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Review

New findings and old controversies in the research of multiple sclerosis and its model experimental autoimmune encephalomyelitis

Pages 423-440 | Published online: 10 Jan 2014

References

  • Compston A, Coles A. Multiple sclerosis. Lancet 372(9648), 1502–1517 (2008).
  • Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 9(5), 520–532 (2010).
  • Charcot JM. Disseminated sclerosis: pathological anatomy. In: Lectures on the Diseases of the Nervous System. The New Sydenham Society, London, UK, 157–181 (1887).
  • Murray TJ. The history of multiple sclerosis: the changing frame of the disease over the centuries. J. Neurol. Sci. 277(Suppl. 1), S3–S8 (2009).
  • Hohlfeld R, Wekerle H. Autoimmune concepts of multiple sclerosis as a basis for selective immunotherapy: from pipe dreams to (therapeutic) pipelines. Proc. Natl Acad. Sci. USA 101(Suppl. 2), 14599–14606 (2004).
  • Lassmann H, Brück W, Lucchinetti CF. The immunopathology of multiple sclerosis: an overview. Brain Pathol. 17(2), 210–218 (2007).
  • Lublin FD, Reingold SC. 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(4), 907–911 (1996).
  • O’Connor P; Canadian Multiple Sclerosis Working Group. Key issues in the diagnosis and treatment of multiple sclerosis. An overview. Neurology 59(6 Suppl. 3), S1–S33 (2002).
  • Miller DH, Chard DT, Ciccarelli O. Clinically isolated syndromes. Lancet Neurol. 11(2), 157–169 (2012).
  • Kira J. Multiple sclerosis in the Japanese population. Lancet Neurol. 2(2), 117–127 (2003).
  • Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann. Neurol. 47(6), 707–717 (2000).
  • Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat. Rev. Neurol. 8(11), 647–656 (2012).
  • Miller A, Avidan N, Tzunz-Henig N et al. Translation towards personalized medicine in multiple sclerosis. J. Neurol. Sci. 274(1-2), 68–75 (2008).
  • Jacob A, McKeon A, Nakashima I et al. Current concept of neuromyelitis optica (NMO) and NMO spectrum disorders. J. Neurol. Neurosurg. Psychiatr. doi:10.1136/jnnp-2012-302310 (2012) (Epub ahead of print).
  • Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann. Neurol. 61(4), 288–299 (2007).
  • Ascherio A, Munger KL, Simon KC. Vitamin D and multiple sclerosis. Lancet Neurol. 9(6), 599–612 (2010).
  • Handel AE, Williamson AJ, Disanto G, Handunnetthi L, Giovannoni G, Ramagopalan SV. An updated meta-analysis of risk of multiple sclerosis following infectious mononucleosis. PLoS One 5(9), 499–503 (2010).
  • Owens GP, Gilden D, Burgoon MP, Yu X, Bennett JL. Viruses and multiple sclerosis. Neuroscientist 17(6), 659–676 (2011).
  • Croxford JL, Olson JK, Miller SD. Epitope spreading and molecular mimicry as triggers of autoimmunity in the Theiler’s virus-induced demyelinating disease model of multiple sclerosis. Autoimmun. Rev. 1(5), 251–260 (2002).
  • Hughes LE, Smith PA, Bonell S et al. Cross-reactivity between related sequences found in Acinetobacter sp., Pseudomonas aeruginosa, myelin basic protein and myelin oligodendrocyte glycoprotein in multiple sclerosis. J. Neuroimmunol. 144(1–2), 105–115 (2003).
  • Hoppenbrouwers IA, Hintzen RQ. Genetics of multiple sclerosis. Biochim. Biophys. Acta 1812(2), 194–201 (2011).
  • Gourraud PA, Harbo HF, Hauser SL, Baranzini SE. The genetics of multiple sclerosis: an up-to-date review. Immunol. Rev. 248(1), 87–103 (2012).
  • Rivers TM, Sprunt DH, Berry GP. Observations on attempts to produce acute disseminated encephalomyelitis in monkeys. J. Exp. Med. 58(1), 39–53 (1933).
