Multiple Sclerosis International Federation. Atlas of MS Database. Multiple Sclerosis International Federation website[online], (2008).
Rosati, G. The prevalence of multiple sclerosis in the world: an update. Neurol. Sci.22, 117–139 (2001). ArticleCASPubMed Google Scholar
Noseworthy, J. H., Lucchinetti, C., Rodriguez, M. & Weinshenker, B. G. Multiple sclerosis. N. Engl. J. Med.343, 938–952 (2000). ArticleCASPubMed Google Scholar
Lublin, F. D., Baier, M. & Cutter, G. Effect of relapses on development of residual deficit in multiple sclerosis. Neurology61, 1528–1532 (2003). ArticlePubMed Google Scholar
Weinshenker, B. G. et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain112, 133–146 (1989). ArticlePubMed Google Scholar
PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet352, 1498–1504 (1998).
The IFNB Multiple Sclerosis Study Group. Interferon β-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology43, 655–661 (1993).
Jacobs, L. D. et al. Intramuscular interferon β-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann. Neurol.39, 285–294 (1996). ArticleCASPubMed Google Scholar
Johnson, K. P. et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology45, 1268–1276 (1995). ArticleCASPubMed Google Scholar
Goodin, D. S. et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology58, 169–178 (2002). ArticleCASPubMed Google Scholar
Patti, F. Optimizing the benefit of multiple sclerosis therapy: the importance of treatment adherence. Patient Prefer. Adherence4, 1–9 (2010). ArticlePubMedPubMed Central Google Scholar
Rice, G. P. et al. Interferon in relapsing-remitting multiple sclerosis. Cochrane Database Syst. Rev. CD002002 (2001).
Steinman, L. Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab. Nature Rev. Drug Discov.4, 510–518 (2005). ArticleCAS Google Scholar
Putzki, N. et al. Natalizumab reduces clinical and MRI activity in multiple sclerosis patients with high disease activity: results from a multicenter study in Switzerland. Eur. Neurol.63, 101–106 (2010). ArticleCASPubMed Google Scholar
Kingwell, E. et al. Cardiotoxicity and other adverse events associated with mitoxantrone treatment for MS. Neurology74, 1822–1826 (2010). ArticleCASPubMedPubMed Central Google Scholar
Buttmann, M. Treating multiple sclerosis with monoclonal antibodies: a 2010 update. Expert Rev. Neurother.10, 791–809 (2010). ArticleCASPubMed Google Scholar
Niino, M. & Sasaki, H. Update on the treatment options for multiple sclerosis. Expert Rev. Clin. Immunol.6, 77–88 (2010). ArticlePubMed Google Scholar
Suzuki, S., Li, X. K., Enosawa, S. & Shinomiya, T. A new immunosuppressant, FTY720, induces bcl-2-associated apoptotic cell death in human lymphocytes. Immunology89, 518–523 (1996). ArticleCASPubMedPubMed Central Google Scholar
Adachi, K. et al. Design, synthesis, and structure-activity relationships of 2-substituted-2-amino-1, 3-propanediols: discovery of a novel immunosuppressant, FTY720. Bioorg. Med. Chem. Lett.5, 853–856 (1995). The first description of fingolimod. ArticleCAS Google Scholar
Chiba, K. et al. FTY720, a novel immunosuppressant possessing unique mechanisms. I. Prolongation of skin allograft survival and synergistic effect in combination with cyclosporine in rats. Transplant. Proc.28, 1056–1059 (1996). CASPubMed Google Scholar
Chiba, K. et al. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J. Immunol.160, 5037–5044 (1998). CASPubMed Google Scholar
Brinkmann, V. & Lynch, K. R. FTY720: targeting G-protein-coupled receptors for sphingosine 1-phosphate in transplantation and autoimmunity. Curr. Opin. Immunol.14, 569–575 (2002). ArticleCASPubMed Google Scholar
Yanagawa, Y. et al. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. II. FTY720 prolongs skin allograft survival by decreasing T-cell infiltration into grafts but not cytokine production in vivo. J. Immunol.160, 5493–5499 (1998). CASPubMed Google Scholar
