| BACKGROUNDDevelopment of immunosuppressive agents over the past decade has improved survival of organ transplantation, but graft injury that results from ischemia and reperfusion (IR) remains a critical issue in kidney transplantation. IR is a major determinant of. delayed graft dysfunction and may increase the immunogenecity of allograft organs. In renal transplantation, IR injury is an unavoidable consequence, the most severe manifestation of graft injury is primary graft nonfunction; a less dramatic sequel of IR injury is early dysfunction that occurs in 10% to 30% of cases but is also an important cause of mortality and morbidity.IR injury involves a complex cascade of inflammatory events, which mediated neutrophil infiltration. The role of lymphocytes in the antigen-independent inflammatory response following kidney IR is not clearly but recent data suggests a contributory role.A novel immunomodulator FTY720 is a synthetic compound of a natural product extracted from the fungus isaria sinclairii. FTY720 has shown potent immunosuppressive activities in a variety of animal organ transplant model used alone or in combination with cyclosporin or rapamycin. However, the exact in vivo immunosuppressive mechanism of FTY720 is still not fully elucidated. Administration of FTY720 induces markedly decrease of lymphocyte count inperipheral blood by accelerated lymphocyte trafficking to peripheral lymphnodes and Peyers' patches. Pretreament with several other immunosuppressive drugs including cyclosporin and anti-T-lymphocyte antibody has been shown to protect against IR injury, although the mechanism is not fully known.There are dissensions that FTY720 display a protective effect on the hepatic damage after warm IR. Mizuta reported pretreatment with FTY720 alone tended to prolong hepatic damage after warm IR in 1999. But in 2002, Anselmo sustained that FTY720 ameliorates the biochemical and histological manifestations of hepatic IR by preventing T-lymphocyte infiltration and prolongs survival following a more severe ischemic insult. Myeloperoxidase data suggest this mechanism is independent of neutrophil activation. These results indicate that T lymphocytes are pivotal mediators in hepatic IR and may have important implications in liver transplantation. In the kidney warm IR injury, Troncoso reported that FTY720 1mg/kg displayed a moderate protective effect on the renal function when administered immediately after ischmia and the protective effect may be related to lymphocyte depletion. Up to now,the exact protective mechanism of action of FTY720 in the damage of IR has still not been elucidated,although it seem to be related to the persistent lymphopenia and the secondary reduction of infiltrating T cells into the IR organ induced by its administration.The aim of the present study was to investigate the efficacy of FTY720 and the impact of peripheral lymphocyte depletion with FTY720 pretreatment on renal recovery in the model of warm ischemia-reperfusion in rats. We will study the precise molecular mechanism of protective action of FTY720 by monitoring the level of mRNA expression cytokine including tumor necrosis factor-1 (TNF- α), interleukin-1 (IL-β ), Regulated on Activation Normal T Expressed and Secreted (RANTES), monocyte chemoattractant protein (MCP-1) with RT-PCR method and determined the activity of nuclear factor- K B (NF- K B) with Western Blotting method. MATERIALS AND METHODSExperiments were performed on adult male Sprague-Dawley rats weighing220-280 g, being anesthetized with an injection of chloral hydrate 150mg/kg IP. Sham rats underwent laparotomy without IR. Treated rats received different dosage of FTY720(0.3, 3 and 10 mg/kg. d-1) from operate day -3 days to day 7 and then underwent 45 minutes of warm renal IR to the left and right kidney pedicle with atraumatic microvascular clips.Control rats were administered distilled water from operate day -3 days to day 7 prior to induction of warm kidney IR. 4-6 animals in each group were sacrificed at 0,4th h...
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