  • Batoulis H, Recks MS, Addicks K, Kuerten S. Experimental autoimmune encephalomyelitis – achievements and prospective advances. APMIS 119(12), 819–830 (2011).
  • Constantinescu CS, Farooqi N, O’Brien K, Gran B. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br. J. Pharmacol. 164(4), 1079–1106 (2011).
  • Mix E, Meyer-Rienecker H, Hartung HP, Zettl UK. Animal models of multiple sclerosis – potentials and limitations. Prog. Neurobiol. 92(3), 386–404 (2010).
  • Mathey EK, Derfuss T, Storch MK et al. Neurofascin as a novel target for autoantibody-mediated axonal injury. J. Exp. Med. 204(10), 2363–2372 (2007).
  • Derfuss T, Parikh K, Velhin S et al. Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals. Proc. Natl Acad. Sci. USA 106(20), 8302–8307 (2009).
  • Krishnamoorthy G, Saxena A, Mars LT et al. Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis. Nat. Med. 15(6), 626–632 (2009).
  • Sakai K, Zamvil SS, Mitchell DJ, Lim M, Rothbard JB, Steinman L. Characterization of a major encephalitogenic T cell epitope in SJL/J mice with synthetic oligopeptides of myelin basic protein. J. Neuroimmunol. 19(1–2), 21–32 (1988).
  • Mendel I, Kerlero de Rosbo N, Ben-Nun A. A myelin oligodendrocyte glycoprotein peptide induces typical chronic experimental autoimmune encephalomyelitis in H-2b mice: fine specificity and T cell receptor V β expression of encephalitogenic T cells. Eur. J. Immunol. 25(7), 1951–1959 (1995).
  • Aharoni R, Vainshtein A, Stock A et al. Distinct pathological patterns in relapsing–remitting and chronic models of experimental autoimmune enchephalomyelitis and the neuroprotective effect of glatiramer acetate. J. Autoimmun. 37(3), 228–241 (2011).
  • Aharoni R, Sasson E, Blumenfeld-Katzir T et al. Magnetic resonance imaging characterization of different experimental autoimmune encephalomyelitis models and the therapeutic effect of glatiramer acetate. Exp. Neurol. 240, 130–144 (2013).
  • Bettelli E, Pagany M, Weiner HL, Linington C, Sobel RA, Kuchroo VK. Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis. J. Exp. Med. 197(9), 1073–1081 (2003).
  • Kipp M, Clarner T, Dang J, Copray S, Beyer C. The cuprizone animal model: new insights into an old story. Acta Neuropathol. 118(6), 723–736 (2009).
  • Oleszak EL, Chang JR, Friedman H, Katsetos CD, Platsoucas CD. Theiler’s virus infection: a model for multiple sclerosis. Clin. Microbiol. Rev. 17(1), 174–207 (2004).
  • Derfuss T, Meinl E. Identifying autoantigens in demyelinating diseases: valuable clues to diagnosis and treatment? Curr. Opin. Neurol. 25(3), 231–238 (2012).
  • Grau-López L, Raïch D, Ramo-Tello C et al. Myelin peptides in multiple sclerosis. Autoimmun. Rev. 8(8), 650–653 (2009).
  • Nylander A, Hafler DA. Multiple sclerosis. J. Clin. Invest. 122(4), 1180–1188 (2012).
  • Carotenuto A, Alcaro MC, Saviello MR et al. Designed glycopeptides with different β-turn types as synthetic probes for the detection of autoantibodies as biomarkers of multiple sclerosis. J. Med. Chem. 51(17), 5304–5309 (2008).
  • Lolli F, Mazzanti B, Pazzagli M et al. The glycopeptide CSF114(Glc) detects serum antibodies in multiple sclerosis. J. Neuroimmunol. 167(1–2), 131–137 (2005).
  • Lolli F, Mulinacci B, Carotenuto A et al. An N-glucosylated peptide detecting disease-specific autoantibodies, biomarkers of multiple sclerosis. Proc. Natl Acad. Sci. USA 102(29), 10273–10278 (2005).
  • Quintana FJ, Farez MF, Izquierdo G, Lucas M, Cohen IR, Weiner HL. Antigen microarrays identify CNS-produced autoantibodies in RRMS. Neurology 78(8), 532–539 (2012).