Miyake, Y., Kozutsumi, Y., Nakamura, S., Fujita, T. & Kawasaki, T. Serine palmitoyltransferase is the primary target of a sphingosine-like immunosuppressant, ISP-1/myriocin. Biochem. Biophys. Res. Commun.211, 396–403 (1995). ArticleCASPubMed Google Scholar
Chen, J. K., Lane, W. S. & Schreiber, S. L. The identification of myriocin-binding proteins. Chem. Biol.6, 221–235 (1999). ArticleCASPubMed Google Scholar
Brinkmann, V. et al. FTY720 alters lymphocyte homing and protects allografts without inducing general immunosuppression. Transplant. Proc.33, 530–531 (2001). ArticleCASPubMed Google Scholar
Brinkmann, V., Pinschewer, D., Chiba, K. & Feng, L. FTY720: a novel transplantation drug that modulates lymphocyte traffic rather than activation. Trends Pharmacol. Sci.21, 49–52 (2000). ArticleCASPubMed Google Scholar
Kim, Y. M., Sachs, T., Asavaroengchai, W., Bronson, R. & Sykes, M. Graft-versus-host disease can be separated from graft-versus-lymphoma effects by control of lymphocyte trafficking with FTY720. J. Clin. Invest.111, 659–669 (2003). ArticleCASPubMedPubMed Central Google Scholar
Morris, M. A. et al. Transient T-cell accumulation in lymph nodes and sustained lymphopenia in mice treated with FTY720. Eur. J. Immunol.35, 3570–3580 (2005). ArticleCASPubMed Google Scholar
Mehling, M. et al. FTY720 therapy exerts differential effects on T-cell subsets in multiple sclerosis. Neurology71, 1261–1267 (2008). This study shows that fingolimod reduces the number of naive T cells and TCMcells, but spares TEMcells, in human blood. ArticleCASPubMed Google Scholar
Henning, G. et al. CC chemokine receptor 7-dependent and -independent pathways for lymphocyte homing: modulation by FTY720. J. Exp. Med.194, 1875–1881 (2001). ArticleCASPubMedPubMed Central Google Scholar
Enosawa, S., Suzuki, S., Kakefuda, T., Li, X. K. & Amemiya, H. Induction of selective cell death targeting on mature T-lymphocytes in rats by a novel immunosuppressant, FTY720. Immunopharmacology34, 171–179 (1996). ArticleCASPubMed Google Scholar
Payne, S. G. et al. The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors. Blood109, 1077–1085 (2007). ArticleCASPubMedPubMed Central Google Scholar
Bandhuvula, P., Tam, Y. Y., Oskouian, B. & Saba, J. D. The immune modulator FTY720 inhibits sphingosine-1-phosphate lyase activity. J. Biol. Chem.280, 33697–33700 (2005). ArticleCASPubMed Google Scholar
Brinkmann, V. et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem.277, 21453–21457 (2002). This study identified S1P receptors as the targets of fingolimod and showed that the drug is phosphorylated by SPHKs. The study also provided the first evidence that the phosphate metabolite is the active principle and that fingolimod-P is effective in treating EAE. ArticleCASPubMed Google Scholar
Mandala, S. et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science296, 346–349 (2002). This study identified S1P receptors as the targets of fingolimod and showed that the drug causes the accumulation of lymphocytes at lymphatic endothelial barriers. ArticleCASPubMed Google Scholar
Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature427, 355–360 (2004). This study showed that egress of lymphocytes from lymph nodes requires lymphocytic S1P1receptors. ArticleCASPubMed Google Scholar
Brinkmann, V., Cyster, J. G. & Hla, T. FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am. J. Transplant.4, 1019–1025 (2004). ArticleCASPubMed Google Scholar
Pinschewer, D. D. et al. FTY720 immunosuppression impairs effector T-cell peripheral homing without affecting induction, expansion, and memory. J. Immunol.164, 5761–5770 (2000). This paper reports that fingolimod does not impair the induction, expansion or memory of T cells. ArticleCASPubMed Google Scholar
