ABSTRACT
Multiple sclerosis (MS) is considered to be primarily an inflammatory autoimmune disease. Over the last 5 years, our view of the pathogenesis of MS has evolved considerably. The axonal damage was recognized as an early event in the disease process and as an important determinant of long‐term disability. Therefore, the antiinflammatory and neuroprotective strategies are thought to represent promising approach to the therapy of MS. The therapeutic potential of glatiramer acetate (GA), a synthetic amino acid polymer composed of a mixture of l‐glutamic acid, l‐lysine, l‐alanine, and l‐tyrosine in defined proportions, in MS has been apparent for many years. GA has been shown to be effective in preventing and suppressing experimental allergic encephalomyelitis (EAE), the animal model of MS. GA has been, therefore, evaluated in several clinical studies and found to alter the natural history of relapsing‐remitting (RR)MS by reducing the relapse rate and affecting disability. These findings were confirmed in open‐label follow‐up trials covering more than 10 years of treatment. The trials demonstrated sustained efficacy for GA in slowing the progression of disability. The clinical therapeutic effect of GA is consistent with the results of magnetic resonance imaging (MRI) findings from various clinical centers. At a daily standard dose of 20 mg, s.c., GA was generally well tolerated. The induction of GA‐reactive T‐helper 2‐like regulatory suppressor cells is thought to be the main mechanism of the therapeutic action of this drug. In addition, it was recently shown that GA‐reactive T cells produce neurotrophic factors (e.g., brain‐derived neurotrophic factor [BDNF]) that protect neurons and axons in the area of injury.
Keywords: Antiinflammatory drugs, EAE, Experimental allergic encephalomyelitis, Glatiramer acetate, Multiple sclerosis, Neuroprotection
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Conflict of Interest: The authors have no conflicts of interest.
REFERENCES
- Aharoni R, Eilam R, Domey H, Labunskay G, Sela M, Arnon R (2005) The immunomodulator glatiramer acetate augments the expression of neurotrophic factors in brains of experimental allergic encephalomyelitis mice. Proc Natl Acad Sci USA 102:19045–19050. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Aharoni R, Kayhan B, Eilam R, Sela M, Arnon R (2003) Glatiramer acetate‐specific T cells in the brain express 2/3 cytokines and brain derived neurotrophic factor in situ. Proc Natl Acad Sci USA 100:14157–14162. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Aharoni R, Schlegel PG, Teitelbaum D, Roikhel‐Karpov O, Chen Y, Arnon R, Sela M, Chao NJ (1997a) Studies on the mechanism and specificity of the effect of the synthetic random copolymer GLAT on graft‐versus‐host disease. Immunol Lett 58:79–87. [DOI] [PubMed] [Google Scholar]
- Aharoni R, Teitelbaum D, Sela M, Arnon R (1997b) Copolymer 1 induces T cells of the T helper type 2 that cross‐react with myelin basic protein and suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 94:10821–10826. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Aharoni R, Teitelbaum D, Sela M, Arnon R (1998) Bystander suppression of experimental autoimmune encephalomyelitis by T cell lines and clones of the Th2 type induced by copolymer 1. J Neuroimmunol 91:135–146. [DOI] [PubMed] [Google Scholar]