  • Tuohy VK, Kinkel RP. Epitope spreading: a mechanism for progression of autoimmune disease. Arch. Immunol. Ther. Exp. (Warsz.) 48(5), 347–351 (2000).
  • Lassmann H. Mechanisms of inflammation induced tissue injury in multiple sclerosis. J. Neurol. Sci. 274(1–2), 45–47 (2008).
  • Becher B, Segal BM. T(H)17 cytokines in autoimmune neuro-inflammation. Curr. Opin. Immunol. 23(6), 707–712 (2011).
  • Lee Y, Awasthi A, Yosef N et al. Induction and molecular signature of pathogenic TH17 cells. Nat. Immunol. 13(10), 991–999 (2012).
  • Aharoni R, Eilam R, Stock A et al. Glatiramer acetate reduces Th-17 inflammation and induces regulatory T-cells in the CNS of mice with relapsing–remitting or chronic EAE. J. Neuroimmunol. 225(1–2), 100–111 (2010).
  • Lock C, Hermans G, Pedotti R et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8(5), 500–508 (2002).
  • Tzartos JS, Friese MA, Craner MJ et al. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am. J. Pathol. 172(1), 146–155 (2008).
  • Lowther DE, Hafler DA. Regulatory T cells in the central nervous system. Immunol. Rev. 248(1), 156–169 (2012).
  • Venken K, Hellings N, Liblau R, Stinissen P. Disturbed regulatory T cell homeostasis in multiple sclerosis. Trends Mol. Med. 16(2), 58–68 (2010).
  • Fritzsching B, Haas J, König F et al. Intracerebral human regulatory T cells: analysis of CD4+ CD25+ FOXP3+ T cells in brain lesions and cerebrospinal fluid of multiple sclerosis patients. PLoS One 6(3), e17988 (2011).
  • Comi C, Fleetwood T, Dianzani U. The role of T cell apoptosis in nervous system autoimmunity. Autoimmun. Rev. 12(2), 150–156 (2012).
  • Filippi M, Rocca MA, De Stefano N et al. Magnetic resonance techniques in multiple sclerosis: the present and the future. Arch. Neurol. 68(12), 1514–1520 (2011).
  • Kuhlmann T, Lassmann H, Brück W. Diagnosis of inflammatory demyelination in biopsy specimens: a practical approach. Acta Neuropathol. 115(3), 275–287 (2008).
  • Lassmann H. Review: the architecture of inflammatory demyelinating lesions: implications for studies on pathogenesis. Neuropathol. Appl. Neurobiol. 37(7), 698–710 (2011).
  • Zeis T, Graumann U, Reynolds R, Schaeren-Wiemers N. Normal-appearing white matter in multiple sclerosis is in a subtle balance between inflammation and neuroprotection. Brain 131(Pt 1), 288–303 (2008).
  • Zeis T, Probst A, Steck AJ, Stadelmann C, Brück W, Schaeren-Wiemers N. Molecular changes in white matter adjacent to an active demyelinating lesion in early multiple sclerosis. Brain Pathol. 19(3), 459–466 (2009).
  • Geurts JJ, Barkhof F. Grey matter pathology in multiple sclerosis. Lancet Neurol. 7(9), 841–851 (2008).
  • Grassiot B, Desgranges B, Eustache F, Defer G. Quantification and clinical relevance of brain atrophy in multiple sclerosis: a review. J. Neurol. 256(9), 1397–1412 (2009).
  • Junker A, Brück W. Autoinflammatory grey matter lesions in humans: cortical encephalitis, clinical disorders, experimental models. Curr. Opin. Neurol. 25(3), 349–357 (2012).
  • Popescu BF, Lucchinetti CF. Meningeal and cortical grey matter pathology in multiple sclerosis. BMC Neurol. 12, 11 (2012).
  • Chard D, Miller D. Grey matter pathology in clinically early multiple sclerosis: evidence from magnetic resonance imaging. J. Neurol. Sci. 282(1–2), 5–11 (2009).
