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Multiple sclerosis (MS), an inflammatory disorder of the central nervous system, is characterized by relapsing-remitting (RR) clinical course. Fingolimod was the first oral therapy to prevent relapses in patients with RRMS, approved in Japan in 2011. In lymph node, fingolimod acts as functional antagonist, leading to internalization of sphingosine-1-phosphate 1(S1P1) receptors of lymphocytes. Lymphocytes in lymph nodes bearing S1P1 receptors cannot egress from lymph nodes. As a result, lymphocyte count in the circulation is reduced. Fingolimod showed reduced relapses, and suppressed the number of enhancing lesion and the progression of brain atrophy of brain MRI, however, it also showed some adverse effects such as bradycardia, herpes zoster infection, macular edema, liver dysfunction, and teratogenic properties. We proposed indications of fingolimod therapy, and reduced dosage therapy of fingolimod for patients with a lymphocyte count below 0.2 x 10(9) cells/L.

The treatment of multiple sclerosis (MS) has been remarkably progressed, especially in disease modifying therapies (DMTs). Recently, fingolimod, a novel oral DMT, was added to treatment options for relapsing-remitting MS (RRMS) in Japan. In Western countries, more kinds of DMTs are available for treatment for RRMS. Further, clinical trials on many drugs including DMTs are on-going, and the arrival of multiple options for MS is promising. This article reviews the recent progress in current therapeutic strategies for MS and the potential options for future MS treatments.

Multiple sclerosis is characterized by temporal and spatial dissemination of demyelination in the central nervous system. After a discovery of disease modifying effects of interferon beta and glatiramer acetate for multiple sclerosis, many drugs for disease modifying therapy have been developed. Recently, some multicenter studies have shown that early introduction of interferon beta or glatiramer acetate into patients with clinically isolated syndrome delayed the conversion to clinically definite multiple sclerosis. Newly developed disease modifying therapies for multiple sclerosis have a specific molecular target changing an immunological reaction and many of them are oral preparations instead of injectable first line therapies. Treatment options for multiple sclerosis are increasing and it is essential for the optimal treatment choice to collect information of the long-term side effects and the combined effects with first line therapies and to acquire the knowledge of the pathomechanisms about multiple sclerosis.

Recently, inflammation has been implicated in the progression of cerebral ischemic injury. Especially, T lymphocytes have been shown to infiltrate into the ischemic brain 24 hours after the onset, however, the function and specific subpopulation of these infiltrated T lymphocytes have not been fully understood. By using cytokine-deficient mice with transient focal ischemia model, we have shown that IL-23 and IL-17 but not IL-6 or IFN-γ play pivotal roles in the ischemic brain injury. We found that IL-23, which was mainly produced from infiltrated macrophages, induced IL-17-producing T lymphocytes in the ischemic brain. IL-23 and IL-17 expression increased 1 day or 3 day after ischemic injury, respectively, and promoted inflammatory responses by increasing the expression of neurotoxic factors. To our surprise, IL-17 was mainly produced by γδT lymphocytes, but not helper T cells. Based on these findings, we have tried to develop new therapeutic strategy for the progression of brain infarction. We found that administration of FTY720 (Fingolimod) and antibody against γδT lymphocytes attenuated ischemic brain damage. Furthermore, antibody against p40 which neutralizes both IL-23 and IL-12 simultaneously was also effective. Therefore, anti-cytokine therapy will be applicable for neuroprotection in the delayed phase of brain ischemia.

Multiple sclerosis (MS) is a chronic central nervous system disease in which autoimmune mechanisms are operative. Although it appears that the prognosis of MS has been significantly improved after interferon-beta and glatiramer acetate were introduced in clinic, many patients are still refractory to available medications, and the necessity to develop new treatment options is obvious. Current trend in the drug discovery is to find or make a drug whose molecular target is clearly identified. This is also the case for the development of drugs for MS. Here I review current status in the development of so-called "molecular target drugs" for MS. In general, effects of such drugs well fit to the expected mechanism of action. Although concerns about opportunistic infections including JC virus-mediated progressive multi-focal leukoencephalopathy (PML) have not been dissolved, better clinical and laboratory monitoring of the immune system of the patients may help minimize potential side effects of these drugs.

