Thus, ASP4058 may provide a novel therapeutic option for patients with MS that is safer than nonselective S1P receptor agonists such as fingolimod. S1P1 is a key mediator of the immunomodulatory effects of S1P receptor agonists. S1P receptor agonists exert these effects, at least in part, by inducing long-term downregulation of S1P1 expressed by lymphocytes, which causes the sequestration of cells in lymphoid tissues and prevents their migration to target organs. Consistent with these findings, treatment of rats with ASP4058 reduced the number of peripheral lymphocytes. The ED50 of ASP4058 required to reduce the number of peripheral lymphocytes after a single dose was higher by a factor of 2.4 than that of fingolimod; however, the effective dose of both compounds after repeated administration for 21 days were equivalent, suggesting a cumulative effect of ASP4058 on reducing peripheral lymphocytes. Trafficking of T cells and B cells depends on S1P1, whereas the trafficking of natural killer cells requires expression of S1P5. Because ASP4058 is an agonist of S1P1 and S1P5, ASP4058 may affect not only T and B cells but NK cells as well. Further investigation is required to identify the lymphocyte subsets affected by ASP4058. Next, we determined the effect of ASP4058 and fingolimod in rodent EAE, which is an autoimmune disease mediated by lymphocytes. While both ASP4058 and fingolimod exerted a prophylactic effect on EAE in Lewis rats, the dose of ASP4058 required to achieve the maximum effect compared with fingolimod was higher by a factor of approximately 3 in this model, possibly due to difference in dose required for each compound to reduce the numbers of lymphocytes at the beginning of the treatment. Lewis rats serve as an acute model of EAE in which clinical symptoms appear approximately 10 days after immunization and remit shortly after onset. Therefore, the immunomodulatory effects of S1P receptor agonists in the early phase may contribute significantly to the efficacy in EAE model in Lewis rats. Consistent with this hypothesis, the maximum effective dose of each compound in this model was equal to the dose required to maximally reduce the population of peripheral lymphocytes after a single administration. We further investigated the effects of ASP4058 and fingolimod on SJL/J mice with EAE, which display a relapsing-remitting clinical course. Each compound was administered after clinical symptoms appeared to investigate the effects on relapse. ASP4058 and fingolimod significantly reduced clinical symptoms during Ibrutinib relapse at the same dose, which may be attributed to the equivalent potency of both compounds for reducing lymphocyte numbers in this system. The results acquired using both EAE models suggest that ASP4058 ameliorates EAE primarily by reducing the number of peripheral lymphocytes, which prevents infiltration of encephalitogenic lymphocytes into the CNS.