  • Siffrin V, Vogt J, Radbruch H, Nitsch R, Zipp F. Multiple sclerosis – candidate mechanisms underlying CNS atrophy. Trends Neurosci. 33(4), 202–210 (2010).
  • Medana I, Martinic MA, Wekerle H, Neumann H. Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. Am. J. Pathol. 159(3), 809–815 (2001).
  • Trapp BD, Nave KA. Multiple sclerosis: an immune or neurodegenerative disorder? Annu. Rev. Neurosci. 31, 247–269 (2008).
  • Dutta R, Trapp BD. Pathogenesis of axonal and neuronal damage in multiple sclerosis. Neurology 68(22 Suppl. 3), S22–S31; discussion S43 (2007).
  • Vigeveno RM, Wiebenga OT, Wattjes MP, Geurts JJ, Barkhof F. Shifting imaging targets in multiple sclerosis: from inflammation to neurodegeneration. J. Magn. Reson. Imaging 36(1), 1–19 (2012).
  • Bruck W. Evidence for primary neurodegeneration in MS. Mult. Scler. 14(1 Suppl.), S9 (2009).
  • Herz J, Zipp F, Siffrin V. Neurodegeneration in autoimmune CNS inflammation. Exp. Neurol. 225(1), 9–17 (2010).
  • Frischer JM, Bramow S, Dal-Bianco A et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 132(Pt 5), 1175–1189 (2009).
  • Aharoni R, Arnon R. Linkage between immunomodulation, neuroprotection and neurogenesis. Drug News Perspect. 22(6), 301–312 (2009).
  • Bettini M, Vignali DA. Regulatory T cells and inhibitory cytokines in autoimmunity. Curr. Opin. Immunol. 21(6), 612–618 (2009).
  • Mann MK, Ray A, Basu S, Karp CL, Dittel BN. Pathogenic and regulatory roles for B cells in experimental autoimmune encephalomyelitis. Autoimmunity 45(5), 388–399 (2012).
  • Sospedra M, Martin R. Immunology of multiple sclerosis. Annu. Rev. Immunol. 23, 683–747 (2005).
  • Clerici M, Saresella M, Trabattoni D et al. Single-cell analysis of cytokine production shows different immune profiles in multiple sclerosis patients with active or quiescent disease. J. Neuroimmunol. 121(1–2), 88–101 (2001).
  • Kalb R. The protean actions of neurotrophins and their receptors on the life and death of neurons. Trends Neurosci. 28(1), 5–11 (2005).
  • Lessmann V, Gottmann K, Malcangio M. Neurotrophin secretion: current facts and future prospects. Prog. Neurobiol. 69(5), 341–374 (2003).
  • Deister C, Schmidt CE. Optimizing neurotrophic factor combinations for neurite outgrowth. J. Neural Eng. 3(2), 172–179 (2006).
  • Cui Q. Actions of neurotrophic factors and their signaling pathways in neuronal survival and axonal regeneration. Mol. Neurobiol. 33(2), 155–179 (2006).
  • Hennigan A, O’Callaghan RM, Kelly AM. Neurotrophins and their receptors: roles in plasticity, neurodegeneration and neuroprotection. Biochem. Soc. Trans. 35(Pt 2), 424–427 (2007).
  • Aharoni R, Eilam R, Domev H, Labunskay G, Sela M, Arnon R. The immunomodulator glatiramer acetate augments the expression of neurotrophic factors in brains of experimental autoimmune encephalomyelitis mice. Proc. Natl Acad. Sci. USA 102(52), 19045–19050 (2005).
  • Rapalino O, Lazarov-Spiegler O, Agranov E et al. Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat. Med. 4(7), 814–821 (1998).
  • Moalem G, Leibowitz-Amit R, Yoles E, Mor F, Cohen IR, Schwartz M. Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat. Med. 5(1), 49–55 (1999).
  • Hohlfeld R, Kerschensteiner M, Stadelmann C, Lassmann H, Wekerle H. The neuroprotective effect of inflammation: implications for the therapy of multiple sclerosis. Neurol. Sci. 27(Suppl. 1), S1–S7 (2006).
