Programmed death-1/B7-H1 negative costimulation protects mouse liver against ischemia and reperfusion injury†‡

摘要: 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, underlying mechanisms remain to be elucidated. This study focused on role PD-1/B7-H1 signaling liver IRI. We used an established mouse model partial warm (90 minutes) followed by (6 hours). disruption PD-1 after anti–B7-H1 monoclonal antibody treatment augmented hepatocellular damage, its stimulation following B7-H1 immunoglobulin (B7-H1Ig) fusion protected livers from IRI, evidenced low serum alanine aminotransferase levels well-preserved architecture. The therapeutic potential engagement was evident diminished intrahepatic lymphocyte, neutrophil, macrophage infiltration/activation; reduced cell necrosis/apoptosis but enhanced anti-necrotic/apoptotic Bcl-2/Bcl-xl; decreased proinflammatory chemokine/cytokine gene expression parallel with selectively increased interleukin (IL)-10. Neutralization IL-10 re-created IRI rendered B7-H1Ig–treated hosts susceptible These findings were confirmed cell–macrophage vitro coculture which B7-H1Ig tumor necrosis factor-α/IL-6 IL-10–dependent manner. Our novel document essential pathway Conclusion: is first demonstrate that stimulating signals ameliorated inhibiting activation Kupffer cell/macrophage function. Harnessing upon cell–Kupffer cross-talk may instrumental maintenance hepatic homeostasis minimizing organ damage promoting cytoprotection. (HEPATOLOGY 2010.)