Search Advanced

AIMS Molecular Science

2014, Volume 1, Issue 4: 162-182. doi: 10.3934/molsci.2014.4.162
Previous Article Next Article
Review Special Issues

Role of sphingosine 1-phosphate (S1P) and effects of fingolimod, an S1P receptor 1 functional antagonist in lymphocyte circulation and autoimmune diseases

  • Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan
  • Received: 29 July 2014 Accepted: 19 November 2014 Published: 25 November 2014

  • Sphingosine 1-phosphate (S1P), a multi-functional phospholipid mediator, is generated from sphingosine by sphingosine kinases and binds to five known G protein-coupled S1P receptors (S1P1, S1P2, S1P3, S1P4, and S1P5). It is widely accepted that S1P receptor 1 (S1P1) plays an essential role in lymphocyte egress from the secondary lymphoid organs (SLO) and thymus, because lymphocyte egress from these organs to periphery is at extremely low levels in mice lacking lymphocytic S1P1. Fingolimod hydrochloride (FTY720) is a first-in-class, orally active S1P1 functional antagonist which was discovered by chemical modification of a natural product, myriocin. Since FTY720 has a structure closely related to sphingosine, the phosphorylated FTY720 (FTY720-P) is converted by sphingosine kinases and binds 4 types of S1P receptors. FTY720-P strongly induces down-regulation of S1P1 by internalization and degradation of this receptor and acts as a functional antagonist at S1P1. Consequently, FTY720 inhibits S1P1-dependent lymphocyte egress from the SLO and thymus to reduce circulating lymphocytes including autoreactive Th17 cells, and is highly effective in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In relapsing remitting MS patients, oral FTY720 shows a superior efficacy when compared to intramuscular interferon-β-1a. Based on these data, it is presumed that modulation of the S1P-S1P1 axis provides an effective therapy for autoimmune diseases including MS.

    Citation: Kenji Chiba, Yasuhiro Maeda, Noriyasu Seki, Hirotoshi Kataoka, Kunio Sugahara. Role of sphingosine 1-phosphate (S1P) and effects of fingolimod, an S1P receptor 1 functional antagonist in lymphocyte circulation and autoimmune diseases[J]. AIMS Molecular Science, 2014, 1(4): 162-182. doi: 10.3934/molsci.2014.4.162

    Related Papers:

  • Sphingosine 1-phosphate (S1P), a multi-functional phospholipid mediator, is generated from sphingosine by sphingosine kinases and binds to five known G protein-coupled S1P receptors (S1P1, S1P2, S1P3, S1P4, and S1P5). It is widely accepted that S1P receptor 1 (S1P1) plays an essential role in lymphocyte egress from the secondary lymphoid organs (SLO) and thymus, because lymphocyte egress from these organs to periphery is at extremely low levels in mice lacking lymphocytic S1P1. Fingolimod hydrochloride (FTY720) is a first-in-class, orally active S1P1 functional antagonist which was discovered by chemical modification of a natural product, myriocin. Since FTY720 has a structure closely related to sphingosine, the phosphorylated FTY720 (FTY720-P) is converted by sphingosine kinases and binds 4 types of S1P receptors. FTY720-P strongly induces down-regulation of S1P1 by internalization and degradation of this receptor and acts as a functional antagonist at S1P1. Consequently, FTY720 inhibits S1P1-dependent lymphocyte egress from the SLO and thymus to reduce circulating lymphocytes including autoreactive Th17 cells, and is highly effective in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In relapsing remitting MS patients, oral FTY720 shows a superior efficacy when compared to intramuscular interferon-β-1a. Based on these data, it is presumed that modulation of the S1P-S1P1 axis provides an effective therapy for autoimmune diseases including MS.