Brinkmann, V. et al. FTY720: dissection of membrane receptor-operated, stereospecific effects on cell migration from receptor-independent antiproliferative and apoptotic effects. Transplant. Proc.33, 3078–3080 (2001). ArticleCASPubMed Google Scholar
Zemann, B. et al. Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720. Blood107, 1454–1458 (2006). ArticleCASPubMed Google Scholar
Albert, R. et al. Novel immunomodulator FTY720 is phosphorylated in rats and humans to form a single stereoisomer. Identification, chemical proof, and biological characterization of the biologically active species and its enantiomer. J. Med. Chem.48, 5373–5377 (2005). ArticleCASPubMed Google Scholar
Parrill, A. L. et al. Identification of Edg1 receptor residues that recognize sphingosine 1-phosphate. J. Biol. Chem.275, 39379–39384 (2000). ArticleCASPubMed Google Scholar
Deng, Q. et al. Identification of Leu276 of the S1P1 receptor and Phe263 of the S1P3 receptor in interaction with receptor specific agonists by molecular modeling, site-directed mutagenesis, and affinity studies. Mol. Pharmacol.71, 724–735 (2007). ArticleCASPubMed Google Scholar
Foster, C. A. et al. Brain penetration of the oral immunomodulatory drug FTY720 and its phosphorylation in the central nervous system during experimental autoimmune encephalomyelitis: consequences for mode of action in multiple sclerosis. J. Pharmacol. Exp. Ther.323, 469–475 (2007). ArticleCASPubMed Google Scholar
Mansoor, M. & Melendez, A. J. Recent trials for FTY720 (fingolimod): a new generation of immunomodulators structurally similar to sphingosine. Rev. Recent Clin. Trials3, 62–69 (2008). ArticleCASPubMed Google Scholar
Brinkmann, V. Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol. Ther.115, 84–105 (2007). A comprehensive summary of S1P biology and its relevance to fingolimod's mode of action. ArticleCASPubMed Google Scholar
Mutoh, T. & Chun, J. Lysophospholipid activation of G protein-coupled receptors. Subcell. Biochem.49, 269–297 (2008). ArticlePubMed Google Scholar
Schwab, S. R. & Cyster, J. G. Finding a way out: lymphocyte egress from lymphoid organs. Nature Immunol.8, 1295–1301 (2007). ArticleCAS Google Scholar
Skoura, A. & Hla, T. Lysophospholipid receptors in vertebrate development, physiology, and pathology. J. Lipid Res.50, S293–S298 (2009). ArticleCASPubMedPubMed Central Google Scholar
Graler, M. H. & Goetzl, E. J. The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors. FASEB J.18, 551–553 (2004). ArticleCASPubMed Google Scholar
Allende, M. L., Dreier, J. L., Mandala, S. & Proia, R. L. Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J. Biol. Chem.279, 15396–15401 (2004). ArticleCASPubMed Google Scholar
Pham, T. H., Okada, T., Matloubian, M., Lo, C. G. & Cyster, J. G. S1P1 receptor signaling overrides retention mediated by Gαi-coupled receptors to promote T-cell egress. Immunity28, 122–133 (2008). This paper provides a description of the antagonistic roles of S1P1and CCR7 in the egress of lymphocytes from lymph nodes. ArticleCASPubMed Google Scholar
Pham, T. H. et al. Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning. J. Exp. Med.207, 17–27 (2010). This study identified lymphatic endothelial cells as the source of S1P required for egress of T cells from lymph nodes. ArticleCASPubMedPubMed Central Google Scholar
Pappu, R. et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science316, 295–298 (2007). This study demonstrates the key role of S1P in the egress of T cells from lymph nodes. ArticleCASPubMed Google Scholar
Grigorova, I. L. et al. Cortical sinus probing, S1P1-dependent entry and flow-based capture of egressing T-cells. Nature Immunol.10, 58–65 (2009). ArticleCAS Google Scholar
