Hepatic B7 homolog 1 expression is essential for controlling cold ischemia/reperfusion injury after mouse liver transplantation.

Abstract

UNLABELLED:

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.

CONCLUSION:

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: Shinya Ueki, Antonino Castellaneta, Osamu Yoshida, Kikumi Ozaki, Matthew Zhang, Shoko Kimura, Kumiko Isse, Mark Ross, Lifang Shao, Donna B Stolz, Angus W Thomson, Anthony J Demetris, David A Geller, Noriko Murase
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 54 Issue 1 Pg. 216-28 (Jul 2011) ISSN: 1527-3350 [Electronic] United States
• PMID: 21503939 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 American Association for the Study of Liver Diseases.

Chemical References

• B7-1 Antigen
• B7-H1 Antigen
• Cd274 protein, mouse
• Membrane Glycoproteins
• Peptides

Topics

• Animals
• Apoptosis
• B7-1 Antigen (genetics, metabolism)
• B7-H1 Antigen
• CD8-Positive T-Lymphocytes (metabolism, pathology)
• Cells, Cultured
• Cold Ischemia (adverse effects)
• Dendritic Cells (metabolism, pathology)
• Hepatocytes (metabolism, pathology)
• Humans
• Liver Transplantation
• Male
• Membrane Glycoproteins (deficiency, genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Models, Animal
• Necrosis
• Peptides (deficiency, genetics, metabolism)
• Reperfusion Injury (metabolism, pathology, prevention & control)