- Aharoni R., Teitelbaum D, Arnon R, Sela M (1999) Copolymer 1 acts against the immunodominant epitome 82‐100 of myelin basic protein by T cell receptor antagonism in additino to major histocompatibility complex blocking. Proc Natl Acad Sci USA 96:634–639. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Aharoni R., Teitelbaum D, Leitner O, Meshorer A, Sela M, Arnon R (2000) Specific Th2 cells accumulate in the central nervous system of mice protected against experimental autoimmune encephalomyelitis by copolymer 1. Proc Natl Acad Sci USA 97:11472–11477. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Aktas O, Ari N, Rieks M, Hoffmann V, Schimrigk S, Przuntek H, Pohlau D (2001) Multiple sclerosis modulation of apoptosis susceptibility by glatiramer acetate. Acta Neurol Scand 104:266–270. [DOI] [PubMed] [Google Scholar]
- Ben‐Nun A, Mendel I, Bakimer R, Fridkis‐Hareli M, Teitelbaum D, Arnon R, Sela M, Kerlero de Rosbo N (1996) The autoimmune reactivity to myelin oligodendrocyte glycoprotein [MOG] in multiple sclerosis is potentially pathogenic: Effect of copolymer‐1 on MOG‐induced disease. J Neurol 243:S14–S22. [DOI] [PubMed] [Google Scholar]
- Boneschi FM, Rovaris M, Johnson KP (2003) Effects of glatiramer acetate on relapse rate and accumulated disability in multiple sclerosis: Meta‐analysis of three double‐blind, randomized, placebo‐controlled clinical trials. Mult Scler 9:349–355. [DOI] [PubMed] [Google Scholar]
- Bornstein MB, Miller A, Slagle S (1987) A pilot trial of Cop 1 in exacerbating‐remitting multiple sclerosis. N Engl J Med 317:408–414. [DOI] [PubMed] [Google Scholar]
- Brenner T, Arnon R, Sela M, Abramsky O, Meiner Z, River‐Kreitman R, Tarcik N, Teitelbaum D (2001) Humoral and cellular immune responses to copolymer 1 in multiple sclerosis patients treated with Copaxone. J Neuroimmunol 115:152–160. [DOI] [PubMed] [Google Scholar]
- Chen M, Dhib‐Jalbut S (2003) Glatiramer acetate (GA)‐reactive T‐cells produce brain‐derived neurotrophic factor (BDNF). J Neurol Sci 215:37–44. [DOI] [PubMed] [Google Scholar]
- Chen M, Gran B, Costello K, Johnson K, Martin R, Dhib‐Jalbut S (2001) Glatiramer acetate induces a Th2‐biased response and cross reactivity with myelin basic protein in patients with MS. MultScler 7:209–219. [DOI] [PubMed] [Google Scholar]
- Cohen J, Rovaris M, Goodman A, Filippi M; The MRI‐AC Study Group (2006) Results of a randomized, double‐blind, parallel‐group study assessing safety and efficacy of 40 mg versus 20 mg of glatiramer acetate on MRI‐measured disease activity in RRMS. Neurology 66:S61. [Google Scholar]
- Comi G, Filippi M, Wolinsky JS (2001) 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. Ann Neurol 49:290–297. [PubMed] [Google Scholar]
- Compston A, Coles A (2000) Multiple sclerosis. Lancet 359:1221–1231. [DOI] [PubMed] [Google Scholar]
- De Stefano N, Matthews PM, Fu L, Narayanan S, Stanley J, Francis GS, Antel JP, Arnold DL (1998) Axonal damage correlates with disability in patients with relapsing‐remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study. Brain 121:1469–1477. [DOI] [PubMed] [Google Scholar]
- Dhib‐Jalbut S (2002) Mechanisms of action of interferons and glatiramer acetate in multiple sclerosis. Neurology 58:S3–S9. [DOI] [PubMed] [Google Scholar]
- Dressel A, Vogelgesang A, Brinkmeier H, Mader M, Weber F (2006) Glatiramer acetate‐specific human CD8+ T cells: Increased IL‐4 production in multiple sclerosis is reduced by glatiramer acetate treatment. J Neuroimmunol 181:133–140. [DOI] [PubMed] [Google Scholar]
- Duda PW, Krieger JI, Schmied MC, Balentine C, Hafler DA (2000a) Human and murine CD4 T cell reactivity to a complex antigen: Recognition of the synthetic random polypeptide glatiramer acetate. J Immunol 165:7300–7307. [DOI] [PubMed] [Google Scholar]
