Neuroprotection and Glatiramer Acetate: The Possible Role in the Treatment of Multiple Sclerosis

  • Tjalf Ziemssen
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 541)


Multiple Sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system (CNS). It is believed to be an immune-mediated disorder in which the myelin sheath or the oligodendrocyte is targeted by the immune system in genetically susceptible people. Oligodendrocytes synthesize and maintain the axonal myelin sheath of up to 40 neighbouring nerve axons in the CNS. Compact myelin consists of a condensed membrane, spiralled around axons to form the insulating segmented sheath needed for saltatory axonal conduction: voltage-gated sodium channels cluster at the unmyelinated nodes of Ranvier, between myelin segments, from where the action potential is propagated and spreads down the myelinated nerve segment to trigger another action potential at the next node.


Multiple Sclerosis Nerve Growth Factor Neurotrophic Factor Experimental Autoimmune Encephalomyelitis Myelin Basic Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Waxman S.G. Demyelinating diseases — new pathological insights, new therapeutic targets. N Eng J Med. 338, 323–5 (1998).Google Scholar
  2. 2.
    Charcot J.M. Lectures on the diseases of the nervous system (translated by R.M. May). London: New Sydenham Society (1877).Google Scholar
  3. 3.
    Doinikow B. Über De-Regenerationserscheinungen an Achsenzylindern bei der multiplen Sklerose. Z Ges Neurol Psychiat 27, 151–78 (1915).CrossRefGoogle Scholar
  4. 4.
    Trapp B.D., Peterson J., Ransohoff R.M., Rudick R., Mork S., Bo L. Axonal transsection in the lesions of multiple sclerosis. N Engl J Med 338, 278–85 (1998).PubMedCrossRefGoogle Scholar
  5. 5.
    Perry V.H., Anthony DC. Axon damage and repair in multiple sclerosis. Phil Trans R Soc London B 354, 1641–7 (1999).CrossRefGoogle Scholar
  6. 6.
    Filippi M., Grossman R.I. MRI techniques to monitor MS evolution. The present and the future. Neurology 58, 1147–53 (2002).PubMedCrossRefGoogle Scholar
  7. 7.
    Urenjak J., Williams S.R., Gadian D.J., Noble M. Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types. J Neurosci 13, 981–9 (1993).PubMedGoogle Scholar
  8. 8.
    Davie C.A., Hawkins C.P., Baker G.J., Brennan A., Tofts P.S., Miller D.H., McDonald W.I. Serial proton magnetic resonance spectroscopy in acute multiple sclerosis lesions. Brain 117, 49–58 (1994).PubMedCrossRefGoogle Scholar
  9. 9.
    Fu L., Matthews P.M., De Stephano N., Worsley K.J., Narayanan S., Francis G.S., Antel J.P., Wolfson C., Arnold D.L. Imaging axonal damage in normal appearing white matter. Brain 121, 103–13 (1998).PubMedCrossRefGoogle Scholar
  10. 10.
    van Waesberghe J.H., van Walderveen M.A., Castelijns J.A., Scheltens P., Lycklama a Nijeholt G.J., Polman C.H., Barkhof F. Patterns of lesion development in multiple sclerosis: longitudinal observations with T1-weighted spin-echo and magnetization transfer. Am J Neuroradiol 19, 675–83 (1998).PubMedGoogle Scholar
  11. 11.
    Brück W., Bitsch A., Kolenda H., Brück Y., Stiefel M., Lassmann H. Inflammatory central nervous system emyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann Neurol 42, 783–93 (1997).PubMedCrossRefGoogle Scholar
  12. 12.
    van Waesberghe J.H., Kamphorst W., De Groot C.J., van Walderveen M.A., Castelijns J.A., Ravid R., Lycklama a Nijeholt G.J., van der Valk P., Polman C.H., Thompson A.J., Barkhof F. Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability. Ann Neurol 46, 747–54 (1999).PubMedCrossRefGoogle Scholar
  13. 13.