    加载中
    [1] Fujita T, Inoue K, Yamamoto S, et al. (1994) Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite. J Antibiot 47: 208-215.
    [2] Fujita T, Inoue K, Yamamoto S, et al. (1994) Fungal metabolites. Part 12. Potent immunosuppressant, 14-deoxomyruiocin, (2S,3R,4R)-(E)-2-amino-3,4-dihydroxy-2- hydroxy- methyleicos-6-enoic acid and structure-activity relationships of myriocin derivatives. J Antibiot 47: 216-224.
    [3] Fujita T, Yoneta M, Hirose R, et al. (1995) Simple compounds, 2-alkyl-2- amino-1,3-propane-diols have potent immunosuppressive activity. Bioorg Med Chem Lett 5: 847-852. doi: 10.1016/0960-894X(95)00126-E
    [4] Adachi K, Kohara T, Nakao N, et al. (1995) Design, synthesis, and structure-activity relationships of 2-substituted-2-amino-1,3-propanediols: Discovery of a novel immuno- suppressant, FTY720. Bioorg Med Chem Lett 5: 853-856. doi: 10.1016/0960-894X(95)00127-F
    [5] Fujita T, Hirose R, Yoneta M, et al. (1996) Potent immunosuppressants, 2-alkyl-2- aminopropane-1,3-diols. J Med Chem 39: 4451-4459. doi: 10.1021/jm960391l
    [6] Kiuchi M, Adachi K, Kohara T, et al. (2000) Synthesis and immunosuppressive activity of 2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols. J Med Chem 43: 2946-2961. doi: 10.1021/jm000173z
    [7] Adachi K, Chiba K (2008) FTY720 story. Its discovery and the following accelerated development of sphingosine 1-phosphate receptor agonists as immunomodulators based on reverse pharmacology. Perspect Medicin Chem 1: 11-23.
    [8] Chiba K, Adachi K (2012) Sphingosine 1-phosphate receptor 1 as a useful target for treatment of multiple sclerosis. Pharmaceuticals 5:514-528. doi: 10.3390/ph5050514
    [9] Chiba K, Hoshino Y, Suzuki C, et al. (1996) 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.
    [10] Hoshino Y, Suzuki C, Ohtsuki M, et al. (1996) FTY720, a novel immunosuppressant possessing unique mechanisms. II. Long-term graft survival induction in rat heterotopic cardiac allografts and synergistic effect in combination with cyclosporine A. Transplant Proc 28: 1060-1061.
    [11] Kawaguchi T, Hoshino Y, Rahman F, et al. (1996) FTY720, a novel immunosuppressant possessing unique mechanisms. III. Synergistic prolongation of canine renal allograft survival in combination with cyclosporine A. Transplant Proc 28: 1062-1063.
    [12] Chiba K. (2005) FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. Pharmacol Ther 108: 308-319. doi: 10.1016/j.pharmthera.2005.05.002
    [13] Matsuura M, Imayoshi T, Chiba K, Okumoto T (2000) Effect of FTY720, a novel immunosuppressant, on adjuvant-induced arthritis in rats. Inflamm Res 49: 404-410. doi: 10.1007/s000110050608
    [14] Chiba K, Yanagawa Y, Masubuchi Y, et al. (1998) 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.
    [15] Yanagawa Y, Sugahara K, Kataoka H, et al. (1998) 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.
    [16] Brinkmann V. Pinschewer D, Chiba K, Feng L (2000) FTY720: A novel transplantation drug that modulates lymphocyte traffic rather than activation. Trends Pharmacol Sci 21: 49-52. doi: 10.1016/S0165-6147(99)01419-4
    [17] Brinkmann V, Davis MD, Heise CE, et al. (2002) The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 277: 21453-21457. doi: 10.1074/jbc.C200176200
    [18] Mandala S, Hajdu R, Bergstrom J, et al. (2002) Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296: 346-349. doi: 10.1126/science.1070238
    [19] Matloubian M, Lo CG, Cinamon G, et al. (2004) Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427: 355-360. doi: 10.1038/nature02284
    [20] Spiegel S, Milstien S (2007) Functions of the multifaceted family od sphingosine kinases and some dose relatives. J Biol Chem 282: 2125-2129. doi: 10.1074/jbc.R600028200