- Duda PW, Schmied MC, Cook SL (2000b) Glatiramer acetate (Copaxone) induces degenerate, Th2‐polarized immune responses in patients with multiple sclerosis. J Clin Invest 105:967–976. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Farina C, Then Berg F, Albrecht H, Meinl E, Yassouridis A, Neuhaus O, Hohlfeld R (2001) Treatment of multiple sclerosis with Copaxone (COP): Elispot assay detects COP‐induced interleukin‐4 and interferon‐γ response in blood cells. Brain 124:705–719. [DOI] [PubMed] [Google Scholar]
- Filippi M, Wolinsky JS, Comi G; The CORAL Study Group (2006) Effect of oral glatiramer acetate on clinical and MRI‐monitored disease activity in patients with relapsing‐remitting multiple sclerosis: A multicentre, double‐blind, randomized, placebo‐controlled study. Lancet Neurol 5:213–220. [DOI] [PubMed] [Google Scholar]
- Ford CC, Johnson KP, Lisak RP, Panitch HS, Shifroni G, Wolinsky JS; The Copaxone Study Group (2006) A prospective open‐label study of glatiramer acetate: Over a decade of continuous use in multiple sclerosis patients. Mult Scler 12:309–320. [DOI] [PubMed] [Google Scholar]
- Fridkis‐Hareli M, Teitelbaum D, Pecht I, Arnon R, Sela M (1997). Binding of copolymer 1 and myelin basic protein leads to clustering of class II MHC molecules on antigen‐presenting cells. Int Immunol 9:925–934. [DOI] [PubMed] [Google Scholar]
- Gilgun‐Sherki Y, Panet H, Holdengrgber V, Mosberg‐Galili R, Offen D (2003) Axonal damage is reduced following glatiramer acetate treatment in C57/bl mice with chronic‐induced experimental autoimmune encephalomyelitis. Neurosci Res 47:201–207. [DOI] [PubMed] [Google Scholar]
- Gran B, Tranquill LR, Chen M, Bielekova B, Zhou W, Dhib‐Jalbut S, Martin R (2000) Mechanisms of immunomodulation by glatiramer acetate. Neurology 55:1704–1714. [DOI] [PubMed] [Google Scholar]
- Hafler DA (2002) Degeneracy, as opposed to specificity, in immunotherapy. J Clin Invest 109:581–584. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hohlfeld R (1999) Therapeutic strategies in multiple sclerosis: Immunotherapy. Philos Trans R Soc Lond B Biol Sci 354:1697–1710. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP (1998) Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Neurology 50:701–708. [DOI] [PubMed] [Google Scholar]
- Johnson KP, Brooks BR, Cohen JA (1995) Copolymer 1 reduces relapse rate and improves disability in relapsing‐remitting multiple sclerosis: Results of phase III multicenter, double blind, placebo‐controlled trial. Neurology 45:1268–1276. [DOI] [PubMed] [Google Scholar]
- Johnson KP, Brooks BR, Ford CC, Goodman A, Guarnaccia J, Lisak RP (2000) Sustained clinical benefits of glatiramer acetate in relapsing remitting multiple sclerosis patients observed for 6 years. Mult Scler 6:255–266. [DOI] [PubMed] [Google Scholar]
- Johnson KP, Brooks BR, Ford CC, Goodman A, Lisak RP, Meyers LW, Pruitt AA, Rizzo MA, Rose JW, Weiner LP, et al (2003) Glatiramer acetate (Copaxone): Comparison of continuous versus delayed therapy in a six‐year organized multiple sclerosis trial. Mult Scler 9:585–591. [DOI] [PubMed] [Google Scholar]
- Johnson KP, Ford CC, Lisak RP, Wolinsky JS (2005) Glatiramer acetate (Copaxone): Neurologic consequence of delaying glatiramer acetate therapy for multiple sclerosis: 8‐year data. Acta Neurol Scand 111:42–47. [DOI] [PubMed] [Google Scholar]
- Khan OA, Shen Y, Caon C (2005) Axonal metabolic recovery and potential neuroprotective effect of glatiramer acetate in relapsing‐remitting multiple sclerosis. Mult Scler 6:646–651. [DOI] [PubMed] [Google Scholar]
- Keith AB, Arnon R, Teitelbaum D, Caspary EA, Wisniewski HM (1979) The effect of Cop 1, a synthetic polypeptide on chronic relapsing experimental allergic encephalomyelitis in guinea pigs. J Neurol Sci 42:267–274. [DOI] [PubMed] [Google Scholar]