    Barde Y.A., Edgar D., Thoenen H. Newneurotrophic factors. Ann Rev Physiol 45, 601–12 (1983).CrossRefGoogle Scholar
  14. 14.
    Baloh R.H., Enomoto H., Johnson E.M., Milbrandt J. The GDNF family ligands and receptors — implications for neural development. Curr Opin Neurobiol 10, 103–10 (2000).PubMedCrossRefGoogle Scholar
  15. 15.
    Ip N.Y. The neurotrophins and neuropoietic cytokines: two families of growth factors acting on neural and hematopoietic cells. Ann N Y Acad Sci 540, 97–106 (1998).CrossRefGoogle Scholar
  16. 16.
    Heck S., Lezoualch F., Engert S., Behl C. Insulin-like growth factor-1-mediated neuroprotection against oxidative stress is associated with activation of nuclear factor kappa. B J Biol Chem 274, 9828–35 (1999).CrossRefGoogle Scholar
  17. 17.
    Lindvall O., Kokaia Z., Bengzon J., Elmer E., Kokaia M. Neurotrophins and brain insults. Trends Neurosci 17, 490–6 (1994).PubMedCrossRefGoogle Scholar
  18. 18.
    Mitsumoto H., Ikeda K., Klinkosz B., Cedarbaum J.M., Wong V., Lindsay R.M. Arrest of motor neuron disease in wobbler mice cotreated with CNTF and BDNF. Science 265, 1107–10 (1994).PubMedCrossRefGoogle Scholar
  19. 19.
    Schnell L., Schneider R., Kolbeck R., Barde Y.A., Schwab M.E. Neurotrophin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion. Nature 367, 170–3 (1994).PubMedCrossRefGoogle Scholar
  20. 20.
    Kumar S., Kahn M.A., Dinh L., de Vellis J. NT-3-mediated TrkC receptor activation promotes proliferation and cell survival of rodent progenitor oligodendrocyte cells in vitro and in vivo. J Neurosci Res 54, 754–65 (1998).PubMedCrossRefGoogle Scholar
  21. 21.
    Laudiero L.B., Aloe L., Levi-Montalcini R., Buttinelli C, Schilter D., Gillessen S., Otten U. Multiple sclerosis patients express increased levels of beta-nerve growth factor in cerebrospinal fluid. Neurosci Lett 147, 9–12 (1992).PubMedCrossRefGoogle Scholar
  22. 22.
    Villoslada P., Hauser S.L., Bartke I., Unger J., Heald N., Rosenberg D., Cheung S.W., Mobley W.C., Fisher S., Genain C.P. Human nerve growth factor protects common marmosets against autoimmune encephalomyelitis by switching the balance of T helper cell type 1 and 2 cytokines within the central nervous system. J Exp Med 191, 1799–806 (2000).PubMedCrossRefGoogle Scholar
  23. 23.
    Wekerle H., Kojiina K., Lannes-Vieira J., Laßmann H., Linington C. Animal models. Ann Neurol 36,S47–53 (1994).PubMedCrossRefGoogle Scholar
  24. 24.
    Schwartz M., Moalem G., Leibowitz-Amit R., Cohen I.R. Innate and adaptive immune responses can be beneficial for CNS repair. Trends Neurosci 22, 295–9 (1999).PubMedCrossRefGoogle Scholar
  25. 25.
    Moalem G., Leibowitz-Amit R., Yoles E., Mor F., Cohen I.Schwartz M. Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nature Med 5, 49–55 (1999).PubMedCrossRefGoogle Scholar
  26. 26.
    Cohen I.R. The cognitive paradigm and the immunological homunculus. Immunol Today 13, 490–4 (1992).PubMedCrossRefGoogle Scholar
  27. 27.
    Rapalino O., Lazarov-Spiegler O., Agranov E., Velan G.J., Yoles E., Fraidakis M., Solomon A., Gepstein R., Katz A., Belkin M., Hadani M., Schwartz M. Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med 4:814–21 (1998).PubMedCrossRefGoogle Scholar
  28. 28.
