Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis
Abstract
:1. Introduction
2. Discovery of FTY720
3. Mechanism of Action of FTY720
3.1. FTY720 Sequesters Circulating Lymphocytes into the SLO
3.2. Role of S1P and S1P1 Receptors in Lymphocyte Egress from the SLO
3.3. FTY720 Acts as a Functional Antagonist at S1P1 Receptor
4. Effects of FTY720 on Experimental Autoimmune Encephalomyelitis
5. Clinical Trails of FTY720 in MS
6. Conclusions
Acknowledgments
Conflict of Interest
References
- Fujita, T.; Inoue, K.; Yamamoto, S.; Ikumoto, T.; Sasaki, S.; Toyama, R.; Chiba, K.; Hoshino, Y.; Okumoto, T. Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite. J. Antibiot. 1994, 47, 208–215. [Google Scholar] [CrossRef]
- Adachi, K.; Kohara, T.; Nakao, N.; Arita, M.; Chiba, K.; Mishina, T.; Sasaki, S.; Fujita, T. Design, synthesis, and structure-activity relationships of 2-substituted-2-amino-1,3-propanediols: Discovery of a novel immunosuppressant, FTY720. Bioorg. Med. Chem. Lett. 1995, 5, 853–856. [Google Scholar] [CrossRef]
- Fujita, T.; Yoneta, M.; Hirose, R.; Sasaki, S.; Inoue, K.; Kiuchi, M.; Hirase, S.; Adachi, K.; Arita, M.; Chiba, K. Simple compounds, 2-alkyl-2-amino-1,3-propane-diols have potent immunosuppressive activity. Bioorg. Med. Chem. Lett. 1995, 5, 847–852. [Google Scholar] [CrossRef]
- Fujita, T.; Hirose, R.; Yoneta, M.; Sasaki, S.; Inoue, K.; Kiuchi, M.; Hirase, S.; Chiba, K.; Sakamoto, H.; Arita, M. Potent immunosuppressants, 2-alkyl-2-aminopropane-1,3-diols. J. Med. Chem. 1996, 39, 4451–4459. [Google Scholar]
- Chiba, K.; Hoshino, Y.; Suzuki, C.; Masubuchi, Y.; Yanagawa, Y.; Ohtsuki, M.; Sasaki, S.; Fujita, T. FTY720, a novel immunosuppressant possessing unique mechanisms. I. Prolongation of skin allograft survival and synergistic effect in combination with cyclosporine in rats. Transplant. Proc. 1996, 28, 1056–1059. [Google Scholar]
- Hoshino, Y.; Suzuki, C.; Ohtsuki, M.; Masubuchi, Y.; Amano, Y.; Chiba, K. 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. 1996, 28, 1060–1061. [Google Scholar]
- Kawaguchi, T.; Hoshino, Y.; Rahman, F.; Amano, Y.; Higashi, H.; Kataoka, H.; Ohtsuki, M.; Teshima, K.; Chiba, K.; Kakefuda, T.; et al. FTY720, a novel immunosuppressant possessing unique mechanisms. III. Synergistic prolongation of canine renal allograft survival in combination with cyclosporine A. Transplant. Proc. 1996, 28, 1062–1063. [Google Scholar]
- Chiba, K. FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptor. Pharmacol. Ther. 2005, 108, 308–319. [Google Scholar] [CrossRef]
- Matsuura, M.; Imayoshi, T.; Chiba, K.; Okumoto, T. Effect of FTY720, a novel immunosuppressant, on adjuvant-induced arthritis in rats. Inflamm. Res. 2000, 49, 404–410. [Google Scholar] [CrossRef]
- Chiba, K.; Yanagawa, Y.; Masubuchi, Y.; Kataoka, H.; Kawaguchi, T.; Ohtsuki, M.; Hoshino, Y. 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. 1998, 160, 5037–5044. [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. 2000, 21, 49–52. [Google Scholar] [CrossRef]
- Yanagawa, Y.; Sugahara, K.; Kataoka, H.; Kawaguchi, T.; Masubuchi, Y.; Chiba, K. 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. 1998, 160, 5493–5499. [Google Scholar]
