FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. II. FTY720 prolongs skin allograft survival by decreasing T cell infiltration into grafts but not cytokine production in vivo

Abstract

FTY720, a novel immunosuppressant, prolonged the survival of WKAH skin allografts transplanted into MHC-incompatible F344 rats. In this allograft model, the median survival time of the control group was 7 days, whereas those of the groups given FTY720 orally at 0.1 mg/kg and cyclosporin A (CsA) at 10 mg/kg were 10.5 and 11 days, respectively. In contrast, FTY720 (0.1 mg/kg) combined with CsA (10 mg/kg) synergistically prolonged allograft survival with a median survival time exceeding 70 days. To elucidate the mechanisms of this remarkable synergistic effect, mRNA expressions of IL-2 and IFN-gamma and that of CD3 (delta-chain), which reflects T cell infiltration, in allografts were temporally analyzed using a semiquantitative PCR method. In WKAH skin allografts, mRNA levels of IL-2, IFN-gamma, and CD3 were increased as compared with isograft controls, peaking on days 4 to 5. CsA (10 mg/kg) significantly inhibited elevations of IL-2 and IFN-gamma mRNA, while slightly inhibiting that of CD3 mRNA in allografts. On the contrary, FTY720 (0.1 mg/kg) markedly inhibited the elevation of CD3 mRNA, while slightly inhibiting those of IL-2 and IFN-gamma mRNA. FTY720 (0.1 mg/kg) combined with CsA (10 mg/kg) almost completely suppressed the intragraft expressions of mRNA for IL-2, IFN-gamma, and CD3. Immunohistochemical staining and flow cytometric analysis also confirmed that FTY720 decreased T cell infiltration into allografts. From these results, the synergistic effect of FTY720 combined with CsA on prolongation of allograft survival is presumably based on the respective inhibitions of T cell infiltration and cytokine production in grafts.