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-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-10-dependent cytoprotection. (HEPATOLOGY 2010;52:1380-1389

B7-H1 Selectively Controls TH17 Differentiation and Central Nervous System Autoimmunity via a Novel Non–PD-1–Mediated Pathway

“…So far there has been no experimental evidence that a signal provided by B7-H1 exerts protective effects in animal models of autoimmunity, although in vivo application of B7-H1 fusion proteins has been shown to protect from liver ischemia and reperfusion injury, as well as from transplant rejection (47,48). Hence our data demonstrate for the first time, to our knowledge, that in vivo delivery of a B7-H1 signal might be useful as therapeutic approach for treatment of autoimmunity.…”

Early cytokine signatures of ischemia/reperfusion injury in human orthotopic liver transplantation

“…Ischemia/reperfusion injury (IRI) occurs as an inevitable consequence of the transplant process, beginning with organ procurement and preservation and followed by reperfusion of the donor organ with recipient blood during transplant (1). Data from murine models have indicated that liver IRI has hypoxic cellular stress and inflammation-mediated injury components (2)(3)(4)(5). Local circulatory damage first induces endogenous reactive oxygen species production causing hepatocyte death.…”

Decreased PD-1/PD-L1 Expression Is Associated with the Reduction in Mucosal Immunoglobulin A in Mice with Intestinal Ischemia Reperfusion

“…1b, c). Of note, Ji et al and Jaworska et al [24,25] found that PD-L1 mimics relieved liver and kidney I/R injury by inhibiting uncontrolled immune and inflammatory activation, strongly implying that liver or kidney I/R injury exerts inhibitory effects on expression of the PD-1 pathway. While our data suggest that intestinal I/R injury interrupts PD-1/PD-L1 expression on a major subset of T lymphocytes in the inductive sites of intestinal mucosal immunity, further studies are needed to explore PD-1/PD-L1 inhibitory mechanisms following I/R injury.…”