    Serpe C.J., Kohm A.P. Huppenbauer C.B., Sanders V.J., Jones K.J. Exacerbation of facial motor-neuron loss after facial nerve transection in severe combined immunodeficient (SCID) mice. J Neurosci RC7, 1–5 (1999).Google Scholar
  29. 29.
    Kerschensteiner M., Stadelmann C, Dechant G., Wekerle H., Hohlfeld R. Neurotrophic cross-talk between the nervous system and immune system: Implications for inflammatory and degenerative neurological diseases. Ann Neurol (in press)Google Scholar
  30. 30.
    Hohlfeld R., Kerschensteiner M., Stadelmann C, Lassmann H., Wekerle H. The neuroprotective effect of inflammation: implications for the therapy of multiple sclerosis. J Neuroimmunol 107, 161–6 (2000).PubMedCrossRefGoogle Scholar
  31. 31.
    Steinman L. Multiple Sclerosis: a two-stage disease. Nat Immunol 2, 762–4 (2001).PubMedCrossRefGoogle Scholar
  32. 32.
    Warrington A.E., Asakura K., Bieber A.J., Ciric B., Van Keulen V., Kaveri S.V., Kyle R.A., Pease L.R., Rodriguez M. Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis. Proc Natl Acad Sci USA 97, 6820–5 (2000).PubMedCrossRefGoogle Scholar
  33. 33.
    Wekerle H. Linington C, Lassmann H., Meyermann R. Cellular immune reactivity within the CNS. Trends Neurosci 9, 271–9 (1986).CrossRefGoogle Scholar
  34. 34.
    Torcia M., Bracci-Laudiero L., Lucibello M., Nencioni L., Labardi D., Rubartelli A., Cozzolino F., Aloe L., Garaci E. Nerve growth factor is an autocrine survival factor for memory B lymphocytes. Cell 85, 345–56 (1996).PubMedCrossRefGoogle Scholar
  35. 35.
    Lewin G.R., Barde Y.A. Physiology of the neurotrophins. Annu Rev Neurosci 19, 289–317 (1996).PubMedCrossRefGoogle Scholar
  36. 36.
    Klein R., Nanduri V., Jing S., Lamballe F., Tapley P., Bryant S., Cordon-Cardo C, Jones K.R., Reichardt L.F., Barbacid M. The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3. Cell 66, 395–403 (1991).PubMedCrossRefGoogle Scholar
  37. 37.
    Kerschensteiner M., Gallmeier E., Behrens L., Leal V.V., Misgeld T., Klinkert W.E., Kolbeck R., Hoppe E., Oropeza-Wekerle R.L., Bartke I., Stadelmann C, Lassmann H., Wekerle H., Hohlfeld R. Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J Exp Med 189, 865–70 (1999).PubMedCrossRefGoogle Scholar
  38. 38.
    Batchelor P.E., Liberatore G.T., Wong J.Y., Porritt M.J., Frerichs F., Donnan G.A., Howells D.W. Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. J Neurosci 19, 1708–16 (1999).PubMedGoogle Scholar
  39. 39.
    Besser M., Wank R. Cutting edge: clonally restricted production of the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 mRNA by human immune cells and Th1/Th2-polarized expression of their receptors. J Immunol 162, 6303–6 (1999).PubMedGoogle Scholar
  40. 40.
    Labouyrie E., Dubus P., Groppi A., Mahon F.X., Ferrer J., Parrens M., Reiffers J., de Mascare A., Merlio J.P. Expression of neurotrophins and their receptors in human bone marrow. Am J Pathol 154, 405–15 (1999).PubMedCrossRefGoogle Scholar
  41. 41.
    Stadelmann C, Kerschensteiner M, Misgeld T., Bruck W., Hohlfeld R., Lassmann H. BDNF and gpl45trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain 125, 75–85 (2002).PubMedCrossRefGoogle Scholar
  42. 42.