Wehrli, N. et al. Changing responsiveness to chemokines allows medullary plasmablasts to leave lymph nodes. Eur. J. Immunol.31, 609–616 (2001). A demonstration that loss of CCR7 in B cells is associated with accelerated egress of these cells from lymph nodes. ArticleCASPubMed Google Scholar
Thangada, S. et al. Cell-surface residence of sphingosine 1-phosphate receptor 1 on lymphocytes determines lymphocyte egress kinetics. J. Exp. Med.207, 1475–1483 (2010). ArticleCASPubMedPubMed Central Google Scholar
Wei, S. H. et al. Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T-cells to lymphatic sinuses. Nature Immunol.6, 1228–1235 (2005). ArticleCAS Google Scholar
Sanna, M. G. et al. Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nature Chem. Biol.2, 434–441 (2006). ArticleCAS Google Scholar
Sallusto, F., Geginat, J. & Lanzavecchia, A. Central memory and effector memory T-cell subsets: function, generation, and maintenance. Annu. Rev. Immunol.22, 745–763 (2004). A comprehensive review of TCMand TEMcell functions and their role in immunological memory. ArticleCASPubMed Google Scholar
Iezzi, G., Scheidegger, D. & Lanzavecchia, A. Migration and function of antigen-primed nonpolarized T lymphocytes in vivo. J. Exp. Med.193, 987–993 (2001). ArticleCASPubMedPubMed Central Google Scholar
Iezzi, G., Karjalainen, K. & Lanzavecchia, A. The duration of antigenic stimulation determines the fate of naive and effector T-cells. Immunity8, 89–95 (1998). ArticleCASPubMed Google Scholar
Lanzavecchia, A. & Sallusto, F. Dynamics of T lymphocyte responses: intermediates, effectors, and memory cells. Science290, 92–97 (2000). ArticleCASPubMed Google Scholar
Reinhardt, R. L., Khoruts, A., Merica, R., Zell, T. & Jenkins, M. K. Visualizing the generation of memory CD4 T-cells in the whole body. Nature410, 101–105 (2001). ArticleCASPubMed Google Scholar
Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature401, 708–712 (1999). This study identified the presence of TCMand TEMcells in humans. ArticleCASPubMed Google Scholar
Wang, X. & Mosmann, T. In vivo priming of CD4 T-cells that produce interleukin (IL)-2 but not IL-4 or interferon (IFN)-γ, and can subsequently differentiate into IL-4- or IFN-γ-secreting cells. J. Exp. Med.194, 1069–1080 (2001). ArticleCASPubMedPubMed Central Google Scholar
Lauvau, G. et al. Priming of memory but not effector CD8 T-cells by a killed bacterial vaccine. Science294, 1735–1739 (2001). ArticleCASPubMed Google Scholar
Masopust, D., Vezys, V., Marzo, A. L. & Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science291, 2413–2417 (2001). ArticleCASPubMed Google Scholar
Metzler, B. et al. Modulation of T-cell homeostasis and alloreactivity under continuous FTY720 exposure. Int. Immunol.20, 633–644 (2008). This study shows that fingolimod reduces the numbers of naive T cells and TCMcells, but not TEMcells, in the blood. ArticleCASPubMed Google Scholar
Brinkmann, V. FTY720 (fingolimod) in multiple sclerosis: therapeutic effects in the immune and the central nervous system. Br. J. Pharmacol.158, 1173–1182 (2009). ArticleCASPubMedPubMed Central Google Scholar
Kivisakk, P. et al. Expression of CCR7 in multiple sclerosis: implications for CNS immunity. Ann. Neurol.55, 627–638 (2004). This study demonstrated that most T cells found in the CNS of patients with MS express TCMand not TEMphenotypes. ArticleCASPubMed Google Scholar
Fabriek, B. O. et al. In vivo detection of myelin proteins in cervical lymph nodes of MS patients using ultrasound-guided fine-needle aspiration cytology. J. Neuroimmunol.161, 190–194 (2005). ArticleCASPubMed Google Scholar
Bartholomäus, I. et al. Effector T-cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature462, 94–98 (2009). ArticleCASPubMed Google Scholar
