FTY720-induced lymphocyte homing modulates post-transplant preservation/reperfusion injury

Abstract

A novel immunomodulator, FTY720, modulates lymphocyte migration to injured tissues via enhanced lymphocyte sequestration to secondary lymphoid organs. We tested whether or not single-dose FTY720 (0.5 mg/kg) pretreatment rescues renal grafts from post-transplant preservation/reperfusion injury. Rat renal grafts were cold-preserved in University of Wisconsin (UW) solution for 4 hours and then transplanted into syngeneic or allogeneic recipients that received a single dose of FTY720 24 hours before transplantation. Flow cytometry analysis of peripheral blood and lymph nodes was performed to confirm the biologic effect of FTY720. Grafts were harvested after 24 hours. Renal sections were examined histologically and stained for intracellular adhesion molecule-1 (ICAM-1), vascular cellular adhesion molecule-1 (VCAM-1), platelet endothelial cellular adhesion molecule-1 (PECAM-1), major histocompatibility complex (MHC) class II, and inflammatory cells. Interleukin-1 (IL-1) production was determined in renal protein extracts. FTY720 pretreatment significantly increased CD3+ T-cell sequestration to lymph nodes in the face of peripheral lymphopenia. Isografts and allografts from the FTY720-treated groups did not develop increased creatinine (0.55 +/- 0.12 in isografts and 0.62 +/- 0.08 mg/dL in allografts), compared with vehicle controls (2.28 +/- 0.20 in isografts and 2.24 +/- 0.18 mg/dL in allografts). Kidneys from FTY720-treated groups also showed lower acute tubular damage scores. Furthermore, FTY720 decreased neutrophil influx, although circulating neutrophils were unchanged. FTY720 also prevented postischemic IL-1 intragraft production not affecting infiltration with recipient ED-1+ macrophages and MHC class II-positive cells. Expression of ICAM-1, VCAM-1, and PECAM did not differ among groups. FTY720 ameliorated morphologic and functional consequences of post-transplant reperfusion injury. Thus, FTY720-induced peripheral T-cell absence may influence intragraft IL-1 production and neutrophil infiltration, despite proadhesive endothelial properties. FTY720 may broaden the utility in renal transplantation as a pretreatment strategy against preservation/reperfusion injury.