Journal
HEPATOLOGY
Volume 52, Issue 4, Pages 1380-1389Publisher
WILEY
DOI: 10.1002/hep.23843
Keywords
-
Categories
Funding
- National Institutes of Health [RO1 DK062357, Al23847]
- Dumont Research Foundation
- American Society of Transplantation Fellowship
Ask authors/readers for more resources
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 B7Hi immunoglobulin (B7-HlIg) 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 Bc1-2/Bc1-xl; and decreased proinflanunatory chemokine/cytolcine gene expression in parallel with selectively increased interleukin (IL)-10. Neutralization of IL-10 re-created liver IRI and rendered B7-HlIg treated hosts susceptible to In These findings were confirmed in T cell macrophage in vitro cocuiture in which B7-HlIg diminished tumor necrosis factor-a/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-i0 dependent cyto protection. (HEPAToLoGY 2010;52:1380-1389)
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available