    [21] Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9: 139-150. doi: 10.1038/nrm2329
    [22] Pyne S, Pyne N (2000) Sphingosine 1-phosphate signalling via the endothelial differentiation gene family of G-protein-coupled receptors. Pharmacol Ther 88: 115-131. doi: 10.1016/S0163-7258(00)00084-X
    [23] Spiegel S (2000) Sphingosine 1-phosphate: A ligand for the EDG-1 family of G-protein-coupled receptors. Ann NY Acad Sci 905: 54-60.
    [24] Rivera J, Proia RL, Olivera A (2008) The alliance of shpingosine-1-phosphate and its receptors in immunity. Nat Rev Immunol 8: 753-763. doi: 10.1038/nri2400
    [25] Spiegel S, Milstien S (2011) The outs and the ins of shingosine-1-phosphate in immunity. Nat Rev Immunol 11: 403-415. doi: 10.1038/nri2974
    [26] Paugh SW, Payne SG, Barbour SE, et al. (2003) The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2. FEBS Lett 554:189-193. doi: 10.1016/S0014-5793(03)01168-2
    [27] Chiba K, Matsuyuki H, Maeda Y, Sugahara K (2006) Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus. Cell Mol Immunol 3: 11-19.
    [28] Maeda Y, Matsuyuki H, Shimano K, et al. (2007) Migration of CD4 T cells and dendritic cells toward sphingosine 1-phosphate (S1P) is mediated by different receptor subtypes: S1P regulates the functions of murine mature dendritic cells via S1P receptor type 3. J Immunol 178: 3437-3446. doi: 10.4049/jimmunol.178.6.3437
    [29] Pham TH, Okada T, Matloubian M, et al. (2008) S1P1 receptor signaling overrides retention mediated by G alpha i-coupled receptors to promote T cell egress. Immunity 28: 122-133. doi: 10.1016/j.immuni.2007.11.017
    [30] Cyster JG (2005) Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol 23: 127-159. doi: 10.1146/annurev.immunol.23.021704.115628
    [31] Mitra P, Oskeritzian CA, Payne SG, et al. (2006) Role of ABCC1 in export of sphingosine- 1-phosphate from mast cells. Proc Natl Acad Sci USA 103: 16394-16399. doi: 10.1073/pnas.0603734103
    [32] Nishi T, Kobayashi N, Hisano Y et al. (2014) Molecular and physiological functions of sphingosine 1-phosphate transporters. Biochim Biophys Acta 1841: 759-765. doi: 10.1016/j.bbalip.2013.07.012
    [33] Mechtcheriakova D, Wlachos A, Sobanov J, et al. (2007) Sphingosine 1-phosphate phosphatase 2 is induced during inflammatory responses. Cell Signal 19: 748-760. doi: 10.1016/j.cellsig.2006.09.004
    [34] Peest U, Sensken SC, Andréani P, et al. (2008) S1P-lyase independent clearance of extracellular sphingosine 1-phosphate after dephosphorylation and cellular uptake. J Cell Biochem 104: 756-772. doi: 10.1002/jcb.21665
    [35] Zhao Y, Kalari SK, Usatyuk PV, et al. (2007) Intracellular generation of sphingosine 1-phosphate in human lung endothelial cells: role of lipid phosphate phosphatase-1 and sphingosine kinase 1. J Biol Chem 282: 14165-14177. doi: 10.1074/jbc.M701279200
    [36] Pappu R, Schwab SR, Cornelissen I, et al. (2007) Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 316: 295-298. doi: 10.1126/science.1139221
    [37] Schwab SR, Pereira JP, Matloubian M, et al. (2005) Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 309: 1735-1739. doi: 10.1126/science.1113640
    [38] Lo CG, Xu Y, Proia RL, Cyster JG (2005) Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit. J Exp Med. 201: 291-301. doi: 10.1084/jem.20041509
    [39] Kiuchi M, Adachi K, Tomatsu A, et al. (2005) Asymmetric synthesis and biological evaluation of the enantiomeric isomers of the immunosuppressive FTY720-phosphate. Bioorg. Med. Chem 13: 425-432. doi: 10.1016/j.bmc.2004.10.008
    [40] Matsuyuki H, Maeda Y, Yano K, et al. (2006) Involvement of sphingosine 1-phosphate (S1P) receptor type 1 and type 4 in migratory response of mouse T cells toward S1P. Cell Mol Immunol 3: 429-437.