- Kipnis J, Yoles E, Porat Z, Cohen A, Mor F, Sela M, Cohen IR, Schwartz M (2000) T cell immunity to copolymer 1 confers neuroprotection on the damaged optic nerve: Possible therapy for optic neuropathies. Proc Natl Acad Sci USA 97:7446–7451. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lenardo MJ, Chan FK, Hornung F, McFarland HF, Siegel R, Wang J, Zheng L (1999) Mature T lymphocyte apoptosis. Immune regulation in a dynamic and unpredictable antigenic environment. Annu Rev Immunol 17:221–253. [DOI] [PubMed] [Google Scholar]
- Mancardi GL, Sardanelli F, Parodi RC, Melani E, Capello E, Inglese M (1998) Effect of copolymer‐1 on serial gadolinium enhanced MRI in relapsing remitting multiple sclerosis. Neurology 50:1127–1133. [DOI] [PubMed] [Google Scholar]
- Miller A, Shapiro S, Gershtein R, Kinarty A, Rawashdeh H, Honigman S, Lahat N (1998) Treatment of multiple sclerosis with copolymer‐1 (Copaxone): Implicating mechanisms of Th1 to Th2/Th3 immune‐deviation. J Neuroimmunol 92:113–121. [DOI] [PubMed] [Google Scholar]
- Milo R, Panitch H (1995) Additive effects of copolymer‐1 and interferon beta‐1b on the immune response to myelin basic protein. J Neuroimmunol 61:185–193. [DOI] [PubMed] [Google Scholar]
- Munari L, Lovati R, Boiko A (2004) Therapy with glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev (1): CD004678. Review. [DOI] [PubMed] [Google Scholar]
- Neuhaus O, Farina C, Yassouridis A, Wiendl H, Then Bergh F, Dose T, Wekerle H, Hohlfeld R (2000) Multiple sclerosis: Comparison of copolymer‐1 reactive T cell lines from treated and untreated subjects reveals cytokine shift from Th1 to Th2. Proc Natl Acad Sci USA 97:7452–7457. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG (2000) Multiple sclerosis. N Engl J Med 343:938–952. [DOI] [PubMed] [Google Scholar]
- Pender MP (1998) Genetically determined failure of activation‐induced apoptosis of autoreactive T cells as a cause of multiple sclerosis. Lancet 351:978–981. [DOI] [PubMed] [Google Scholar]
- Qin Y, Zhang DQ, Prat A, Pouly S, Antel J (2000) Characterization of T cell lines derived from glatiramer acetate‐treated multiple sclerosis patients. J Neuroimmunol 108:201–206. [DOI] [PubMed] [Google Scholar]
- Ramtahal J, Jacob A, Das K, Boggild M (2006) Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing‐remitting multiple sclerosis. J Neurol 253:1160–1164. [DOI] [PubMed] [Google Scholar]
- Rieks M, Hoffmann V, Aktas O, Juschka M, Spitzer I, Brune N, Schimrigk S, Przuntek H, Pohlau D (2003) Induction of apoptosis of CD4 +T cells by immunomodulatory therapy of multiple sclerosis with glatiramer acetate. Eur Neurol 50:200–206. [DOI] [PubMed] [Google Scholar]
- Ruggieri M, Avolio C, Scacco S, Pica C, Lia A, Zimatore GB, Papa S, Livrea P, Trojano M (2006) Glatiramer acetate induces pro‐apoptotic mechanisms involving Bcl‐2, Bax, and Cyt‐c in peripheral lymphocytes from multiple sclerosis patients. J Neurol 253:231–236. [DOI] [PubMed] [Google Scholar]
- Sela M, Teitelbaum D (2001) Glatiramer acetate in the treatment of multiple sclerosis. Expert Opin Pharmacother 2:1149–1165. [DOI] [PubMed] [Google Scholar]
- Sela M (1999) The concept of specific immune treatment against autoimmune diseases. Int Rev Immunol 18:201–216. [DOI] [PubMed] [Google Scholar]
- Sharief MK, Douglas M, Noori MA, Semra YK (2002) The expression of pro‐ and anti‐apoptosis Bcl‐2 family proteins in lymphocytes from patients with multiple sclerosis. J Neuroimmunol 125:155–162. [DOI] [PubMed] [Google Scholar]
