2):559-69
references.pmid: 20093775
references.citation: Transplantation. 2009 Oct 15;88(7):864-73
references.pmid: 19935456
references.citation: Ann Surg. 1999 Aug;230(2):185-93
references.pmid: 10450732
references.citation: Immunity. 2004 Mar;20(3):327-36
references.pmid: 15030776
references.citation: J Immunol. 2007 Oct 15;179(8):5204-10
references.pmid: 17911605
references.citation: Mol Ther. 2004 Jan;9(1):38-45
references.pmid: 14741776
references.citation: J Exp Med. 2007 Feb 19;204(2):299-309
references.pmid: 17261633
references.citation: Transpl Infect Dis. 2010 Aug 1;12(4):363-70
references.pmid: 20070620