- Cyster, J.G. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu. Rev. Immunol. 2005, 23, 127–159. [Google Scholar] [CrossRef]
- Matloubian, M.; Lo, C.G.; Cinamon, G.; Lesneski, M.J.; Xu, Y.; Brinkmann, V.; Allende, M.L.; Proia, R.L.; Cyster, J.G. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 2004, 427, 355–360. [Google Scholar]
- Brinkmann, V.; Davis, M.D.; Heise, C.E.; Albert, R.; Cottens, S.; Hof, R.; Bruns, C.; Prieschl, E.; Baumruker, T.; Hiestand, P.; et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem. 2002, 277, 21453–21457. [Google Scholar]
- Paugh, S.W.; Payne, S.G.; Barbour, S.E.; Milstien, S.; Spiegel, S. The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2. FEBS Lett. 2003, 554, 189–193. [Google Scholar] [CrossRef]
- Chiba, K.; Matsuyuki, H.; Maeda, Y.; Sugahara, K. Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus. Cell. Mol. Immunol. 2006, 3, 11–19. [Google Scholar]
- Maeda, Y.; Matsuyuki, H.; Shimano, K.; Kataoka, H.; Sugahara, K.; Chiba, K. 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. 2007, 178, 3437–3446. [Google Scholar]
- Pham, T.H.; Okada, T.; Matloubian, M.; Lo, C.G.; Cyster, J.G. S1P1 receptor signaling overrides retention mediated by G alpha i-coupled receptors to promote T cell egress. Immunity 2008, 28, 122–133. [Google Scholar] [CrossRef]
- Fujita, T.; Inoue, K.; Yamamoto, S.; Ikumoto, T.; Sasaki, S.; Toyama, R.; Chiba, K.; Hoshino, Y.; Okumoto, T. Fungal metabolites. Part 12. Potent immunosuppressant, 14-deoxomyruiocin, (2S,3R,4R)-(E)-2-amino-3,4-dihydroxy-2-hydroxymethyleicos-6-enoic acid and structure-activity relationships of myriocin derivatives. J. Antibiot. 1994, 47, 216–224. [Google Scholar] [CrossRef]
- Chiba, K. Immunoregulation by sphinfosine 1-phosphate receptor modulator, FTY720. Kagaku To Seibutsu 2008, 46, 259–264. [Google Scholar] [CrossRef]
- Kiuchi, M.; Adachi, K.; Kohara, T.; Minoguchi, M.; Hanano, T.; Aoki, Y.; Mishina, T.; Arita, M.; Nakao, N.; Ohtsuki, M.; et al. Synthesis and immunosuppressive activity of 2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols. J. Med. Chem. 2000, 43, 2946–2961. [Google Scholar]
- Adachi, K.; Chiba, K. FTY720 story. Its discovery and the following accelerated development of sphingosine 1-phosphate receptor agonists as immunomodulators based on reverse pharmacology. Perspect. Medicin. Chem. 2008, 1, 11–23. [Google Scholar]
- Suzuki, S.; Kakefuda, T.; Amemiya, H.; Chiba, K.; Hoshino, Y.; Kawaguchi, T.; Kataoka, H.; Rahman, F. An immunosuppressive regimen using FTY720 combined with cyclosporin in canine kidney transplantation. Transpl. Int. 1998, 11, 95–101. [Google Scholar]
- Yanagawa, Y.; Masubuchi, Y.; Chiba, K. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats, III. Increase in frequency of CD62L-positive T cells in Peyer's patches by FTY720-induced lymphocyte homing. Immunology 1998, 95, 591–594. [Google Scholar] [CrossRef]
- Kataoka, H.; Sugahara, K.; Shimano, K.; Teshima, K.; Koyama, M.; Fukunari, A.; Chiba, K. FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. Cell. Mol. Immunol. 2005, 2, 439–448. [Google Scholar]