    [41] Oo ML, Thangada S, Wu MT, et al. (2007) Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor. J Biol Chem 282: 9082-9089. doi: 10.1074/jbc.M610318200
    [42] Ladi E, Yin X, Chtanova T, Robey EA (2006) Thymic microenvironments for T cell differentiation and selection. Nat Immunol 7: 338-343. doi: 10.1038/ni1323
    [43] Drennan MB, Elewaut D, Hogquist KA (2009) Thymic emigration: sphingosine-1-phosphate receptor-1-dependent models and beyond. Eur J Immunol 39: 925-930. doi: 10.1002/eji.200838912
    [44] Kato S, Schoefl GI (1989) Microvasculature of normal and involuted mouse thymus. Light- and electron-microscopic study. Acta Anat (Basel) 135: 1-11.
    [45] Kato S (1997) Thymic microvascular system. Microsc Res Tech 38: 287-299. doi: 10.1002/(SICI)1097-0029(19970801)38:3<287::AID-JEMT9>3.0.CO;2-J
    [46] Mori K, Itoi M, Tsukamoto N, et al. (2007) The perivascular space as a path of hematopoietic progenitor cells and mature T cells between the blood circulation and the thymic parenchyma. Int Immunol 19: 745-753. doi: 10.1093/intimm/dxm041
    [47] Zachariah MA, Cyster JG (2010) Neural crest-derived pericytes promote egress of mature thymocytes at the corticomedullary junction. Science 328: 1129-1135. doi: 10.1126/science.1188222
    [48] Cyster JG, Schwab SR (2012) Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu Rev Immunol 30: 69-94. doi: 10.1146/annurev-immunol-020711-075011
    [49] Yagi H, Kamba R, Chiba K, et al. (2000) Immunosuppressant FTY720 inhibits thymocyte emigration. Eur J Immunol 30:1435.
    [50] Maeda Y, Yagi H, Takemoto K, et al. (2014) S1P lyase in thymic perivascular space promotes egress of mature thymocytes via up-regulation of S1P receptor 1. Int Immunol 26: 245-255. doi: 10.1093/intimm/dxt069
    [51] Allende ML, Dreier JL, Mandala S, Proia RL (2004) Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J Biol Chem 279: 15396-15401. doi: 10.1074/jbc.M314291200
    [52] Saba JD, Hla T (2004) Point-counterpoint of sphingosine 1-phosphate metabolism. Circ Res 94: 724-734. doi: 10.1161/01.RES.0000122383.60368.24
    [53] Breart B, Ramos-Perez WD, Mendoza A, et al. (2011) Lipid phosphate phosphatase 3 enables efficient thymic egress. J Exp Med 208: 1267-1278. doi: 10.1084/jem.20102551
    [54] Vogel P, Donoviel MS, Read R, et al. (2009) Incomplete inhibition of sphingosine 1-phosphate lyase modulates immune system function yet prevents early lethality and non-lymphoid lesions. PLoS One 4:e4112.
    [55] Borowsky AD, Bandhuvula P, Kumar A, , et al. (2012) Sphingosine-1-phosphate lyase expression in embryonic and adult murine tissues. J Lipid Res 53: 1920-1931. doi: 10.1194/jlr.M028084
    [56] Suzuki S, Li XK, Enosawa S, and Shinomiya T (1996) A new immunosuppressant, FTY720, induces bcl-2-associated apoptotic cell death in human lymphocytes. Immunology 89:518-23. doi: 10.1046/j.1365-2567.1996.d01-777.x
    [57] Nagahara Y, Enosawa S, Ikekita M, et al. (2000) Evidence that FTY720 induces T cell apoptosis in vivo. Immunopharmacology 48:75-85. doi: 10.1016/S0162-3109(00)00181-8
    [58] Luo ZJ, Tanaka T, Kimura F, Miyasaka M (1999) Analysis of the mode of action of a novel immunosuppressant FTY720 in mice. Immunopharmacology. 41:199-207. doi: 10.1016/S0162-3109(99)00004-1
    [59] Sugito K, Koshinaga T, Inoue M, et al. (2005) The effect of a novel immunosuppressant, FTY720, in mice without secondary lymphoid organs. Surg Today 35:662-7. doi: 10.1007/s00595-005-3011-x
    [60] Maeda Y, Seki N, Sato N, et al. (2010) Sphingosine 1-phosphate receptor type 1 regulates egress of mature T cells from mouse bone marrow. Int Immunol 22: 515-525. doi: 10.1093/intimm/dxq036
