Fingolimod in multiple sclerosis: Mechanisms of action and clinical efficacy

Clinical Immunology - Tập 142 - Trang 15-24 - 2012
Jens Ingwersen1, Orhan Aktas1, Patrick Kuery1, Bernd Kieseier1, Alexey Boyko2, Hans-Peter Hartung1
1Multiple Sclerosis Center, Department of Neurology, Heinrich-Heine-University of Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
2Department of Neurology and Neurosurgery, Russian State Medical University and Moscow MS Center, Moscow, Russia

Tài liệu tham khảo

Fujita, 1994, Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite, J. Antibiot. (Tokyo), 47, 208, 10.7164/antibiotics.47.208 Brinkmann, 2009, FTY720 (fingolimod) in multiple sclerosis: therapeutic effects in the immune and the central nervous system, Br. J. Pharmacol., 158, 1173, 10.1111/j.1476-5381.2009.00451.x Schwab, 2007, Finding a way out: lymphocyte egress from lymphoid organs, Nat. Immunol., 8, 1295, 10.1038/ni1545 Foster, 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, 10.1124/jpet.107.127183 Miron, 2010, Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices, Am. J. Pathol., 176, 2682, 10.2353/ajpath.2010.091234 Choi, 2011, FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation, Proc. Natl. Acad. Sci. U. S. A., 108, 751, 10.1073/pnas.1014154108 Kim, 2011, Neurobiological effects of sphingosine 1-phosphate receptor modulation in the cuprizone model, FASEB J., 25, 1509, 10.1096/fj.10-173203 Fukushima, 2001, Lysophospholipid receptors, Annu. Rev. Pharmacol. Toxicol., 41, 507, 10.1146/annurev.pharmtox.41.1.507 Gardell, 2006, Emerging medicinal roles for lysophospholipid signaling, Trends Mol. Med., 12, 65, 10.1016/j.molmed.2005.12.001 Spiegel, 2003, Sphingosine-1-phosphate: an enigmatic signalling lipid, Nat. Rev. Mol. Cell Biol., 4, 397, 10.1038/nrm1103 Takabe, 2008, “Inside-out” signaling of sphingosine-1-phosphate: therapeutic targets, Pharmacol. Rev., 60, 181, 10.1124/pr.107.07113 Dev, 2008, Brain sphingosine-1-phosphate receptors: implication for FTY720 in the treatment of multiple sclerosis, Pharmacol. Ther., 117, 77, 10.1016/j.pharmthera.2007.08.005 Budde, 2002, First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients, J. Am. Soc. Nephrol., 13, 1073, 10.1681/ASN.V1341073 Yanagawa, 1998, J. Immunol., 160, 5493, 10.4049/jimmunol.160.11.5493 Brinkmann, 2002, The immune modulator FTY720 targets sphingosine 1-phosphate receptors, J. Biol. Chem., 277, 21453, 10.1074/jbc.C200176200 Mandala, 2002, Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists, Science, 296, 346, 10.1126/science.1070238 Matloubian, 2004, Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1, Nature, 427, 355, 10.1038/nature02284 Mullershausen, 2009, Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors, Nat. Chem. Biol., 5, 428, 10.1038/nchembio.173 Hla, 2011, Sphingosine 1-phosphate (S1P): physiology and the effects of S1P receptor modulation, Neurology, 76, S3, 10.1212/WNL.0b013e31820d5ec1 Beer, 2000, EDG receptors as a therapeutic target in the nervous system, Ann. N. Y. Acad. Sci., 905, 118, 10.1111/j.1749-6632.2000.tb06544.x Teshima, 1995, FTY720, a Novel Immunosuppressant, Possessing Unique Mechanisms. III. Pharmacological Activities in Several Autoimmune and Inflammatory Models, 5172 Gold, 2006, Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70years of merits and culprits in experimental autoimmune encephalomyelitis research, Brain, 129, 1953, 10.1093/brain/awl075 Steinman, 2005, Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis, Trends Immunol., 26, 