Roscoe, W. A., Welsh, M. E., Carter, D. E. & Karlik, S. J. VEGF and angiogenesis in acute and chronic MOG(35–55) peptide induced EAE. J. Neuroimmunol.209, 6–15 (2009). ArticleCASPubMed Google Scholar
Chang, T. T. et al. Recovery from EAE is associated with decreased survival of encephalitogenic T-cells in the CNS of B7–1/B7-2-deficient mice. Eur. J. Immunol.33, 2022–2032 (2003). ArticleCASPubMed Google Scholar
Fujino, M. et al. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J. Pharmacol. Exp. Ther.305, 70–77 (2003). The first demonstration that fingolimod inhibits recirculation of T cells to the CNS in EAE. ArticleCASPubMed Google Scholar
Mehling, M. et al. TH17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. Neurology75, 403–410 (2010). ArticleCASPubMed Google Scholar
Zhang, Z., Zhang, Z. Y., Fauser, U. & Schluesener, H. J. FTY720 ameliorates experimental autoimmune neuritis by inhibition of lymphocyte and monocyte infiltration into peripheral nerves. Exp. Neurol.210, 681–690 (2008). ArticleCASPubMed Google Scholar
Zhang, Z. Y., Zhang, Z. & Schluesener, H. J. FTY720 attenuates lesional interleukin-17+ cell accumulation in rat experimental autoimmune neuritis. Neuropathol. Appl. Neurobiol.35, 487–495 (2009). ArticleCASPubMed Google Scholar
Huppert, J. et al. Cellular mechanisms of IL-17-induced blood–brain barrier disruption. FASEB J.24, 1023–1034 (2010). ArticleCASPubMed Google Scholar
Kebir, H. et al. Human TH17 lymphocytes promote blood–brain barrier disruption and central nervous system inflammation. Nature Med.13, 1173–1175 (2007). ArticleCASPubMed Google Scholar
Aktas, O. et al. Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL. Neuron46, 421–432 (2005). ArticleCASPubMed Google Scholar
Rausch, M. et al. Predictability of FTY720 efficacy in experimental autoimmune encephalomyelitis by in vivo macrophage tracking: clinical implications for ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging. J. Magn. Reson. Imaging20, 16–24 (2004). ArticlePubMed Google Scholar
Yagi, H. et al. Immunosuppressant FTY720 inhibits thymocyte emigration. Eur. J. Immunol.30, 1435–1444 (2000). ArticleCASPubMed Google Scholar
Kirk, S. L. & Karlik, S. J. VEGF and vascular changes in chronic neuroinflammation. J. Autoimmun.21, 353–363 (2003). ArticleCASPubMed Google Scholar
McVerry, B. J. & Garcia, J. G. In vitro and in vivo modulation of vascular barrier integrity by sphingosine 1-phosphate: mechanistic insights. Cell Signal.17, 131–139 (2005). ArticleCASPubMed Google Scholar
Rosen, H., Sanna, M. G., Cahalan, S. M. & Gonzalez-Cabrera, P. J. Tipping the gatekeeper: S1P regulation of endothelial barrier function. Trends Immunol.28, 102–107 (2007). ArticleCASPubMed Google Scholar
Sanchez, T. et al. Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability. J. Biol. Chem.278, 47281–47290 (2003). ArticleCASPubMed Google Scholar
Peng, X. et al. Protective effects of sphingosine 1-phosphate in murine endotoxin-induced inflammatory lung injury. Am. J. Respir. Crit. Care Med.169, 1245–1251 (2004). ArticlePubMed Google Scholar
Foster, C. A. et al. FTY720 rescue therapy in the dark agouti rat model of experimental autoimmune encephalomyelitis: expression of central nervous system genes and reversal of blood–brain-barrier damage. Brain Pathol.19, 254–266 (2009). ArticleCASPubMed Google Scholar
Balatoni, B. et al. FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encephalomyelitis. Brain Res. Bull.74, 307–316 (2007). This study shows that fingolimod restores neuronal function in EAE. ArticleCASPubMed Google Scholar
LaMontagne, K. et al. Antagonism of sphingosine-1-phosphate receptors by FTY720 inhibits angiogenesis and tumor vascularization. Cancer Res.66, 221–231 (2006). ArticleCASPubMed Google Scholar