  • Muhallab S, Lundberg C, Gielen AW et al. Differential expression of neurotrophic factors and inflammatory cytokines by myelin basic protein-specific and other recruited T cells infiltrating the central nervous system during experimental autoimmune encephalomyelitis. Scand. J. Immunol. 55(3), 264–273 (2002).
  • Aharoni R, Kayhan B, Eilam R, Sela M, Arnon R. Glatiramer acetate-specific T cells in the brain express T helper 2/3 cytokines and brain-derived neurotrophic factor in situ. Proc. Natl Acad. Sci. USA 100(24), 14157–14162 (2003).
  • Jin K, Sun Y, Xie L et al. Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum. Mol. Cell. Neurosci. 24(1), 171–189 (2003).
  • Magavi SS, Leavitt BR, Macklis JD. Induction of neurogenesis in the neocortex of adult mice. Nature 405(6789), 951–955 (2000).
  • Picard-Riera N, Decker L, Delarasse C et al. Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice. Proc. Natl Acad. Sci. USA 99(20), 13211–13216 (2002).
  • Aharoni R, Arnon R, Eilam R. Neurogenesis and neuroprotection induced by peripheral immunomodulatory treatment of experimental autoimmune encephalomyelitis. J. Neurosci. 25(36), 8217–8228 (2005).
  • Albert M, Antel J, Brück W, Stadelmann C. Extensive cortical remyelination in patients with chronic multiple sclerosis. Brain Pathol. 17(2), 129–138 (2007).
  • Brück W, Kuhlmann T, Stadelmann C. Remyelination in multiple sclerosis. J. Neurol. Sci. 206(2), 181–185 (2003).
  • Aktas O, Prozorovski T, Zipp F. Death ligands and autoimmune demyelination. Neuroscientist 12(4), 305–316 (2006).
  • Baumann N, Pham-Dinh D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol. Rev. 81(2), 871–927 (2001).
  • Hanafy KA, Sloane JA. Regulation of remyelination in multiple sclerosis. FEBS Lett. 585(23), 3821–3828 (2011).
  • Alvarez-Buylla A, Garcia-Verdugo JM. Neurogenesis in adult subventricular zone. J. Neurosci. 22(3), 629–634 (2002).
  • van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH. Functional neurogenesis in the adult hippocampus. Nature 415(6875), 1030–1034 (2002).
  • Iwai M, Sato K, Omori N et al. Three steps of neural stem cells development in gerbil dentate gyrus after transient ischemia. J. Cereb. Blood Flow Metab. 22(4), 411–419 (2002).
  • Kerschensteiner M, Bareyre FM, Buddeberg BS et al. Remodeling of axonal connections contributes to recovery in an animal model of multiple sclerosis. J. Exp. Med. 200(8), 1027–1038 (2004).
  • Schirmer L, Merkler D, König FB, Brück W, Stadelmann C. Neuroaxonal regeneration is more pronounced in early multiple sclerosis than in traumatic brain injury lesions. Brain Pathol. 23(1), 2–12 (2013).
  • Revel M, Chebath J, Mangelus M, Harroch S, Moviglia GA. Antagonism of interferon β on interferon gamma: inhibition of signal transduction in vitro and reduction of serum levels in multiple sclerosis patients. Mult. Scler. 1(Suppl. 1), S5–S11 (1995).
  • Clerico M, Contessa G, Durelli L. Interferon-β1a for the treatment of multiple sclerosis. Expert Opin. Biol. Ther. 7(4), 535–542 (2007).
  • Markowitz CE. Interferon-β: mechanism of action and dosing issues. Neurology 68(24 Suppl. 4), S8–S11 (2007).
  • Sorensen PS, Ross C, Clemmesen KM et al.; Danish Multiple Sclerosis Study Group. Clinical importance of neutralising antibodies against interferon β in patients with relapsing–remitting multiple sclerosis. Lancet 362(9391), 1184–1191 (2003).
  • Teitelbaum D, Meshorer A, Hirshfeld T, Arnon R, Sela M. Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide. Eur. J. Immunol. 1(4), 242–248 (1971).
  • Aharoni R. The mechanism of action of glatiramer acetate in multiple sclerosis and beyond. Autoimmun. Rev. 12(5), 543–553 (2013).
