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

Abstract

FTY720, a potent immunosuppressant, dramatically decreases the number of peripheral blood lymphocytes within a few hours after administration. The current study assessed the significance of timing of FTY720 administration on the immunosuppressive effect to prolong rat skin allograft survival (WKAH donor to F344 recipient). The median survival time of allografts was 7 days in the control recipients. FTY720 (1 mg/kg/day) significantly prolonged allograft 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 number of intragraft CD8⁺ T cells on day 5 when administered from days 0 and 3. In recipients administered with FTY720 from day 4, the number of intragraft CD8⁺ T cells were only partially decreased on day 5. Intragraft CD8⁺ 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 increase in frequency of CD25⁺ cells in the CD8⁺ T-cell subset in allografts. It is likely that recipients treated with FTY720 from day 4 reject allografts by intragraft immune responses involved in CD8⁺ T cells which had infiltrated before day 4, similar to control recipients. These findings suggest that FTY720 should be administered before increase in T cell infiltration into grafts to inhibit acute allograft rejection.