- Lo, C.G.; Xu, Y.; Proia, R.L.; Cyster, J.G. Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit. J. Exp. Med. 2005, 201, 291–301. [Google Scholar] [CrossRef]
- Pappu, R.; Schwab, S.R.; Cornelissen, I.; Pereira, J.P.; Regard, J.B.; Xu, Y.; Camerer, E.; Zheng, Y.W.; Huang, Y.; Cyster, J.G.; et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 2007, 316, 295–298. [Google Scholar]
- Pyne, S.; Pyne, N. Sphingosine 1-phosphate signalling via the endothelial differentiation gene family of G-protein-coupled receptors. Pharmacol. Ther. 2000, 88, 115–131. [Google Scholar] [CrossRef]
- Spiegel, S. Sphingosine 1-phosphate: A ligand for the EDG-1 family of G-protein-coupled receptors. Ann. NY Acad. Sci. 2000, 905, 54–60. [Google Scholar] [CrossRef]
- Mandala, S.; Hajdu, R.; Bergstrom, J.; Quackenbush, E.; Xie, J.; Milligan, J.; Thornton, R.; Shei, G.J.; Card, D.; Keohane, C.; et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 2002, 296, 346–349. [Google Scholar]
- Kiuchi, M.; Adachi, K.; Tomatsu, A.; Chino, M.; Takeda, S.; Tanaka, Y.; Maeda, Y.; Sato, N.; Mitsutomi, N.; Sugahara, K.; et al. Asymmetric synthesis and biological evaluation of the enantiomeric isomers of the immunosuppressive FTY720-phosphate. Bioorg. Med. Chem. 2005, 13, 425–432. [Google Scholar]
- Matsuyuki, H.; Maeda, Y.; Yano, K.; Sugahara, K.; Chiba, K.; Kohno, T.; Igarashi, Y. Involvement of sphingosine 1-phosphate (S1P) receptor type 1 and type 4 in migratory response of mouse T cells toward S1P. Cell. Mol. Immunol. 2006, 3, 429–437. [Google Scholar]
- Webb, M.; Tham, C.S.; Lin, F.F.; Lariosa-Willingham, K.; Yu, N.; Hale, J.; Mandala, S.; Chun, J.; Rao, T.S. Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J. Neuroimmunol. 2004, 153, 108–121. [Google Scholar] [CrossRef]
- Balatoni, B.; Storch, M.K.; Swoboda, E.M.; Schonborn, V.; Koziel, A.; Lambrou, G.N.; Hiestand, P.C.; Weissert, R.; Foster, C.A. FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encephalomyelitis. Brain Res. Bull. 2007, 74, 307–316. [Google Scholar] [CrossRef]
- Brinkmann, V. Sphingosine 1-phosphate receptors in health and disease: Mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol. Ther. 2007, 115, 84–105. [Google Scholar] [CrossRef]
- Foster, C.A.; Howard, L.M.; Schweitzer, A.; Persohn, E.; Hiestand, P.C.; Balatoni, B.; Reuschel, R.; Beerli, C.; Schwartz, M.; Billich, A. 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. 2007, 323, 469–475. [Google Scholar] [CrossRef]
- Chiba, K.; Kataoka, H.; Seki, N.; Shimano, K.; Koyama, M.; Fukunari, A.; Sugahara, K.; Sugita, T. Fingolimod (FTY720), sphingosine 1-phosphate receptor modulator, shows superior efficacy as compared with interferon-β in mouse experimental autoimmune encephalomyelitis. Int. Immunopharmacol. 2011, 11, 366–372. [Google Scholar] [CrossRef]
- Langrish, C.L.; Chen, Y.; Blumenschein, W.M.; Mattson, J.; Basham, B.; Sedgwick, J.D.; McClanahan, T.; Kastelein, R.A.; Cua, D.J. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 2005, 201, 233–240. [Google Scholar] [CrossRef]
- Komiyama, Y.; Nakae, S.; Matsuki, T.; Nambu, A.; Ishigame, H.; Kakuta, S.; Sudo, K.; Iwakura, Y. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 2006, 177, 566–573. [Google Scholar]
