Me. Wang et al., IMMUNOSUPPRESSIVE EFFECTS OF FTY720 ALONE OR IN COMBINATION WITH CYCLOSPORINE AND OR SIROLIMUS/, Transplantation, 65(7), 1998, pp. 899-905
Background. We examined the ability of FTY720, a novel immunosuppressa
nt that prolongs the survival of allografts in experimental animal mod
els, to potentiate the immunosuppressive effects of cyclosporine (CsA)
and/or sirolimus (SRL) in vitro and in vivo. Methods. FTY720 alone (1
0-5000 ng/ml) or in combination with other drugs was added to human pe
ripheral blood lymphocytes (PBLs) undergoing stimulation in vitro with
phytohemagglutinin (PHA) or OKT3 monoclonal antibody. The combination
index (CI) values were calculated to evaluate the nature of the inter
actions between FTY720 and CsA and/or SRL: CI values <1 reflect synerg
istic, CI=1, additive, and CI>1, antagonistic interactions, In additio
n, Wistar Furth (RT1(u)) rat recipients of Buffalo (RT1(b)) heart allo
grafts were treated with FTY720 alone or in combination with other age
nts. FTY720 alone was also tested to block small bowel or liver allogr
aft rejection in rats. Results. FTY720 alone produced only modest inhi
bition of the proliferation of human PBL stimulated with PHA or OKT3 m
onoclonal antibody. In combination with CsA or SRL, however, FTY720 pr
oduced synergistic effects, namely, CI values of 0.58 and 0.36, respec
tively. A 14-day course of FTY720 (0.05-8.0 mg/kg/day) by oral gavage
prolonged heart allograft survival in dose-dependent fashion. Although
a 14-day oral course of CsA (1.0 mg/kg/day) alone was ineffective (me
an survival time=7.0 +/- 0.7 vs, 6.4 +/- 0.6 days in treated vs, untre
ated hosts), treatment with a combination of 1.0 mg/kg/day CsA and 0.1
mg/kg/day FTY720 extended allograft survival to 62.4 +/- 15.6 days (P
<0.001; CI=0.15). Similarly, a 14-day oral course of 0.08 mg/kg/day SR
L alone was ineffective (6.8 +/- 0.6 days; NS), but the combination of
SRL with 0.5 mg/kg/day FTY720 extended the mean survival time to 34.4
+/- 8.8 days (CI=0.28), The CsA/SRL (0.5/0.08 mg/kg/day) combination
acted synergistically with FTY720 (0.1 mg/kg/day) to prolong heart sur
vivals to >60 days (CI=0.18). Conclusions. FTY720 potentiates the immu
nosuppressive effects of CsA and/or SRL both in vitro (by inhibiting o
f T-cell proliferative response) and in vivo (by inhibiting allograft
rejection).