    Gravel C., Gotz R., Lorrain A., Sendtner M. Adenoviral gene transfer of ciliary neurotrophic factor and brain-derived neurotrophic factor leads to long-term survival of axotomized motor neurons. Nat Med 3, 765–70 (1997).PubMedCrossRefGoogle Scholar
  43. 43.
    Kobayashi N.R., Fan D.P., Giehl K.M., Bedard A.M., Wiegand S.J., Tetzlaff W. BDNF and NT-4/5 prevent atrophy of rat rubrospinal neurons after cervical axotomy, stimulate GAP-43 and Talphal-tubulin mRNA expression, and promote axonal regeneration. J Neurosci 17, 9583–95 (1997).PubMedGoogle Scholar
  44. 44.
    Sagot Y.,. Rossé T., Vejsada R., Perrelet D., Kato A.C Differential effects of neurotrophic factors on motoneuron retrograde labeling in a murine model of motoneuron disease. J Neurosci 18, 1132–41 (1998).Google Scholar
  45. 45.
    Weibel D., Kreutzberg G.W., Schwab M.E Brain-derived neurotrophic factor (BDNF) prevents lesion-induced axonal die-back in young rat optic nerve. Brain Res 679, 249–54 (1995).PubMedCrossRefGoogle Scholar
  46. 46.
    Mamounas L.A., Altar C.A., Blue M.E., Kaplan D.R., Tessarollo L., Lyons W.E. BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain. J Neurosci 20, 771–82 (2000).PubMedGoogle Scholar
  47. 47.
    McTigue D.M., Homer P.J., Stokes B.T., Gage F.H. Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord. J Neurosci 18, 5354–65 (1998).PubMedGoogle Scholar
  48. 48.
    Neumann H., Misgeld T., Matsumuro K., Wekerle H. Neurotrophins inhibit major histocompatibility class II inducibility of microglia: involvement of the p75 neurotrophin receptor. Proc Natl Acad Sci USA 95, 5779–84 (1998).PubMedCrossRefGoogle Scholar
  49. 49.
    Compston A. Future prospects for the management of multiple sclerosis. Ann Neurol 36,S146–50 (1994).PubMedCrossRefGoogle Scholar
  50. 50.
    Sagot Y., Vejsada R., Kato A.C. Clinical and molecular aspects of motor-neuron diseases: Animal models, neurotrophic factors and Bcl-2 oncoprotein. Trends Pharmacol Sci 18, 330–7 (1997).PubMedGoogle Scholar
  51. 51.
    Kramer R., Zhang Y., Gehrmann J., Gold R., Thoenen H., Wekerle H. Gene transfer through the blood-nerve barrier: NGF-engineered neuritogenic T lymphocytes attenuate experimental autoimmune neuritis. Nat Med 1, 1162–6 (1995).PubMedCrossRefGoogle Scholar
  52. 52.
    Flügel A., Matsumuro K., Neumann H., Klinkert W.E., Birnbacher R., Lassmann H., Otten U., Wekerle H. Anti-inflammatory activity of nerve growth factor in experimental autoimmune encephalomyelitis: inhibition of monocyte transendothelial migration. Eur J Immunol 31, 11–22 (2001).PubMedCrossRefGoogle Scholar
  53. 53.
    Teitelbaum D., Arnon R., Sela M. Copolymer 1: from basic research to clinical application. Cell Mol Life Sci 53, 24–28 (1997).PubMedCrossRefGoogle Scholar
  54. 54.
    Arnon R., Sela M., Teitelbaum D. New insights into the mechanism of action of copolymer 1 in experimental allergic encephalomyelitis and multiple sclerosis. J Neurol 243 (Suppl 1),S8–13 (1996).PubMedCrossRefGoogle Scholar
  55. 55.