    [61] Webb M, Tham CS, Lin FF, et al. (2004) Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J Neuroimmunol 153: 108-121. doi: 10.1016/j.jneuroim.2004.04.015
    [62] Kataoka H, Sugahara K, Shimano K, et al. (2005) FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. Cell Mol Immunol 2: 439-448.
    [63] Balatoni B, Storch MK, Swoboda EM, et al. (2007) FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encephalomyelitis. Brain Res Bull 74: 307-316. doi: 10.1016/j.brainresbull.2007.06.023
    [64] Foster CA, Howard LM, Schweitzer A, et al. (2007) 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. doi: 10.1124/jpet.107.127183
    [65] Brinkmann V (2007) Sphingosine 1-phosphate receptors in health and disease: Mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol Ther 115: 84-105. doi: 10.1016/j.pharmthera.2007.04.006
    [66] Chiba K, Kataoka H, Seki N, et al. (2011) Fingolimod (FTY720), sphingosine 1-phosphate receptor modulator, shows superior efficacy as compared with interferon-β in mouse experimental autoimmune encephalomyelitis. Int Immunopharmacol 11: 366-372. doi: 10.1016/j.intimp.2010.10.005
    [67] Langrish CL, Chen Y, Blumenschein WM, et al. (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201: 233-240. doi: 10.1084/jem.20041257
    [68] Komiyama Y, Nakae S, Matsuki T, et al. (2006) IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol 177: 566-573. doi: 10.4049/jimmunol.177.1.566
    [69] Stromnes IM, Cerretti LM, Liggitt D, et al. (2008) Differential regulation of central nervous system autoimmunity by TH1 and TH17 cells. Nat Med 14: 337-342. doi: 10.1038/nm1715
    [70] Seki N, Maeda Y, Kataoka H, et al. (2013) Role of sphingosine 1-phosphate (S1P) receptor 1 in experimental autoimmune encephalomyelitis. I. S1P-S1P1 axis induces migration of Th1 and Th17 cells. Pharmacology & Pharmacy 4: 628-637.
    [71] Brinkmann V (2009) FTY720 (fingolimod) in Multiple Sclerosis: Therapeutic effects in the immune and the central nervous system. Br J Pharmacol 158: 1173-1182. doi: 10.1111/j.1476-5381.2009.00451.x
    [72] Choi JW, Gardell SE, Herr DR, et al. (2011) FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci USA 108: 751-756. doi: 10.1073/pnas.1014154108
    [73] Seki N, Kataoka H, Sugahara K, et al. (2013) Role of sphingosine 1-phosphate (S1P) receptor 1 in experimental autoimmune encephalomyelitis. II. S1P-S1P1 axis induces pro-inflammatory cytokine production in astrocytes. Pharmacology & Pharmacy 4: 638-646.
    [74] Matsuura M, Imayoshi T, Okumoto T (2000) Effect of FTY720, a novel immunosuppressant, on adjuvant- and collagen-induced arthritis in rats. Int J Immunopharmacol 22: 323-331. doi: 10.1016/S0192-0561(99)00088-0
    [75] Tsunemi S, Iwasaki T, Kitano S, et al. (2010) Effects of the novel immunosuppressant FTY720 in a murine rheumatoid arthritis model. Clin Immunol 136: 197-204. doi: 10.1016/j.clim.2010.03.428
    [76] Okazaki H, Hirata D, Kamimura T, et al. (2002) Effects of FTY720 in MRL-lpr/lpr mice: therapeutic potential in systemic lupus erythematosus. J Rheumatol 29: 707-716.
    [77] Wenderfer SE, Stepkowski SM, Braun MC (2008) Increased survival and reduced renal injury in MRL/lpr mice treated with a novel sphingosine-1-phosphate receptor agonist. Kidney Int 74: 1319-1326. doi: 10.1038/ki.2008.396
    [78] Alperovich G, Rama I, Lloberas N, et al. (2007) New immunosuppresor strategies in the treatment of murine lupus nephritis. Lupus 16: 18-24. doi: 10.1177/0961203306073136
    [79] Mizushima T, Ito T, Kishi D, et al. (2004) Therapeutic effects of a new lymphocyte homing reagent FTY720 in interleukin-10 gene-deficient mice with colitis. Inflamm Bowel Dis 10: 182-192. doi: 10.1097/00054725-200405000-00002