  • Fridkis-Hareli M, Teitelbaum D, Gurevich E et al. Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen-presenting cells – specificity and promiscuity. Proc. Natl Acad. Sci. USA 91(11), 4872–4876 (1994).
  • Weber MS, Prod’homme T, Youssef S et al. Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat. Med. 13(8), 935–943 (2007).
  • Hestvik AL, Skorstad G, Price DA, Vartdal F, Holmoy T. Multiple sclerosis: glatiramer acetate induces anti-inflammatory T cells in the cerebrospinal fluid. Mult. Scler. 14(6), 749–758 (2008).
  • Begum-Haque S, Sharma A, Kasper IR et al. Downregulation of IL-17 and IL-6 in the central nervous system by glatiramer acetate in experimental autoimmune encephalomyelitis. J. Neuroimmunol. 204(1–2), 58–65 (2008).
  • Berger T. Current therapeutic recommendations in multiple sclerosis. J. Neurol. Sci. 287(Suppl. 1), S37–S45 (2009).
  • Ebers GC, Rice G, Konieczny A et al. The interferon β-1b 16-year long-term follow-up study: the final results. Neurology 66(Suppl. 2), Abstract A32 (2006).
  • Ford C, Goodman AD, Johnson K et al. Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the US prospective open-label study of glatiramer acetate. Mult. Scler. 16(3), 342–350 (2010).
  • Aharoni R. Immunomodulatory drug treatment in multiple sclerosis. Expert Rev. Neurother. 10(9), 1423–1436 (2010).
  • Leary SM, Porter B, Thompson AJ. Multiple sclerosis: diagnosis and the management of acute relapses. Postgrad. Med. J. 81(955), 302–308 (2005).
  • Marta M, Giovannoni G. Disease-modifying drugs in multiple sclerosis: mechanisms of action and new drugs in the horizon. CNS Neurol. Disord. Drug Targets 11(5), 610–623 (2012).
  • Perumal J, Khan O. Emerging disease-modifying therapies in multiple sclerosis. Curr. Treat. Options Neurol. 14(3), 256–263 (2012).
  • Morrissey SP, Le Page E, Edan G. Mitoxantrone in the treatment of multiple sclerosis. Int. MS J. 12(3), 74–87 (2005).
  • Rice GP, Hartung HP, Calabresi PA. Anti-α4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology 64(8), 1336–1342 (2005).
  • Engelhardt B, Kappos L. Natalizumab: targeting α4-integrins in multiple sclerosis. Neurodegener. Dis. 5(1), 16–22 (2008).
  • Kleinschmidt-DeMasters BK, Miravalle A, Schowinsky J, Corboy J, Vollmer T. Update on PML and PML-IRIS occurring in multiple sclerosis patients treated with natalizumab. J. Neuropathol. Exp. Neurol. 71(7), 604–617 (2012).
  • Scott LJ. Fingolimod: a review of its use in the management of relapsing–remitting multiple sclerosis. CNS Drugs 25(8), 673–698 (2011).
  • Papadopoulou A, D’Souza M, Kappos L, Yaldizli O. Dimethyl fumarate for multiple sclerosis. Expert Opin. Investig. Drugs 19(12), 1603–1612 (2010).
  • Brück W, Zamvil SS. Laquinimod, a once-daily oral drug in development for the treatment of relapsing–remitting multiple sclerosis. Expert Rev. Clin. Pharmacol. 5(3), 245–256 (2012).
  • Klotz L, Meuth SG, Wiendl H. Immune mechanisms of new therapeutic strategies in multiple sclerosis – a focus on alemtuzumab. Clin. Immunol. 142(1), 25–30 (2012).
  • Martin R. Humanized anti-CD25 antibody treatment with daclizumab in multiple sclerosis. Neurodegener. Dis. 5(1), 23–26 (2008).
  • von Büdingen HC, Bar-Or A, Zamvil SS. B cells in multiple sclerosis: connecting the dots. Curr. Opin. Immunol. 23(6), 713–720 (2011).
  • Hauser SL, Waubant E, Arnold DL et al.; HERMES Trial Group. B-cell depletion with rituximab in relapsing–remitting multiple sclerosis. N. Engl. J. Med. 358(7), 676–688 (2008).