    Teitelbaum D., Webb C, Bree M., Meshorer A., Arnon R., Sela M. Suppression of experimental allergic encephalomyelitis in Rhesus monkeys by a synthetic basic copolymer. Clin Immunol Immunopathol 3, 256–62 (1974).PubMedCrossRefGoogle Scholar
  56. 56.
    Teitelbaum D., Webb C, Meshorer A., Arnon R., Sela M. Suppression by several synthetic polypeptides of experimental allergic encephalomyelitis induced in guinea pigs and rabbits with bovine and human basic encephalitogen. Eur J Immunol 3, 273–9 (1973).PubMedCrossRefGoogle Scholar
  57. 57.
    Teitelbaum D., Webb C, Meshorer A., Amon R., Sela M. Protection against experimental allergic encephalomyelitis. Nature 240, 564–6 (1974).CrossRefGoogle Scholar
  58. 58.
    Teitelbaum D., Meshorer A., Hirshfeld T., Arnon R., Sela M. Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide. Eur J Immunol 1, 242–8 (1971).PubMedCrossRefGoogle Scholar
  59. 59.
    Teitelbaum D., Sela M., Arnon R. Copolymer 1 from the laboratory to FDA. Isr J Med Sci 33, 280–4 (1997).PubMedGoogle Scholar
  60. 60.
    Abramsky O., Teitelbaum D., Arnon R. Effect of a synthetic polypeptide (COP 1) on patients with multiple sclerosis and with acute disseminated encephalomeylitis. Preliminary report. J Neurol Sci 31, 433–8 (1977).PubMedCrossRefGoogle Scholar
  61. 61.
    Bornstein M.B., Miller A.I., Slagle S., Arnon R., Sela M., Teitelbaum D. Clinical trials of copolymer I in multiple sclerosis. Ann N Y Acad Sci 436, 366–72 (1984).PubMedCrossRefGoogle Scholar
  62. 62.
    Bomstein M.B., Miller A.I., Teitelbaum D., Arnon R., Sela M. Multiple sclerosis: trial of a synthetic polypeptide. Ann Neurol 11, 317–9 (1982).CrossRefGoogle Scholar
  63. 63.
    Bornstein M.B., Miller A., Slagle S., Weitzman M., Drexler E., Keilson M. et al. A placebo-controlled, double-blind, randomized, two-center, pilot trial of Cop 1 in chronic progressive multiple sclerosis. Neurology 41, 533–539 (1999).CrossRefGoogle Scholar
  64. 64.
    Johnson K.P. A review of the clinical efficacy profile of copolymer 1: new U.S. phase III trial data. J Neurol 243(Suppl 1),S3–S7 (1996).PubMedCrossRefGoogle Scholar
  65. 65.
    Johnson K.P., Brooks B.R., Cohen J.A., Ford C.C., Goldstein J., Lisak R.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. Neurology 45, 1268–76 (1995).PubMedCrossRefGoogle Scholar
  66. 66.
    Neuhaus O., Farina C., Wekerle H., Hohlfeld R. Mechanisms of action of glatiramer acetate in multiple sclerosis. Neurology 56, 702–8 (2001).PubMedCrossRefGoogle Scholar
  67. 67.
    Brosnan C.F., Litwak M., Neighbour P.A., Lyman W.D., Carter T.H., Bornstein M.B. et al. Immunogenic potentials of copolymer I in normal human lymphocytes. Neurology 35, 1754–9 (1985).PubMedCrossRefGoogle Scholar
  68. 68.
    Qin Y., Zhang D.Q., Prat A., Pouly S., Antel J. Characterization of T cell lines derived from glatirameracetate-treated multiple sclerosis patients. J Neuroimmunol 108, 201–6 (2000).PubMedCrossRefGoogle Scholar
  69. 69.
    Burns J., Krasner L.J., Guerrero F. Human cellular immune response to copolymer I and myelin basic protein. Neurology 136, 92–4 (1986).CrossRefGoogle Scholar
  70. 70.