    [80] Deguchi Y, Andoh A, Yagi Y, et al (2006) The S1P receptor modulator FTY720 prevents the development of experimental colitis in mice. Oncol Rep 16: 699-703.
    [81] Daniel C, Sartory N, Zahn N, et al. (2007) FTY720 ameliorates Th1-mediated colitis in mice by directly affecting the functional activity of CD4+CD25+ regulatory T cells. J Immunol 178: 2458-2468. doi: 10.4049/jimmunol.178.4.2458
    [82] Radi ZA, Heuvelman DM, Masferrer JL, et al (2011) Pharmacologic evaluation of sulfasalazine, FTY720, and anti-IL-12/23p40 in a TNBS-induced Crohn's disease model. Dig Dis Sci 56: 2283-2291. doi: 10.1007/s10620-011-1628-8
    [83] Budde K, Schmouder RL, Brunkhorst R, et al. (2002) Human first trail of FTY720, a novel immunomodulator, in stable renal transplant patients. J Am Soc Nephrol 13: 1073-1083.
    [84] Budde K, Schmouder RL, Nashan B, et al. (2003) Pharmacodynamics of single doses of the novel immunosuppressant FTY720 in stable renal transplant patients. Am J Transplant 3: 846-854. doi: 10.1034/j.1600-6143.2003.00130.x
    [85] Kahan BD, Karlix JL, Ferguson RM, et al. (2003) Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study. Transplantation 76: 1079-1084. doi: 10.1097/01.TP.0000084822.01372.AC
    [86] Martin R, McFarland HF, McFarlin DE (1992) Immunological aspects of demyelinating diseases. Annu Rev Immunol 10: 153-187. doi: 10.1146/annurev.iy.10.040192.001101
    [87] Kornek B, Storch MK, Weissert R, et al. (2000) Multiple sclerosis and chronic autoimmune encephalomyelitis: A comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 157: 267-276. doi: 10.1016/S0002-9440(10)64537-3
    [88] Lublin FD, Reingold SC (1996) Defining the clinical course of multiple sclerosis: Results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 46: 907-911.
    [89] Goodkin DE, Reingold S, Sibley W, et al. (1999) Guidelines for clinical trials of new therapeutic agents in multiple sclerosis: Reporting extended results from phase III clinical trials. National Multiple Sclerosis Society Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Ann Neurol 46: 132-134.
    [90] Kappos L, Antel J, Comi G, et al. (2006) Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Eng J Med 355: 1124-1140. doi: 10.1056/NEJMoa052643
    [91] Mehling M, Lindberg R, Raulf F, et al. (2011) Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. Neurology 75: 403-410.
    [92] Kappos L, Radue EW, O’Connor P, et al. (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362: 387-401. doi: 10.1056/NEJMoa0909494
    [93] Saida T, Kikuchi S, Itoyama Y, et al. (2012) A randomized, controlled trial of fingolimod (FTY720) in Japanese patients with multiple sclerosis. Mult Scler 18:1267-1277.
    [94] Kira J, Itoyama Y, Kikuchi S, et al. (2014) Fingolimod (FTY720) therapy in Japanese patients with relapsing multiple sclerosis over 12 months: results of a phase 2 observational extension. BMC Neurology 14: 21. doi: 10.1186/1471-2377-14-21
    [95] Cohen JA, Barkhof F, Comi G, et al. (2010) Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 362: 402-415. doi: 10.1056/NEJMoa0907839
    [96] Deogracias R, Yazdani M, Dekkers MP, et al (2013) Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome. Proc Natl Acad Sci USA 109: 14230-14235.
    [97] Igarashi J, Erwin PA, Dantas AP, et al. (2003) VEGF induces S1P1 receptors in endothelial cells: implications for crosstalk between sphingolipid and growth factors receptors. Proc Natl Acad Sci USA 100: 10664-10669. doi: 10.1073/pnas.1934494100
    [98] Sanna MG, Liao J, Jo E, et al. (2004). Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem 279: 13839-13848. doi: 10.1074/jbc.M311743200