  • Sospedra M, Martin R. Antigen-specific therapies in multiple sclerosis. Int. Rev. Immunol. 24(5–6), 393–413 (2005).
  • Weiner HL, Mackin GA, Matsui M et al. Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science 259(5099), 1321–1324 (1993).
  • Panitch H, Francis G. Clinical results of a Phase III trial of oral myelin in relapsing–remitting multiple sclerosis. Ann. Neurol. 42, 459 (1997).
  • Correale J, Farez M, Gilmore W. Vaccines for multiple sclerosis: progress to date. CNS Drugs 22(3), 175–198 (2008).
  • Kappos L, Comi G, Panitch H et al. Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized Phase II trial. The Altered Peptide Ligand in Relapsing MS Study Group. Nat. Med. 6(10), 1176–1182 (2000).
  • Fissolo N, Montalban X, Comabella M. DNA-based vaccines for multiple sclerosis: current status and future directions. Clin. Immunol. 142(1), 76–83 (2012).
  • Garren H, Robinson WH, Krasulová E et al.; BHT-3009 Study Group. Phase 2 trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis. Ann. Neurol. 63(5), 611–620 (2008).
  • Vandenbark AA, Abulafia-Lapid R. Autologous T-cell vaccination for multiple sclerosis: a perspective on progress. BioDrugs 22(4), 265–273 (2008).
  • Luessi F, Siffrin V, Zipp F. Neurodegeneration in multiple sclerosis: novel treatment strategies. Expert Rev. Neurother. 12(9), 1061–1076; quiz 1077 (2012).
  • Biernacki K, Antel JP, Blain M, Narayanan S, Arnold DL, Prat A. Interferon β promotes nerve growth factor secretion early in the course of multiple sclerosis. Arch. Neurol. 62(4), 563–568 (2005).
  • Kieseier BC, Hartung HP. Interferon-β and neuroprotection in multiple sclerosis – facts, hopes and phantasies. Exp. Neurol. 203(1), 1–4 (2007).
  • Bagnato F, Evangelou IE, Gallo A, Gaindh D, Yao K. The effect of interferon-β on black holes in patients with multiple sclerosis. Expert Opin. Biol. Ther. 7(7), 1079–1091 (2007).
  • Zivadinov R, Locatelli L, Cookfair D et al. Interferon β-1a slows progression of brain atrophy in relapsing–remitting multiple sclerosis predominantly by reducing gray matter atrophy. Mult. Scler. 13(4), 490–501 (2007).
  • Azoulay D, Vachapova V, Shihman B, Miler A, Karni A. Lower brain-derived neurotrophic factor in serum of relapsing remitting MS: reversal by glatiramer acetate. J. Neuroimmunol. 167(1–2), 215–218 (2005).
  • Aharoni R, Herschkovitz A, Eilam R et al. Demyelination arrest and remyelination induced by glatiramer acetate treatment of experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 105(32), 11358–11363 (2008).
  • Filippi M, Rovaris M, Rocca MA, Sormani MP, Wolinsky JS, Comi G; Eurpoean/Canadian Glatiramer Acetate Study Group. Glatiramer acetate reduces the proportion of new MS lesions evolving into ‘black holes’. Neurology 57(4), 731–733 (2001).
  • Khan O, Shen Y, Caon C et al. Axonal metabolic recovery and potential neuroprotective effect of glatiramer acetate in relapsing–remitting multiple sclerosis. Mult. Scler. 11(6), 646–651 (2005).
  • Aktas O, Küry P, Kieseier B, Hartung HP. Fingolimod is a potential novel therapy for multiple sclerosis. Nat. Rev. Neurol. 6(7), 373–382 (2010).
  • Miron VE, Ludwin SK, Darlington PJ et al. Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices. Am. J. Pathol. 176(6), 2682–2694 (2010).
  • Hu Y, Lee X, Ji B et al. Sphingosine 1-phosphate receptor modulator fingolimod (FTY720) does not promote remyelination in vivo. Mol. Cell. Neurosci. 48(1), 72–81 (2011).