565, 10.1016/j.it.2005.08.014 Stromnes, 2006, Active induction of experimental allergic encephalomyelitis, Nat. Protoc., 1, 1810, 10.1038/nprot.2006.285 Ben-Nun, 1981, The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis, Eur. J. Immunol., 11, 195, 10.1002/eji.1830110307 Aktas, 2007, Neuronal damage in brain inflammation, Arch. Neurol., 64, 185, 10.1001/archneur.64.2.185 Ransohoff, 2006, EAE: pitfalls outweigh virtues of screening potential treatments for multiple sclerosis, Trends Immunol., 27, 167, 10.1016/j.it.2006.02.007 Bartholomaus, 2009, Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions, Nature, 462, 94, 10.1038/nature08478 Greter, 2005, Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis, Nat. Med., 11, 328, 10.1038/nm1197 Aktas, 2005, Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL, Neuron, 46, 421, 10.1016/j.neuron.2005.03.018 Krishnamoorthy, 2009, Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis, Nat. Med., 15, 626, 10.1038/nm.1975 Fujino, 2003, Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment, J. Pharmacol. Exp. Ther., 305, 70, 10.1124/jpet.102.045658 Kataoka, 2005, FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration, Cell. Mol. Immunol., 2, 439 Webb, 2004, Sphingosine 1-phosphate receptor agonists attenuate relapsing–remitting experimental autoimmune encephalitis in SJL mice, J. Neuroimmunol., 153, 108, 10.1016/j.jneuroim.2004.04.015 Balatoni, 2007, FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encephalomyelitis, Brain Res. Bull., 74, 307, 10.1016/j.brainresbull.2007.06.023 Papadopoulos, 2010, FTY720 ameliorates MOG-induced experimental autoimmune encephalomyelitis by suppressing both cellular and humoral immune responses, J. Neurosci. Res., 88, 346, 10.1002/jnr.22196 Rausch, 2004, 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. Imaging, 20, 16, 10.1002/jmri.20057 Foster, 2009, 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, 10.1111/j.1750-3639.2008.00182.x Zozulya, 2008, The role of regulatory T cells in multiple sclerosis, Nat. Clin. Pract. Neurol., 4, 384, 10.1038/ncpneuro0832 Sawicka, 2005, The sphingosine 1-phosphate receptor agonist FTY720 differentially affects the sequestration of CD4+/CD25+ T-regulatory cells and enhances their functional activity, J. Immunol., 175, 7973, 10.4049/jimmunol.175.12.7973 Daniel, 2007, FTY720 ameliorates Th1-mediated colitis in mice by directly affecting the functional activity of CD4+CD25+ regulatory T cells, J. Immunol., 178, 2458, 10.4049/jimmunol.178.4.2458 Sehrawat, 2008, Anti-inflammatory effects of FTY720 against viral-induced immunopathology: role of drug-induced conversion of T cells to become Foxp3+ regulators, J. Immunol., 180, 7636, 10.4049/jimmunol.180.11.7636 Heng, 2010, Adoptive transfer of FTY720-treated immature BMDCs significantly prolonged cardiac allograft survival, Transpl. Int., 23, 1259, 10.1111/j.1432-2277.2010.01119.x Zhou, 2009, Immunomodulatory drug FTY720 induces regulatory CD4(+)CD25(+) T cells in vitro, Clin. Exp. Immunol., 157, 40, 10.1111/j.1365-2249.2009.03942.x Commodaro, 2010, Evaluation of experimental autoimmune uveitis in mice treated with FTY720, Invest. Ophthalmol. Vis. Sci., 51, 2568, 10.1167/iovs.09-4769 Zhang, 2009, Distribution of Foxp3(+) T-regulatory cells in experimental autoimmune neuritis rats, Exp. Neurol., 216, 75, 10.1016/j.expneurol.2008.11.014 Jorns, 2010, Diabetes prevention by immunomodulatory FTY720 treatment in the LEW.1AR1-iddm rat despite immune cell activation, Endocrinology, 151, 3555, 