Interestingly, the levels of anti-inflammatory IL-10 (but not IL-4) were selectively heightened, in agreement with the ability of B7-H1Ig–treated T cells to preferentially secrete IL-10,32 and increased PD-1 and IL-10 levels were found in liver transplantation patients at high risk for CMV disease.33 Moreover, PD-1–induced IL-10
may impair CD4+ T cell activation during HIV infection.34 Such an altered local inflammation was responsible for liver protection, because IL-10 neutralization restored inflammation and hepatocellular damage. In support of this notion, we have reported that IL-10 was required for liver protection in mice deficient in CXCL-10,4 and that viral IL-10 gene transfer in WT recipients prevented hepatic IR insult in association with depressed Th1 cytokine/chemokine programs.35 It is plausible XL184 mw that by virtue of selective IL-10 expression, B7-H1Ig might
raise the defensive threshold to inflammatory response in IR-exposed livers. Our results suggest that PD-1/B7-H1 interaction mediates local inflammatory cell infiltration and activation. In the first phase of IR-mediated inflammation response, activation of macrophages and Kupffer cells results in the release of TNF-α, GW-572016 cost IL-1β, IL-6, CXCL-10, and CCL-2, the signature markers of liver IRI.1-5 These cytokines and chemokines also influence T cell and macrophage trafficking patterns, as evidenced by increased numbers of infiltrating CD3+ cells and F4/80+ cells. However, stimulating PD-1 signals blunted the number of macrophages sequestered in the liver and their inflammation/chemotactic expression programs. In the second phase of IRI, activated neutrophils dominate local damage cascade.1, 2 We observed a marked increase in Ly-6G+ neutrophil
infiltration and myeloperoxidase activity in control Megestrol Acetate livers compared with sham controls. Unlike the control group, livers in B7-H1Ig–treated mice were characterized by decreased neutrophil sequestration, along with diminished CXCL-1 and CXCL-5, the key chemoattractants facilitating neutrophil recruitment in hepatic IR inflammation. As T helper 1–derived IFN-γ acts directly on neutrophils to enhance their sequestration in the liver, B7-H1 cross-linking can regulate neutrophil function through cytokine/chemokine networks. One of the principal mechanisms by which PD-1/B7-H1 ligation affects host alloimmunity is through modulation of T cell apoptosis.12 B7-H1 but not PD-1 blockade inhibited apoptosis of alloantigen-specific T cells in transplant recipients,20 and B7-H1 was identified as a key protein controlling deletion of hepatic CD8+ T cells.