The significance of timing of FTY720 administration on the immunosuppressive effect to prolong rat skin allograft survival

FTY720, a potent immunosuppressant, dramatically decreases the number of pe ripheral blood lymphocytes within a few hours after administration. The cur rent study assessed the significance of timing of FTY720 administration on the immunosuppressive effect to prolong rat skin allograft survival (WKAH d onor to F344 recipient). The median survival time of allografts was 7 days in the control recipients. FTY720 (1 mg/kg/day) significantly prolonged all ograft survival when administered from days 0 and 3, but failed to exert an immunosuppressive effect when administered from day 4. Intragraft T cells, especially CD8(+) T cells, were markedly increased in number from day 4 to 6, peaking on day 5 in control recipients. FTY720 markedly decreased the n umber of intragraft CD8(+) T cells on day 5 when administered from days 0 a nd 3. In recipients administered with FTY720 from day 4, the number of intr agraft CD8(+) T cells were only partially decreased on day 5. Intragraft CD 8(+) T-cell number in those recipients on day 5 was almost the same as that in control recipients on day 4. In addition, FTY720 did not affect the inc rease in frequency of CD25(+) cells in the CD8(+) T-cell subset in allograf ts. It is likely that recipients treated with FTY720 From day 4 reject allo grafts by intragraft immune responses involved in CD8(+) T cells which had infiltrated before day 4, similar to control recipients. These findings sug gest that FTY720 should be administered before increase in 7 cell infiltrat ion into grafts to inhibit acute allograft rejection. (C) 2000 Internationa l Society for Immunopharmacology. Published by Elsevier Science Ltd. All ri ghts reserved.