- Stromnes, I.M.; Cerretti, L.M.; Liggitt, D.; Harris, R.A.; Goverman, J.M. Differential regulation of central nervous system autoimmunity by TH1 and TH17 cells. Nat. Med. 2008, 14, 337–342. [Google Scholar]
- Seki, N.; Maeda, Y.; Kataoka, H.; Sugahara, K.; Sugita, T.; Chiba, K. Fingolimod (FTY720) ameliorates Experimental Autoimmune Encephalomyelitis (EAE) II. FTY720 decreases infiltration of Th17 and Th1 cells into the central nervous system in EAE. Inflamm. Regen. 2010, 30, 545–551. [Google Scholar]
- Brinkmann, V. FTY720 (fingolimod) in Multiple Sclerosis: Therapeutic effects in the immune and the central nervous system. Br. J. Pharmacol. 2009, 158, 1173–1182. [Google Scholar] [CrossRef]
- Choi, J.W.; Gardell, S.E.; Herr, D.R.; Rivera, R.; Lee, C.W.; Noguchi, K.; Teo, S.T.; Yung, Y.C.; Lu, M.; Kennedy, G.; et al. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc. Natl. Acad. Sci. USA 2011, 108, 751–756. [Google Scholar]
- Martin, R.; McFarland, H.F.; McFarlin, D.E. Immunological aspects of demyelinating diseases. Annu. Rev. Immunol. 1992, 10, 153–187. [Google Scholar] [CrossRef]
- Kornek, B.; Storch, M.K.; Weissert, R.; Wallstroem, E.; Stefferl, A.; Olsson, T.; Linington, C.; Schmidbauer, M.; Lassmann, H. Multiple sclerosis and chronic autoimmune encephalomyelitis: A comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am. J. Pathol. 2000, 157, 267–276. [Google Scholar] [CrossRef]
- Lublin, F.D.; Reingold, S.C. 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 1996, 46, 907–911. [Google Scholar] [CrossRef]
- Goodkin, D.E.; Reingold, S.; Sibley, W.; Wolinsky, J.; McFarland, H.; Cookfair, D.; Lublin, F.D. 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. 1999, 46, 132–134. [Google Scholar] [CrossRef]
- Kappos, L.; Antel, J.; Comi, G.; Montalban, X.; O’Connor, P.; Polman, C.H.; Haas, T.; Korn, A.A.; Karlsson, G.; Radue, E.W. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N. Engl. J. Med. 2006, 355, 1124–1140. [Google Scholar] [CrossRef]
- Mehling, M.; Lindberg, R.; Raulf, F.; Kuhle, J.; Hess, C.; Kappos, L.; Brinkmann, V. Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. Neurology 2010, 75, 403–410. [Google Scholar] [CrossRef]
- Kappos, L.; Radue, E.W.; O’Connor, P.; Polman, C.; Hohlfeld, R.; Calabresi, P.; Selmaj, K.; Agoropoulou, C.; Leyk, M.; Zhang-Auberson, L.; et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 2010, 362, 387–401. [Google Scholar] [CrossRef]
- Cohen, J.A.; Barkhof, F.; Comi, G.; Hartung, H.P.; Khatri, B.O.; Montalban, X.; Pelletier, J.; Capra, R.; Gallo, P.; Izquierdo, G.; et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N. Engl. J. Med. 2010, 362, 402–415. [Google Scholar]
© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
Share and Cite
Chiba, K.; Adachi, K. Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis. Pharmaceuticals 2012, 5, 514-528. https://doi.org/10.3390/ph5050514
Chiba K, Adachi K. Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis. Pharmaceuticals. 2012; 5(5):514-528. https://doi.org/10.3390/ph5050514
Chicago/Turabian StyleChiba, Kenji, and Kunitomo Adachi. 2012. "Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis" Pharmaceuticals 5, no. 5: 514-528. https://doi.org/10.3390/ph5050514