Hiestand, P. & Schnell, C. Oral therapy with FTY720 inhibits angiogenesis in the spinal cord of lewis rats in the relapse phase of experimental autoimmune encephalomyelitis. Clin. Immunol.123, S143 (2007). Article Google Scholar
Oo, M. L. et al. Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor. J. Biol. Chem.282, 9082–9089 (2007). ArticleCASPubMed Google Scholar
Allende, M. L., Yamashita, T. & Proia, R. L. G-protein-coupled receptor S1P1 acts within endothelial cells to regulate vascular maturation. Blood102, 3665–3667 (2003). ArticleCASPubMed Google Scholar
Mullershausen, F. et al. Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors. Nature Chem. Biol.5, 428–434 (2009). ArticleCAS Google Scholar
Igarashi, J., Erwin, P. A., Dantas, A. P., Chen, H. & Michel, T. VEGF induces S1P1 receptors in endothelial cells: implications for cross-talk between sphingolipid and growth factor receptors. Proc. Natl Acad. Sci. USA100, 10664–10669 (2003). ArticleCASPubMedPubMed Central Google Scholar
Jaillard, C. et al. Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J. Neurosci.25, 1459–1469 (2005). ArticleCASPubMedPubMed Central Google Scholar
Kimura, A. et al. Essential roles of sphingosine 1-phosphate/S1P1 receptor axis in the migration of neural stem cells toward a site of spinal cord injury. Stem Cells25, 115–124 (2007). ArticleCASPubMed Google Scholar
Wu, Y. P., Mizugishi, K., Bektas, M., Sandhoff, R. & Proia, R. L. Sphingosine kinase 1/S1P receptor signaling axis controls glial proliferation in mice with Sandhoff disease. Hum. Mol. Genet.17, 2257–2264 (2008). ArticleCASPubMedPubMed Central Google Scholar
Sorensen, S. D. et al. Common signaling pathways link activation of murine PAR-1, LPA, and S1P receptors to proliferation of astrocytes. Mol. Pharmacol.64, 1199–1209 (2003). ArticleCASPubMed Google Scholar
Yamagata, K. et al. Sphingosine 1-phosphate induces the production of glial cell line-derived neurotrophic factor and cellular proliferation in astrocytes. Glia41, 199–206 (2003). ArticlePubMed Google Scholar
Rao, T. S. et al. Pharmacological characterization of lysophospholipid receptor signal transduction pathways in rat cerebrocortical astrocytes. Brain Res.990, 182–194 (2003). ArticleCASPubMed Google Scholar
Mullershausen, F. et al. Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors. J. Neurochem.102, 1151–1161 (2007). ArticleCASPubMed Google Scholar
Miron, V. E. et al. FTY720 modulates human oligodendrocyte progenitor process extension and survival. Ann. Neurol.63, 61–71 (2008). ArticleCASPubMed Google Scholar
Miron, V. E. et al. Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices. Am. J. Pathol.176, 2682–2694 (2010). ArticleCASPubMedPubMed Central Google Scholar
Mizugishi, K. et al. Essential role for sphingosine kinases in neural and vascular development. Mol. Cell Biol.25, 11113–11121 (2005). ArticleCASPubMedPubMed Central Google Scholar
Chalfant, C. E. & Spiegel, S. Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling. J. Cell Sci.118, 4605–4612 (2005). A comprehensive review of the role of S1P in inflammation. ArticleCASPubMed Google Scholar
Nayak, D. et al. Sphingosine kinase 1 regulates the expression of proinflammatory cytokines and nitric oxide in activated microglia. Neuroscience166, 132–144 (2010). ArticleCASPubMed Google Scholar
Kulakowska, A. et al. Intrathecal increase of sphingosine 1-phosphate at early stage multiple sclerosis. Neurosci. Lett.477, 149–152 (2010). ArticleCASPubMed Google Scholar
Choi, J. W., Herr, D., Kennedy, G. & Chun, J. Astrocytic sphingosine 1-phosphate (S1P) receptor subtype 1 signalling influences levels of S1P and cytokines during experimental autoimmune encephalimyelitis and fingolimod (FTY720) intervention. Mult. Scler.15, S58 (2009). Google Scholar
