FTY720 Pretreatment Reduces Warm Hepatic Ischemia Reperfusion Injury Through Inhibition of T-Lymphocyte Infiltration

Abstract

Ischemia and reperfusion (IR) injury remains a significant problem in clinical liver transplantation. We investigated the effects of lymphocyte depletion with FTY720 in models of warm hepatic IR. Using 60-min partial warm hepatic IR, three groups of rats were studied: Sham--laparotomy alone; Control--water p.o. x 3 d before ischemia; Treatment--FTY720 p.o. x 3 d before ischemia. Animals were sacrificed for analysis at 6 h and 24 h post reperfusion. The effect of FTY720 pretreatment on survival was also studied using 150 min total hepatic IR with portojugular shunt. FTY720 treatment significantly reduced serum glutamic pyruvic transaminase and peripheral blood lymphocytes compared to controls at 6h and 24h (p < 0.0005). Histological grade was significantly improved in treated livers vs. controls (p < 0.05). CD3 immunocytochemical analysis revealed a significant reduction in T-cell infiltration in FTY720-treated livers (p < 0.0002). No difference in tissue myeloperoxidase levels was observed. Seven-day survival was significantly improved in treated rats vs. controls following total hepatic ischemia (p < 0.05). In conclusion, 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.

Microcirculatory Disturbances in the Pathogenesis of Acute Pancreatitis

“…Evidence is mounting on the importance of T cells in mediating both short-and long-term damage during I/R injury, which in turn could explain why I/R contributes to poor late allograft function [37,38]. The demonstration that systemic immunosuppression (CsA, FK506) attenuates hepatocellular injury following I/R implies the involvement of T lymphocytes in the pathophysiology of the injury [39,40], data supported by Shen et al in T-cell-deficient (nude) mice [41,42], as well as in rats in which treatment with FTY720 prevented hepatic I/R insult in parallel with massive redistribution of recirculating T cells from host peripheral blood into the lymph node compartment [43]. The adherence of lymphocytes in hepatic sinusoids occurs early duringreperfusion and impairs liver function following prolonged cold ischemic times [44].…”

CD4+ T cells contribute to postischemic liver injury in mice by interacting with sinusoidal endothelium and platelets

“…[9][10][11] Based on classic models of tissue injury, T cells were not suspected to play a role in postischemic tissue damage. However, the surprising protective effect of immunosuppressive drugs on the antigenindependent postischemic liver injury, 12,13 as well as reduction of hepatic postischemic damage in athymic mice, 9 point to a potential role of T cells. The mechanisms by which T cells contribute to hepatic I/R injury are not fully understood.…”

Ischemia–reperfusion and immediate T cell responses

“…In the warm liver IRI model, the protection of FTY720 was partially attributed to the reduction of T lymphocyte infiltration and inhibition of MAPK (Raf-MEKErk) pathway [23]. However, FTY720 may have effects on endothelial cells that are independent of T cell function [24].…”

“…immunosuppressant, FTY720 that modulates lymphocyte migration was found to attenuate renal and liver IRI in rodents [19][20][21][22][23]. FTY720 pretreatment resulted in improved renal function in association with reduced T cell infiltration in both cold and warm IRI models.…”