    Duda P.W., Schmied M.C., Cook S.L., Krieger J.I., Hafler D.A. Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J Clin Invest 105, 967–76 (2000).PubMedCrossRefGoogle Scholar
  71. 71.
    Farina C, Then Bergh F., Albrecht H., Meinl E., Yassouridis A., Neuhaus O., Hohlfeld R. Treatment of multiple sclerosis with Copaxone (COP): Elispot assay detects COP-induced interleukin-4 and interferon-gamma response in blood cells. Brain 124, 705–19 (2001).PubMedCrossRefGoogle Scholar
  72. 72.
    Duda P.W., Krieger J.I., Schmied M.C., Balentine C, Hafler D.A. Human and murine CD4 T cell reactivity to a complex antigen: recognition of the synthetic random polypeptide glatiramer acetate. J Immunol 165, 7300–7 (2000).PubMedGoogle Scholar
  73. 73.
    Brenner T., Arnon R., Sela M., Abramsky O., Meiner Z., Riven-Krietman R. et al. Humoral and cellular immune responses to Copolymer 1 in multiple sclerosis patients treated with Copaxone. J Neuroimmunol 115, 152–60 (2001).PubMedCrossRefGoogle Scholar
  74. 74.
    Ziemssen T., Neuhaus O., Farina C, Hartung H.P., Hohlfeld R. Treatment of multiple sclerosis with glatiramer acetate-new information about ist mechanisms of action, pharmacokinetics, adverse effects and clinical studies [German], Nervenarzt 73, 321–31 (2002).PubMedCrossRefGoogle Scholar
  75. 75.
    Fridkis-Hareli M., Strominger J.L. Promiscuous binding of synthetic copolymer 1 to purified HLA-DR molecules. J Immunol 160, 4386–97 (1998).PubMedGoogle Scholar
  76. 76.
    Ragheb S, Lisak R.P. The lymphocyte proliferative response to glatiramer acetate in normal humans is dependent on both major histocompatibility complex (MHC). J Neurol 247 (Suppl 3):111/119 [abstract] (2000).Google Scholar
  77. 77.
    Aharoni R., Teitelbaum D., Arnon R., Sela M. Copolymer 1 acts against the immunodominant epitope 82-100 of myelin basic protein by T cell receptor antagonism in addition to major histocompatibility complex blocking. Proc Natl Acad Sci USA 96, 634–9 (1999).PubMedCrossRefGoogle Scholar
  78. 78.
    Gran B., Tranquill L.R., Chen M., Bielekova B., Zhou W., Dhib-Jalbut S. et al. Mechanisms of immunomodulation by glatiramer acetate. Neurology 55, 1704–14 (2000).PubMedCrossRefGoogle Scholar
  79. 79.
    Nishimura Y., Chen Y.Z., Kanai T., Yokomizo H., Matsuoka T., Matsushita S. Modification of human T-cell responses by altered peptide ligands: a new approach to antigen-specific modification. Intern Med 37, 804–17 (1998).PubMedCrossRefGoogle Scholar
  80. 80.
    Teitelbaum D., Milo R., Arnon R., Sela M. Synthetic copolymer 1 inhibits human T-cell lines specific for myelin basic protein. Proc Natl Acad Sci USA 89, 137–41 (1992).PubMedCrossRefGoogle Scholar
  81. 81.
    Webb C, Teitelbaum D., Arnon R., Sela M. In vivo and in vitro immunological cross-reactions between basic encephalitogen and synthetic basic polypeptides capable of suppressing experimental allergic encephalomyelitis. Eur J Immunol 3, 279–86 (1973).PubMedCrossRefGoogle Scholar
  82. 82.
    Teitelbaum D., Aharoni R., Arnon R., Sela M. Specific inhibition of the T-cell response to myelin basic protein by the synthetic copolymer Cop 1. Proc Natl Acad Sci USA 85, 9724–8 (1988).PubMedCrossRefGoogle Scholar
  83. 83.
