title: Hepatic B7 homolog 1 expression is essential for controlling cold ischemia/reperfusion injury after mouse liver transplantation.
abstract: Ischemia/reperfusion (I/R) injury remains a key risk factor significantly affecting morbidity and mortality after liver transplantation (LT). B7 homolog 1 (B7-H1), a recently identified member of the B7 family, is known to play important roles in regulating local immune responses. We hypothesized that B7-H1 plays crucial roles during innate immune responses induced by hepatic I/R injury, and using B7-H1 knockout (KO) liver grafts, we tested this hypothesis in the mouse LT model with 24 hours of cold storage. Cold I/R injury in wild type (WT)-to-WT LT enhanced constitutive B7-H1 expression on dendritic cells and sinusoidal endothelial cells and promptly induced B7-H1 on hepatocytes. When B7-H1 KO liver grafts were transplanted into WT recipients, serum alanine aminotransferase (ALT) and graft necrosis levels were significantly higher than those after WT-to-WT LT. Augmented tissue injury in B7-H1 KO grafts was associated with increased frequencies and absolute numbers of graft CD3(+) T cells (particularly CD8(+) T cells). B7-H1 KO grafts had significantly fewer annexin V(+) CD8(+) T cells, and this indicated a failure to delete infiltrating CD8(+) T cells. To evaluate the relative contributions of parenchymal cell and bone marrow-derived cell (BMDC) B7-H1 expression, we generated and transplanted into WT recipients chimeric liver grafts lacking B7-H1 on parenchymal cells or BMDCs. A selective B7-H1 deficiency on parenchymal cells or BMDCs resulted in similar levels of ALT and liver injury, and this suggested that parenchymal cell and BMDC B7-H1 expression was involved in liver damage control. Human livers up-regulated B7-H1 expression after LT.
  
  
  CONCLUSIONS
  The study demonstrates that graft tissue expression of B7-H1 plays a critical role in regulating inflammatory responses during LT-induced hepatic I/R injury, and negative coregulatory signals may have an important function in hepatic innate immune responses.
authors.affiliation: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Shinya
authors.initials: S
authors.lastname: Ueki
authors.forename: Antonino
authors.initials: A
authors.lastname: Castellaneta
authors.forename: Osamu
authors.initials: O
authors.lastname: Yoshida
authors.forename: Kikumi
authors.initials: K
authors.lastname: Ozaki
authors.forename: Matthew
authors.initials: M
authors.lastname: Zhang
authors.forename: Shoko
authors.initials: S
authors.lastname: Kimura
authors.forename: Kumiko
authors.initials: K
authors.lastname: Isse
authors.forename: Mark
authors.initials: M
authors.lastname: Ross
authors.forename: Lifang
authors.initials: L
authors.lastname: Shao
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.forename: Angus W
authors.initials: AW
authors.lastname: Thomson
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Demetris
authors.forename: David A
authors.initials: DA
authors.lastname: Geller
authors.forename: Noriko
authors.initials: N
authors.lastname: Murase
mesh_terms: D000818:Animals; D017209:Apoptosis; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism*; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D050377:Cold Ischemia / Q000009:adverse effects*; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D009336:Necrosis; D010455:Peptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; D010455:Peptides