Rouach, N. et al. S1P inhibits gap junctions in astrocytes: involvement of G and Rho GTPase/ROCK. Eur. J. Neurosci.23, 1453–1464 (2006). ArticlePubMed Google Scholar
Kang, Z. et al. Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity32, 414–425 (2010). ArticleCASPubMedPubMed Central Google Scholar
Van Doorn, R. et al. Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. Glia58, 1465–1476 (2010). ArticlePubMed Google Scholar
Webb, M. et al. Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J. Neuroimmunol.153, 108–121 (2004). ArticleCASPubMed Google Scholar
Kataoka, H. et al. FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T-cell infiltration. Cell. Mol. Immunol.2, 439–448 (2005). CASPubMed Google Scholar
Kovarik, J. M. et al. Oral-intravenous crossover study of fingolimod pharmacokinetics, lymphocyte responses and cardiac effects. Biopharm. Drug Dispos.28, 97–104 (2007). ArticleCASPubMed Google Scholar
Kovarik, J. M., Schmouder, R. L. & Slade, A. J. Overview of FTY720 clinical pharmacokinetics and pharmacology. Ther. Drug Monit.26, 585–587 (2004). ArticleCASPubMed Google Scholar
Budde, K. et al. First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients. J. Am. Soc. Nephrol.13, 1073–1083 (2002). CASPubMed Google Scholar
Kahan, B. D. et al. Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study. Transplantation76, 1079–1084 (2003). ArticleCASPubMed Google Scholar
Kovarik, J. M. et al. Screening for a drug interaction of FTY720 on cyclosporine in renal transplant patients. Am. J. Trans.3, 483 (2003). Google Scholar
Cohen, J. A. et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N. Engl. J. Med.362, 402–415 (2010). The first Phase III clinical study comparing fingolimod with IFN-β1a in relapsing MS. ArticleCASPubMed Google Scholar
Comi, G. et al. Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results. Mult. Scler.16, 197–207 (2010). A Phase II extension study of fingolimod in relapsing MS. ArticleCASPubMed Google Scholar
Kappos, L. et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med.362, 387–401 (2010). A 2-year Phase III clinical study comparing fingolimod with placebo in relapsing MS. ArticleCASPubMed Google Scholar
Tedesco-Silva, H. et al. FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2A study in de novo renal transplantation. Transplantation77, 1826–1833 (2004). CASPubMed Google Scholar
Kappos, L. et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N. Engl. J. Med.355, 1124–1140 (2006). The first Phase II study of fingolimod in relapsing MS. ArticleCASPubMed Google Scholar
O'Connor, P. et al. Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study. Neurology72, 73–79 (2009). A 2-year Phase II extension study of fingolimod in relapsing MS. ArticleCASPubMed Google Scholar
Mazurais, D. et al. Cell type-specific localization of human cardiac S1P receptors. J. Histochem. Cytochem.50, 661–670 (2002). ArticleCASPubMed Google Scholar
Koyrakh, L., Roman, M. I., Brinkmann, V. & Wickman, K. The heart rate decrease caused by acute FTY720 administration is mediated by the G protein-gated potassium channel, I. Am. J. Transplant.5, 529–536 (2005). A demonstration that bradycardia induced by fingolimod is due to activation of the cardiac inwardly rectifying potassium (IKACh) channels. ArticleCASPubMed Google Scholar
Kurachi, Y. G protein regulation of cardiac muscarinic potassium channel. Am. J. Physiol.269, C821–C830 (1995). ArticleCASPubMed Google Scholar
Kovarik, J. M. et al. The ability of atropine to prevent and reverse the negative chronotropic effect of fingolimod in healthy subjects. Br. J. Clin. Pharmacol.66, 199–206 (2008). ArticleCASPubMedPubMed Central Google Scholar
Kovarik, J. M. et al. A mechanistic study to assess whether isoproterenol can reverse the negative chronotropic effect of fingolimod. J. Clin. Pharmacol.48, 303–310 (2008). ArticleCASPubMed Google Scholar