10.1210/en.2010-0202 Wolf, 2009, The sphingosine 1-phosphate receptor agonist FTY720 potently inhibits regulatory T cell proliferation in vitro and in vivo, J. Immunol., 183, 3751, 10.4049/jimmunol.0901011 Liu, 2009, The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR, Nat. Immunol., 10, 769, 10.1038/ni.1743 Cohen, 2011, Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis, Ann. Neurol., 69, 759, 10.1002/ana.22426 Miron, 2008, Central nervous system-directed effects of FTY720 (fingolimod), J. Neurol. Sci., 274, 13, 10.1016/j.jns.2008.06.031 Miron, 2008, FTY720 modulates human oligodendrocyte progenitor process extension and survival, Ann. Neurol., 63, 61, 10.1002/ana.21227 Van, 2010, Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions, Glia, 58, 1465, 10.1002/glia.21021 Coelho, 2007, The immunomodulator FTY720 has a direct cytoprotective effect in oligodendrocyte progenitors, J. Pharmacol. Exp. Ther., 323, 626, 10.1124/jpet.107.123927 Jung, 2007, Functional consequences of S1P receptor modulation in rat oligodendroglial lineage cells, Glia, 55, 1656, 10.1002/glia.20576 Miron, 2008, Cyclical and dose-dependent responses of adult human mature oligodendrocytes to fingolimod, Am. J. Pathol., 173, 1143, 10.2353/ajpath.2008.080478 Novgorodov, 2007, Activation of sphingosine-1-phosphate receptor S1P5 inhibits oligodendrocyte progenitor migration, FASEB J., 21, 1503, 10.1096/fj.06-7420com Rau, 2011, Anti-inflammatory effects of FTY720 do not prevent neuronal cell loss in a rat model of optic neuritis, Am. J. Pathol., 178, 1770, 10.1016/j.ajpath.2011.01.003 Osinde, 2007, Phosphorylated FTY720 stimulates ERK phosphorylation in astrocytes via S1P receptors, Neuropharmacology, 52, 1210, 10.1016/j.neuropharm.2006.11.010 Rouach, 2006, S1P inhibits gap junctions in astrocytes: involvement of G and Rho GTPase/ROCK, Eur. J. Neurosci., 23, 1453, 10.1111/j.1460-9568.2006.04671.x Sofroniew, 2009, Molecular dissection of reactive astrogliosis and glial scar formation, Trends Neurosci., 32, 638, 10.1016/j.tins.2009.08.002 Kremer, 2009, p57kip2 is dynamically regulated in experimental autoimmune encephalomyelitis and interferes with oligodendroglial maturation, Proc. Natl. Acad. Sci. U. S. A., 106, 9087, 10.1073/pnas.0900204106 Prozorovski, 2008, Sirt1 contributes critically to the redox-dependent fate of neural progenitors, Nat. Cell Biol., 10, 385, 10.1038/ncb1700 Mullershausen, 2007, Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors, J. Neurochem., 102, 1151, 10.1111/j.1471-4159.2007.04629.x Pebay, 2001, Sphingosine-1-phosphate induces proliferation of astrocytes: regulation by intracellular signalling cascades, Eur. J. Neurosci., 13, 2067, 10.1046/j.0953-816x.2001.01585.x Edsall, 1997, Involvement of sphingosine 1-phosphate in nerve growth factor-mediated neuronal survival and differentiation, J. Neurosci., 17, 6952, 10.1523/JNEUROSCI.17-18-06952.1997 Moore, 1999, Sphingosine-1-phosphate induces apoptosis of cultured hippocampal neurons that requires protein phosphatases and activator protein-1 complexes, Neuroscience, 94, 405, 10.1016/S0306-4522(99)00288-2 Postma, 1996, Sphingosine-1-phosphate rapidly induces Rho-dependent neurite retraction: action through a specific cell surface receptor, EMBO J., 15, 2388, 10.1002/j.1460-2075.1996.tb00595.x Toman, 2004, Differential transactivation of sphingosine-1-phosphate receptors modulates NGF-induced neurite extension, J. Cell Biol., 166, 381, 10.1083/jcb.200402016 Harada, 2004, Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells, J. Neurochem., 