Fingolimod (FTY720) is the first substance in the new immunomodulator class called sphingosine 1-phosphate (S1P) receptor modulators. We isolated an immunosuppressive natural product, myrocin, from the culture broth of Isaria sinclairii, a kind of vegetative wasp. The chemical modification of myriocin yielded a new compound, FTY720, which has more potent immunosuppressive activity and less toxicity than myriocin. FTY720 has been shown to be highly effective in experimental allograft models and autoimmune disease models such as autoimmune encephalomyelitis, collagen-induced arthritis, and lupus nephritis. The most striking feature of FTY720 is the induction of a marked decrease in peripheral blood lymphocytes at doses that show immunosuppressive activity in these models. FTY720 is rapidly converted to FTY720-phosphate (FTY720-P) by sphingosine kinases. FTY720-P acts as a potent agonist at S1P receptor type 1 (S1P(1)), internalizes S1P(1) on lymphocytes, and inhibits the migration of lymphocytes toward S1P. It is highly likely that the reduction of peripheral blood lymphocytes by FTY720 is due to the inhibition of S1P(1)-dependent lymphocyte egress from secondary lymphoid organs and thymus. Recently, it has been reported that FTY720 exerted considerable therapeutic effects in a placebo-controlled clinical trail involving patients with relapsing multiple sclerosis. Patients who received FTY720 orally had a significant reduction in the clinical disease activity, the number of lesions in the central nervous system, and the relapse rates. Since FTY720 possesses a new mechanism of action that has not been observed with other immunosuppressive agents, it is believed that FTY720 provides a new therapeutic approach for autoimmune diseases including multiple sclerosis.

Fingolimod (FTY720) is the first of a new immunomodulator class : sphingosine 1-phosphate (S1P) receptor modulator. We have found FTY720 by chemical modification of a natural product, myriocin derived from Isaria sinclairii, a kind of vegetative wasp. FTY720 has shown to be highly effective in experimental allograft models and autoimmune disease models. A most striking feature of FTY720 is the induction of a marked decrease in peripheral blood lymphocytes at doses that show immunomodulating effects in these models. It is revealed that the reduction of circulating lymphocytes by FTY720 is due to sequestration of lymphocytes into secondary lymphoid organs and thymus. FTY720 is rapidly converted to FTY720-phosphate (FTY720-P) by sphingosine kinases. FTY720-P acts as a potent agonist at S1P receptor type 1 (S1P(1)), internalizes S1P(1) on lymphocytes, and inhibits the migration of lymphocytes toward S1P. Thus, it is highly likely that immunomodulating effects of FTY720 are caused by inhibition of S1P/S1P(1)-dependent lymphocyte egress from secondary lymphoid organs and thymus. Since FTY720 possesses a novel mechanism of action and is reported to be highly effective in multiple sclerosis patients, it is presumed that FTY720 provides a new therapeutic approach for autoimmune diseases including multiple sclerosis.

FTY720 is a sphingosine-1-phosphate receptor modulator, which inhibits T-cell egress from lymph nodes, thereby prevents pathogenic T cells from migrating towards disease sites. In inflammatory bowel diseases, it is thought that colitogenic memory CD4+ T cells are intermittently reactivated in regional lymphoid organs, and return to inflammatory tissues. Little is known about how FTY720 controls the migration property of memory T cells and whether FTY720 could control the trafficking of T cells without the presence of lymphoid tissues. First, we here demonstrated that FTY720 prevents the development of colitis induced by the adoptive transfer of colitogenic lamina propria effector-memory CD4+ T (T(EM)) cells into SCID mice. Next, We demonstrated that FTY720 treatment suppresses the recirculation of CD4(+) T cells in splenectomized lymphotoxin-alpha(-/-) mice that lack lymph nodes and spleen. Cell number of CD4+ T cells was markedly decreased in peripheral blood of FTY720-treated mice, but conversely increased in bone marrow. Notably, FTY720 treatment prevented the development of colitis induced by transfer of colitogenic T(EM) cells into SPX LT-a(-/-) x RAG-2(-/-) mice. Collectively, the present data indicate that FTY720 treatment may offer an additional role to direct trafficking of CD4+ T cells in BM, resulting in the prevention of memory T cell-mediated diseases including inflammatory bowel diseases.