FTY720 induces the sequestration of circulating lymphocytes into the bone marrow in alymphoplasia mice

Fingolimod (FTY720), a sphingosine 1-phosphate (S1P) receptor modulator, is highly effective in various autoimmune disease models and decreases circulating mature lymphocytes by inhibiting S1P-dependent lymphocyte egress from secondary lymphoid organs (SLO). On the contrary, FTY720 at an oral dose of 1 mg/kg also induces a significant decrease in the number of peripheral blood lymphocytes (PBL), particularly T cells, in alymphoplasia (aly/aly) mice lacking SLO. We demonstrated that there was no contribution of thymus or spleen for the reduction of PBL by FTY720 because FTY720 could also decrease the number of PBL in thymectomized and/or splenectomized aly/aly mice. When mice were given FTY720 at 1 mg/kg orally, the blood concentration of FTY720 is approximately 0.2 μM or less. On the other hand, no apoptosis was seen in aly/aly lymphocytes when they were treated with FTY720 at a concentration of up to 1 μM. Moreover, we found that oral administration of FTY720 at 1 mg/kg to aly/aly mice induced the accumulation of mature lymphocytes, particularly T cells, into the bone marrow but not spleen or thymus. Consequently, it is highly probable that mature lymphocytes depleted from blood by FTY720 were sequestered into the bone marrow in aly/aly mice. The sequestration of T cells into the bone marrow was also induced by S1P lyase inhibitor that disrupts S1P gradients. These results demonstrate that the reduction of PBL in aly/aly mice by FTY720 is due to inhibition of S1P-dependent lymphocyte egress from the bone marrow, but not induction of lymphocyte apoptosis.