88, 1026, 10.1046/j.1471-4159.2003.02219.x Kimura, 2007, Essential roles of sphingosine 1-phosphate/S1P1 receptor axis in the migration of neural stem cells toward a site of spinal cord injury, Stem Cells, 25, 115, 10.1634/stemcells.2006-0223 Menn, 2006, Origin of oligodendrocytes in the subventricular zone of the adult brain, J. Neurosci., 26, 7907, 10.1523/JNEUROSCI.1299-06.2006 Picard-Riera, 2002, Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice, Proc. Natl. Acad. Sci. U. S. A., 99, 13211, 10.1073/pnas.192314199 Mizugishi, 2005, Essential role for sphingosine kinases in neural and vascular development, Mol. Cell. Biol., 25, 11113, 10.1128/MCB.25.24.11113-11121.2005 Kappos, 2006, Oral fingolimod (FTY720) for relapsing multiple sclerosis, N. Engl. J. Med., 355, 1124, 10.1056/NEJMoa052643 Mehling, 2008, FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis, Neurology, 71, 1261, 10.1212/01.wnl.0000327609.57688.ea Mehling, 2011, Antigen-specific adaptive immune responses in fingolimod-treated multiple sclerosis patients, Ann. Neurol., 69, 408, 10.1002/ana.22352 Racke, 2010, Understanding the effects of FTY720 on leukocyte trafficking, Arch. Neurol., 67, 1433, 10.1001/archneurol.2010.299 Johnson, 2010, Distinct properties of circulating CD8+ T cells in FTY720-treated patients with multiple sclerosis, Arch. Neurol., 67, 1449, 10.1001/archneurol.2010.312 O'Connor, 2009, Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study, Neurology, 72, 73, 10.1212/01.wnl.0000338569.32367.3d Cohen, 2010, Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis, N. Engl. J. Med., 362, 402, 10.1056/NEJMoa0907839 Kappos, 2010, A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis, N. Engl. J. Med., 362, 387, 10.1056/NEJMoa0909494 Hartung, 2009, Bleak prospects for primary progressive multiple sclerosis therapy: downs and downs, but a glimmer of hope, Ann. Neurol., 66, 429, 10.1002/ana.21880 Hartung, 2009, New cases of progressive multifocal leukoencephalopathy after treatment with natalizumab, Lancet Neurol., 8, 28, 10.1016/S1474-4422(08)70281-3 Johnson, 2010, Reconstitution of circulating lymphocyte counts in FTY720-treated MS patients, Clin. Immunol., 137, 15, 10.1016/j.clim.2010.06.005 Leypoldt, 2009, Hemorrhaging focal encephalitis under fingolimod (FTY720) treatment: a case report, Neurology, 72, 1022, 10.1212/01.wnl.0000344567.51394.e3 Schwarz, 2010, Critical vasospasm during fingolimod (FTY720) treatment in a patient with multiple sclerosis, Neurology, 74, 2022, 10.1212/WNL.0b013e3181e3972b Kowarik, 2011, Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS, Neurology, 76, 1214, 10.1212/WNL.0b013e3182143564 Schmouder, 2006, FTY720: placebo-controlled study of the effect on cardiac rate and rhythm in healthy subjects, J. Clin. Pharmacol., 46, 895, 10.1177/0091270006289853 Gergely, 2009, 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 Sanna, 2004, Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate, J. Biol. Chem., 279, 13839, 10.1074/jbc.M311743200 Kovarik, 2006, Fingolimod (FTY720) in severe hepatic impairment: pharmacokinetics and relationship to markers of liver function, J. Clin. Pharmacol., 46, 149, 10.1177/0091270005283464 Hohlfeld, 2011, Future clinical challenges in multiple sclerosis: relevance to sphingosine 1-phosphate receptor modulator therapy, Neurology, 76, S28, 10.1212/WNL.0b013e31820db40f Mehling, 2010, Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis, Neurology, 75, 403, 10.1212/WNL.0b013e3181ebdd64