  • Aharoni R, Saada R, Eilam R, Hayardeny L, Sela M, Arnon R. Oral treatment with laquinimod augments regulatory T-cells and brain-derived neurotrophic factor expression and reduces injury in the CNS of mice with experimental autoimmune encephalomyelitis. J. Neuroimmunol. 251(1–2), 14–24 (2012).
  • Thöne J, Ellrichmann G, Seubert S et al. Modulation of autoimmune demyelination by laquinimod via induction of brain-derived neurotrophic factor. Am. J. Pathol. 180(1), 267–274 (2012).
  • Kremer D, Aktas O, Hartung HP, Küry P. The complex world of oligodendroglial differentiation inhibitors. Ann. Neurol. 69(4), 602–618 (2011).
  • Karnezis T, Mandemakers W, McQualter JL et al. The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated demyelination. Nat. Neurosci. 7(7), 736–744 (2004).
  • Mi S, Hu B, Hahm K et al. LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis. Nat. Med. 13(10), 1228–1233 (2007).
  • Waxman SG. Mechanisms of disease: sodium channels and neuroprotection in multiple sclerosis – current status. Nat. Clin. Pract. Neurol. 4(3), 159–169 (2008).
  • Pikoulas TE, Fuller MA. Dalfampridine: a medication to improve walking in patients with multiple sclerosis. Ann. Pharmacother. 46(7–8), 1010–1015 (2012).
  • Loeb JA. Neuroprotection and repair by neurotrophic and gliotrophic factors in multiple sclerosis. Neurology 68(22 Suppl. 3), S38–S42; discussion S43 (2007).
  • Magy L, Mertens C, Avellana-Adalid V et al. Inducible expression of FGF2 by a rat oligodendrocyte precursor cell line promotes CNS myelination in vitro. Exp. Neurol. 184(2), 912–922 (2003).
  • Butt AM, Dinsdale J. Fibroblast growth factor 2 induces loss of adult oligodendrocytes and myelin in vivo. Exp. Neurol. 192(1), 125–133 (2005).
  • Mason JL, Jones JJ, Taniike M, Morell P, Suzuki K, Matsushima GK. Mature oligodendrocyte apoptosis precedes IGF-1 production and oligodendrocyte progenitor accumulation and differentiation during demyelination/remyelination. J. Neurosci. Res. 61(3), 251–262 (2000).
  • Frank JA, Richert N, Lewis B et al. A pilot study of recombinant insulin-like growth factor-1 in seven multiple sderosis patients. Mult. Scler. 8(1), 24–29 (2002).
  • Wiendl H, Hohlfeld R. Therapeutic approaches in multiple sclerosis: lessons from failed and interrupted treatment trials. BioDrugs 16(3), 183–200 (2002).
  • Fujiwara M, Egashira N. New perspectives in the studies on endocannabinoid and cannabis: abnormal behaviors associate with CB1 cannabinoid receptor and development of therapeutic application. J. Pharmacol. Sci. 96(4), 362–366 (2004).
  • Hasseldam H, Johansen FF. Cannabinoid treatment renders neurons less vulnerable than oligodendrocytes in experimental autoimmune encephalomyelitis. Int. J. Neurosci. 121(9), 510–520 (2011).
  • Ben-Hur T. Cell therapy for multiple sclerosis. Neurotherapeutics 8(4), 625–642 (2011).
  • Einstein O, Grigoriadis N, Mizrachi-Kol R et al. Transplanted neural precursor cells reduce brain inflammation to attenuate chronic experimental autoimmune encephalomyelitis. Exp. Neurol. 198(2), 275–284 (2006).
  • Pluchino S, Quattrini A, Brambilla E et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 422(6933), 688–694 (2003).
  • Karussis D, Kassis I, Kurkalli BG, Slavin S. Immunomodulation and neuroprotection with mesenchymal bone marrow stem cells (MSCs): a proposed treatment for multiple sclerosis and other neuroimmunological/neurodegenerative diseases. J. Neurol. Sci. 265(1–2), 131–135 (2008).
  • Freedman MS, Bar-Or A, Atkins HL et al.; MSCT Study Group. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult. Scler. 16(4), 503–510 (2010).

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