    Neuhaus O., Farina C, Yassouridis A., Wiendl H., Then Bergh F., Dose T. et al. Multiple sclerosis: comparison of copolymer-1-reactive T cell lines from treated and untreated subjects reveals cytokine shift from T helper 1 to T helper 2 cells. Proc Natl Acad Sci USA 97, 7452–7 (2000).PubMedCrossRefGoogle Scholar
  84. 84.
    Aharoni R., Teitelbaum D., Sela M., Arnon R. Bystander suppression of experimental autoimmune encephalomyelitis by T cell lines and clones of the Th2 type induced by copolymer 1. J Neuroimmunol 91, 135–46 (1998).PubMedCrossRefGoogle Scholar
  85. 85.
    Aharoni R., Teitelbaum D., Sela M, Arnon R. Copolymer 1 induces T cells of the T helper type 2 that crossreact with myelin basic protein and suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 94, 10821–6 (1997).PubMedCrossRefGoogle Scholar
  86. 86.
    Miller A., Shapiro S., Gershtein R., Kinarty A., Rawashdeh H., Honigman S. et al. Treatment of multiple sclerosis with copolymer-1 (Copaxone): implicating mechanisms of Thl to Th2/Th3 immune-deviation. J Neuroimmunol 92, 113–21 (1998).PubMedCrossRefGoogle Scholar
  87. 87.
    Dabbert D., Rosner S., Kramer M., Scholl U., Tumani H., Mader M. et al. Glatiramer acetate (copolymer-1)-specific, human T cell lines: cytokine profile and suppression of T cell lines reactive against myelin basic protein. Neurosci Lett 289, 205–8 (2000).PubMedCrossRefGoogle Scholar
  88. 88.
    Paul W.E., Seder R.A. Lymphocyte responses and cytokines. Cell 76, 241–51 (1994).PubMedCrossRefGoogle Scholar
  89. 89.
    Allen J.E., Maizels R.M. Thl-Th2: reliable paradigm or dangerous dogma? Immunol Today 18, 387–92 (1997).PubMedCrossRefGoogle Scholar
  90. 90.
    Mosmann T.R., Sad S. The- expanding universe of T-cell subsets: Thl, Th2 and more. Immunol Today 17, 138–46 (1996).PubMedCrossRefGoogle Scholar
  91. 91.
    Farina C, Wagenpfeil S., Hohlfeld R. Immunological assay for assessing the efficacy of glatiramer acetate (Copaxone) in MS. A pilot study. J Neurol 249, 1587–92 (2002).PubMedCrossRefGoogle Scholar
  92. 92.
    Chen M., Conway K., Johnson K.P., Martin R., Dhib-Jalbut S. Sustained immunological effects of Glatiramer acetate in patients with multiple sclerosis treated for over 6 years. J Neurol Sci 201, 71–7 (2002).PubMedCrossRefGoogle Scholar
  93. 93.
    Karandikar N.J., Crawford M.P., Yan X., Ratts R.B., Brenchley J.M., Ambrozak D.R., Lovett-Racke A.E., Frohman E.M., Stastny P., Douek D.C., Koup R.A., Racke M.K. Glatiramer acetate (Copaxone) therapy induces CD8(+) T cell responses in patients with multiple sclerosis. J Clin Invest 109, 641–9 (2002).PubMedGoogle Scholar
  94. 94.
    Ure D.R., Rodriguez M. Polyreactive antibodies to glatiramer acetate promote myelin repair in murine model of demyelinating disease. FASEB J 16, 1260–2 (2002).PubMedGoogle Scholar
  95. 95.
    Ziemssen T., Kümpfel T., Klinkert W.E., Neuhaus O., Hohlfeld R. Glatiramer acetate-specific T-helper 1-and 2-type cell lines produce BDNF: implications for multiple sclerosis therapy. Brain-derived neurotrophic factor. Brain 125, 2381–91 (2002).PubMedCrossRefGoogle Scholar
  96. 96.