    [99] Shimizu H, Takahashi M, T. Kaneko T et al. (2005) KRP-203, a novel synthetic immunosuppressant, prolongs graft survival and attenuates chronic rejection in rat skin and heart allografts. Circulation 111: 222-229. doi: 10.1161/01.CIR.0000152101.41037.AB
    [100] Hamada M, Nakamura M, Kiuchi M et al. (2010) Removal of sphingosine 1-phosphate receptor-3 (S1P3) agonism is essential, but inadequate to obtain immunomodulating 2-aminopropane-1,3-diol S1P1 agonists with reduced effect on heart rate. J Med Chem 53: 3154-3168. doi: 10.1021/jm901776q
    [101] Hale JJ, Lynch, CL, Neway WE, et al. (2004) A unique utilization of high throughput screening leads to afford selective, orally bioavailable 1-benzyl-3-carboxyazetidine S1P1 receptor agonists. J Med Chem 47: 6662-6665. doi: 10.1021/jm0492507
    [102] Vachal P, Toth LM, Hale JJ, et al. (2006) Highly selective and potent agonists of sphingosine-1-phosphate 1 (S1P1) receptor. Bioorg Med Chem Lett 16: 3684-3687. doi: 10.1016/j.bmcl.2006.04.064
    [103] Foss FW, Snyder AH, Davis MD, et al. (2007) Synthesis and biological evaluation of gammma-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists. Bioorg Med Chem 15: 663–677.
    [104] Hanessian S, Charron G, Billich A, et al. (2007) Constrained azacyclic analogues of the immunomodulatory agent FTY720 as molecular probes for sphingosine 1-phosphate receptors. Bioorg Med Chem Lett 17: 491-494. doi: 10.1016/j.bmcl.2006.10.014
    [105] Pan S, Gray NS, Gao W, et al. (2013) Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator. ACS Med Chem Lett 4: 333-337. doi: 10.1021/ml300396r
    [106] Gergely P, Nuesslein-Hildesheim B, Guerini D, et al. (2012) The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br J Pharmacol 167: 1035-1047. doi: 10.1111/j.1476-5381.2012.02061.x
    [107] Selmaj K, Li DK, Hartung HP, et al. (2013) Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol 12: 756-767. doi: 10.1016/S1474-4422(13)70102-9
    [108] Biswal S, Veldandi UK, Derne C, et al. (2014) Effect of oral siponimod (BAF312) on the pharmacokinetics and pharmacodynamics of a monophasic oral contraceptive in healthy female subjects. Int J Clin Pharmacol Ther Aug 27. [Epub ahead of print]
    [109] Olsson T, Boster A, Fernández O, et al (2014) Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial. J Neurol Neurosurg Psychiatry 85: 1198-1208. doi: 10.1136/jnnp-2013-307282
    [110] Vaclavkova A, Chimenti S, Arenberger P, et al. (2014) Oral ponesimod in patients with chronic plaque psoriasis: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet pii: S0140-6736: 60803-60805.
    [111] Mazurais D, Robert P, Gout B, et al. (2002) Cell type-specific localization of human cardiac S1P receptors. J Histochem Cytochem 50: 661-670. doi: 10.1177/002215540205000507
    [112] Lukas S, Patnaude L, Haxhinasto S, et al. (2014) No differences observed among multiple clinical S1P1 receptor agonists (functional antagonists) in S1P1 receptor down-regulation and degradation. J Biomol Screen 19: 407-416. doi: 10.1177/1087057113502234
    [113] Oo ML, Chang SH, Thangada S, et al. (2011) Engagement of S1P1-degradative mechanisms leads to vascular leak in mice. J Clin Invest 121: 2290-2300. doi: 10.1172/JCI45403
    [114] Violin JD, Crombie AL, Soergel DG, et al. (2014) Biased ligands at G-protein-coupled receptors: promise and progress. Trends Pharmacol Sci 35: 308-316. doi: 10.1016/j.tips.2014.04.007
  • Reader Comments
  • © 2014 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索
AIMS Molecular Science
0.7

Metrics

Article views(11919) PDF downloads(2062) Cited by(8)

Preview PDF
Download XML
Export Citation
Article outline

Figures and Tables

Figures(5)

Other Articles By Authors

Related pages

Tools

/

DownLoad:  Full-Size Img  PowerPoint
Return
Return

Catalog