8-10 Our studies have shown that CD4 T cells can function by way of CD154 without de novo antigen-specific activation, and innate immunity-induced CD40 may trigger CD154–CD40 engagement to facilitate tissue inflammation and injury.11 Our recent study has focused on the distinctive features of newly identified TIM-1–TIM-4 signaling in liver IRI.12 Collectively, these studies have documented a previously unrecognized mechanism through which a CD4 T cell–generated positive costimulation signal can amplify Kupffer XAV-939 chemical structure cell activity/function

and cross-talk to facilitate IR-triggered immune cascade. Programmed death-1 (PD-1; CD279) is the CD28 homologue expressed selectively by activated T, B, and myeloid cells.13 When cross-linked with PD-L1 (B7-H1; CD274) on hemopoetic and many nonhemopoetic tissues, the PD-1/B7-H1 interaction delivers a potent negative signal that inhibits Lumacaftor research buy T and B cell activation and may promote immune tolerance. This study is the first to examine the putative role of PD-1/B7-H1 in the pathophysiology of liver IRI. Our results demonstrate that stimulating PD-1 negative signals ameliorates local inflammation and liver damage and suggest that engaging PD-1/B7-H1 costimulation is required for maintaining liver homeostasis during IR-induced insult. AU, absorbance units; B7-H1Ig, B7-H1 immunoglobulin; BMM,bone marrow–derived macrophage; H&E, hematoxylin-eosin;

IFN-γ, interferon-γ; IL, interleukin; IRI, ischemia and reperfusion injury; mAb, monoclonal antibody; PD-1, programmed death-1; sALT, serum alanine aminotransferase; TLR, Toll-like receptor; TNF-α, tumor necrosis factor α; TUNEL, terminal deoxynucleotidyl transferase –mediated dUTP nick-end labeling; WT, wild-type. Male C57BL/6 wild-type (WT) mice (8-12 weeks old) (Jackson Laboratory, Bar Harbor, ME) were housed in the University of California Los Angeles animal facility under specific pathogen-free conditions and received humane care according to the criteria outlined in the Guide for the Care and Use of Laboratory Animals (prepared by the National Academy of Sciences; National Institutes of Health

publication 86-23, revised 1985). We MCE公司 used a mouse model of warm partial hepatic IRI.3-5, 7-12 Mice were anesthetized, injected with heparin (100 U/kg intraperitoneally), and the arterial and portal venous blood supply to the cephalad lobes was interrupted by an atraumatic clip. After 90 minutes of local ischemia, the clip was removed. Animals were sacrificed after 6 or 24 hours of reperfusion. Sham-operated mice underwent the same procedure, but without vascular occlusion. Rat anti–B7-H1 monoclonal antibody (mAb) (10F.9G2; Bio X Cell, West Lebanon, NH), recombinant B7-H1 immunoglobulin (B7-H1Ig), a dimeric B7-H1 immunoglobulin fusion protein14 (courtesy of Dr. Xian C. Li, Harvard Medical School, Boston, MA), or control Ig (Bio X Cell) was administered intravenously prior to the onset of ischemia (0.25 mg at day −1 and 0.5 mg at day 0).