Analysis of the mode of action of a novel immunosuppressant FTY720 in mice

Accelerated lymphocyte homing and apoptosis have been suggested to contribu te to potent immunosuppressive effects of FTY720, however, its main mechani sm of action remains to be fully elucidated. Here, we examined the mode of action of FTY720 in mice. FTY720, when given at a single dose of 1 mg/kg, m arkedly decreased the number of peripheral blood lymphocytes (PBL) but mode rately increased the lymphocyte numbers in lymph nodes (LN) and Peyer's pat ches (PP) in normal mice, as previously observed in rats. However, the shar p decrease in PBL numbers was also observed in aly/aly mice lacking LN and PP, indicating that this phenomenon is not explained by accelerated lymphoc yte homing to LN and PP. in addition, the finding that a single administrat ion of FTY720 did not suppress proliferative responses of T cells suggested that the PBL reduction could occur without inhibiting lymphocyte functions . However, when administered at the same dose for 2 weeks, FTY720 induced s evere systemic lymphopenia, as well as marked suppression of lymphocyte pro liferative responses in normal mice. The same treatment also prolonged skin allograft survival in aly/aly mice. Our results suggest that FTY720 suppre sses in vivo immune functions mainly by inducing systemic lymphopenia and a lso by inhibiting T cell functions. (C) 1999 Elsevier Science B.V. All righ ts reserved.