- Sharief MK, Matthews H, Noori MA (2003) Expression ratios of the Bcl‐2 family proteins and disease activity in multiple sclerosis. J Neuroimmunol 134:158–165. [DOI] [PubMed] [Google Scholar]
- Stuve O, Youssef S, Weber MS, Nessler S, Von Budingen HC, Hemmer B, Prod'homme T, Sobel RA, Steinman L, Zamvil SS (2006) Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity. J Clin Invest 116:1037–1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Teitelbaum D, Arnon R, Sela M (1997) Copolymer‐1: From basic research to clinical application. Cell Mol Life Sci 53:24–28. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Teitelbaum, D , Fridkis‐Hareli M, Arnon R, Sela M (1996) Copolymer 1 inhibits chronic relapsing experimental allergic encephalomyelitis induced by proteolipid protein (PLP) peptides in mice and interferes with PLP‐specific T cell responses. J Neuroimmunol 64:209–217. [DOI] [PubMed] [Google Scholar]
- Teitelbaum, D , Meshorer A, Hirshfield T, Arnon R, Sela M (1971) Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide. Eur J Immunol 1:242–248. [DOI] [PubMed] [Google Scholar]
- Teitelbaum, D , Milo R, Arnon R, Sela M (1992) Synthetic copolymer 1 inhibits human T‐cell lines specific for myelin basic protein. Proc Natl Acad Sci USA 89 1:137–141. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Teitelbaum D, Webb C, Bree M, Meshorer A, Arnon R, Sela M (1974) Suppression of experimental allergic encephalomyelitis in Rhesus monkeys by a synthetic basic copolymer. Clin Immunol Immunopathol 3:256–262. [DOI] [PubMed] [Google Scholar]
- Ure DR, Rodriguez M (2002) Polyreactive antibodies to glatiramer acetate promote myelin repair in murine model of demyelinating disease. FASEB J 16:1260–1262. [DOI] [PubMed] [Google Scholar]
- Van Parijs L, Abbas AK (1998) Homeostasis and self‐tolerance in the immune system: Turning lymphocytes off. Science 280:243–248. [DOI] [PubMed] [Google Scholar]
- Vollmer T, Panitch HS, Freedman MS (2006) Short‐term induction with mitoxantrone preceding treatment with glatiramer acetate offers early and pronounced effects on MRI‐disease activity in patients with relapsing forms of multiple sclerosis. Mult Scler 12 (Suppl 1): S11–S12. [Google Scholar]
- Weber MS, Starck M, Wagenpfeil S, Meinl E, Hohlfeld R, Farina C (2004) Multiple sclerosis: Glatiramer acetate inhibits monocyte reactivity in vitro and in vivo. Brain 127:1370–1378. [DOI] [PubMed] [Google Scholar]
- Wolinsky JS, Narayana PA, O'connor P, Coyle PK, Ford C, Johnson K, Miller A, Pardo L, Kadosh S, Ladkani D (2007) Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double‐blind, placebo‐controlled trial. Ann Neurol 61:14–24. [DOI] [PubMed] [Google Scholar]
- Ziemssen T, Kumpfel T, Klinkert WE, Neuhaus O, Hohlfeld R (2002a) Glatiramer acetate‐specific T‐helper 1‐and 2‐type cell lines produce BDNF: Implications for multiple sclerosis therapy. Brain 125:2381–2391. [DOI] [PubMed] [Google Scholar]
- Ziemssen T, Kuempfel T, Klinkert W (2002b) Glatiramer acetate‐specific T cell lines produce brain‐derived neurotrophic factor (BDNF) after activation upon antigen challenge in vitro: A novel mechanism of action? Neurology 58(Suppl 3):A326. [Google Scholar]
- Ziemssen T, Neuhaus O, Hohlfeld R (2001) Risk‐benefit assessment of glatiramer acetate in multiple sclerosis. Drug Saf 24:979–990. [DOI] [PubMed] [Google Scholar]
- Zipp F (2000) Apoptosis in multiple sclerosis. Cell tissue Res 301:163–171. [DOI] [PubMed] [Google Scholar]
- Zipp F, Krammer PH, Weller M (1999) Immune dysregulation in multiple sclerosis: Role of the CD95/CD95 ligand system. Immunol Today 20:550–554. [DOI] [PubMed] [Google Scholar]