Forrest, M. et al. Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes. J. Pharmacol. Exp. Ther.309, 758–768 (2004). ArticleCASPubMed Google Scholar
Bunemann, M. et al. Activation of muscarinic K+ current in guinea-pig atrial myocytes by sphingosine-1-phosphate. J. Physiol.489, 701–707 (1995). ArticlePubMedPubMed Central Google Scholar
Sanna, M. G. et al. Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J. Biol. Chem.279, 13839–13848 (2004). ArticleCASPubMed Google Scholar
Gergely, P. et al. Phase I study with the selective S1P1/S1P5 receptor modulator BAF312 indicates that S1P1 rather than S1P3 mediates transient heart rate reduction in humans. Mult. Scler.15, S125 (2009). The first demonstration that an S1P1and S1P5-selective agonist causes bradycardia in humans independent of S1P3receptors. Google Scholar
Rosen, H. & Liao, J. Sphingosine 1-phosphate pathway therapeutics: a lipid ligand-receptor paradigm. Curr. Opin. Chem. Biol.7, 461–468 (2003). ArticleCASPubMed Google Scholar
Lee, J. F. et al. Balance of S1P1 and S1P2 signaling regulates peripheral microvascular permeability in rat cremaster muscle vasculature. Am. J. Physiol. Heart Circ. Physiol.296, H33–H42 (2009). ArticleCASPubMed Google Scholar
Huang, P. L. et al. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature377, 239–242 (1995). ArticleCASPubMed Google Scholar
Schwarz, A., Korporal, M., Hosch, W., Max, R. & Wildemann, B. Critical vasospasm during fingolimod (FTY720) treatment in a patient with multiple sclerosis. Neurology74, 2022–2024 (2010). ArticleCASPubMed Google Scholar
Tawadrous, M. N., Mabuchi, A., Zimmermann, A. & Wheatley, A. M. Effects of immunosuppressant FTY720 on renal and hepatic hemodynamics in the rat. Transplantation74, 602–610 (2002). ArticleCASPubMed Google Scholar
Martin, M. et al. Protective effects of early CD4+ T-cell reduction in hepatic ischemia/reperfusion injury. J. Gastrointest. Surg.14, 511–519 (2010). ArticlePubMed Google Scholar
Appay, V., van Lier, R. A., Sallusto, F. & Roederer, M. Phenotype and function of human T lymphocyte subsets: consensus and issues. Cytometry A73, 975–983 (2008). ArticlePubMed Google Scholar
Mehling, M. et al. Cellular and humoral influenza vaccine-specific immune responses in patients with multiple sclerosis treated with FTY720 or interferon-β. Neurology74, A372 (2010). Article Google Scholar
Kursar, M. et al. Requirement of secondary lymphoid tissues for the induction of primary and secondary T-cell responses against Listeria monocytogenes. Eur. J. Immunol.38, 127–138 (2008). ArticleCASPubMed Google Scholar
Bartholomäus, I., Schläger, C., Brinkmann, V., Wekerle, H. & Flügel, A. Intravital 2-photon imaging of encephalitogenic effector cells during fingolimod (FTY720) treatment of experimental autoimmune encephalomyelitis. Mult. Scler.14, S30 (2008). Google Scholar
Connor, L. M. et al. Lung-resident memory lymphocytes are sufficient for protection against a mycobacterial lung infectious challenge. Eur. J. Immunol. (in the press).
Lopez-Diego, R. S. & Weiner, H. L. Novel therapeutic strategies for multiple sclerosis — a multifaceted adversary. Nature Rev. Drug Discov.7, 909–925 (2008). ArticleCAS Google Scholar
Paty, D. W. & Li, D. K. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology43, 662–667 (1993). ArticleCASPubMed Google Scholar
Comi, G., Filippi, M. & Wolinsky, J. S. European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Ann. Neurol.49, 290–297 (2001). ArticleCASPubMed Google Scholar
Polman, C. H. et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med.354, 899–910 (2006). ArticleCASPubMed Google Scholar
Miller, D. H. et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology68, 1390–1401 (2007). ArticleCASPubMed Google Scholar