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Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd., Iruma, Saitama, Japan
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-
and that of
CD3 (
-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-, 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- 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- mRNA. FTY720 (0.1 mg/kg)
combined with CsA (10 mg/kg) almost completely suppressed the
intragraft expressions of mRNA for IL-2, IFN-, 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.
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