    Aharoni R., Teitelbaum D., Leitner O., Meshorer A., Sela M., Arnon R. Specific Th2 cells accumulate in the central nervous system of mice protected against experimental autoimmune encephalomyelitis by copolymer 1. Proc Natl Acad Sci USA 97, 11472–7 (2000).PubMedCrossRefGoogle Scholar
  97. 97.
    Kipnis J., Yoles E., Porat Z., Cohen A., Mor F., Sela M., Schwartz M. T cell immunity to copolymer 1 confers neuroprotection on the damaged optic nerve: possible therapy for optic neuropathies. Proc Natl Acad Sci USA 97, 7446–51 (2000).PubMedCrossRefGoogle Scholar
  98. 98.
    Schori H., Kipnis J., Yoles E., WoldeMussie E., Ruiz G., Wheeler L.A., Schwartz M. Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: implications for glaucoma. Proc Natl Acad Sci USA 98, 3398–403 (2001).PubMedCrossRefGoogle Scholar
  99. 99.
    Offen D. et al. Treatment with glatiramer acetate induces neuroprotective effects in chronic MOG-induced EAE. J Neurol 249 Suppl. 1 [abstract] (2002)Bornstein M.B., Miller A., Slagle S., Weitzman M., Crystal H., Drexler E. et al. A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N Engl J Med 317, 408–14 (1987).CrossRefGoogle Scholar
  100. 101.
    Kurtzke J.F. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33, 1444–52 (1983).PubMedCrossRefGoogle Scholar
  101. 102.
    Johnson K.P., Brooks B.R., Cohen J.A., Ford C.C., Goldstein J., Lisak R.P. et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group. Neurology 50, 701–8 (1998).PubMedCrossRefGoogle Scholar
  102. 103.
    Johnson K.P., Brooks B.R., Ford C.C., Goodman A., Guarnaccia J., Lisak R.P. et al. Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Copolymer 1 Multiple Sclerosis Study Group. Mult Scler 6, 255–66 (2000).PubMedGoogle Scholar
  103. 104.
    Ge Y., Grossman R.I., Udupa J.K., Fulton J., Constantinescu C.S., Gonzales-Scarano F. et al. Glatiramer acetate (Copaxone) treatment in relapsing-remitting MS: quantitative MR assessment. Neurology 54, 813–7 (2000).PubMedCrossRefGoogle Scholar
  104. 105.
    Mancardi G.L., Sardanelli F., Parodi R.C., Melani E., Capello E., Inglese M. et al. Effect of copolymer-1 on serial gadolinium-enhanced MRI in relapsing remitting multiple sclerosis. Neurology 50, 1127–1133 (1998).PubMedCrossRefGoogle Scholar
  105. 106.
    Wolinsky J.S., Nurayana P.A., Johnson K.P., and the Copolymer 1 Multiple Sclerosis study group and the MRI Analysis Center. United States open-label glatiramer acetate extension trial for relapsing multiple sclerosis. Mult Scler 7, 33–41 (2001).PubMedGoogle Scholar
  106. 107.
    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, 290–7 (2001).PubMedCrossRefGoogle Scholar
  107. 108.
    Filippi M., Rovaris M., Rocca M.A., Sormani M.P., Wolinsky J.S., Comi G. European/Canadian Glatiramer Acetate Study Group. Glatiramer acetate reduces the proportion of new MS lesions evolving into “black holes”. Neurology 57, 731–3 (2001).PubMedCrossRefGoogle Scholar
  108. 109.
    Ziemssen T., Neuhaus O., Hohlfeld R. Risk-Benefit Assessment of Glatiramer Acetate in Multiple Sclerosis. Drug Safety 24, 979–90 (2001).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Tjalf Ziemssen
    • 1
    • 2
  1. 1.Department of NeuroimmunologyMax-Planck-Institute of NeurobiologyMartinsriedGermany
  2. 2.Neurological ClinicCarl Gustav Carus Universitiy ClinicDresdenGermany

Personalised recommendations