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. 2007 Oct;4(4):647–653. doi: 10.1016/j.nurt.2007.08.002

Mechanism of action of glatiramer acetate in treatment of multiple sclerosis

Martin S Weber 1, Reinhard Hohlfeld 2,3, Scott S Zamvil 1,✉
PMCID: PMC7479674  PMID: 17920545

Summary

Glatiramer acetate (GA) (Copolymer-1, Copaxone, Teva, Israel, YEAK) is a polypeptide-based therapy approved for the treatment of relapsing-remitting multiple sclerosis. Most investigations have attributed the immunomodulatory effect of GAs to its capability to alter T-cell differentiation. Specifically, GA treatment is believed to promote development of Th2-polarized GA-reactive CD4+ T-cells, which may dampen neighboring inflammation within the central nervous system. Recent reports indicate that the deficiency in CD4+CD25+FoxP3+ regulatory T-cells in multiple sclerosis is restored by GA treatment. GA also exerts immunomodulatory activity on antigen presenting cells, which participate in innate immune responses. These new findings represent a plausible explanation for GA-mediated T-cell immune modulation and may provide useful insight for the development of new and more effective treatment options for multiple sclerosis.

Key Words: Multiple sclerosis, glatiramer acetate, immunomodulatory agents, mechanism of action, antigen presenting cells

References

  • 1.Teitelbaum D, Meshorer A, Hirshfeld T, Amon R, Sela M. Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide. Eur J Immunol. 1971;1:242–248. doi: 10.1002/eji.1830010406. [DOI] [PubMed] [Google Scholar]
  • 2.Bomstein MB, Miller AI, Teitelbaum D, Amon R, Sela M. Multiple sclerosis: trial of a synthetic polypeptide. Ann Neurol. 1982;11:317–319. doi: 10.1002/ana.410110314. [DOI] [PubMed] [Google Scholar]
  • 3.Bomstein MB, Miller A, Slagle S, et al. A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N Engl J Med. 1987;317:408–414. doi: 10.1056/NEJM198708133170703. [DOI] [PubMed] [Google Scholar]
  • 4.Johnson KP, Brooks BR, Cohen JA, 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. Neurology. 1995;45:1268–1276. doi: 10.1212/wnl.45.7.1268. [DOI] [PubMed] [Google Scholar]
  • 5.Comi G, Filippi M, Wolinsky JS. 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. 2001;49:290–297. doi: 10.1002/ana.64. [DOI] [PubMed] [Google Scholar]
  • 6.Filippi M, Rovaris M, Rocca MA, Sormani MP, Wolinsky JS, Comi G. Glatiramer acetate reduces the proportion of new MS lesions evolving into “black holes.”. Neurology. 2001;57:731–733. doi: 10.1212/wnl.57.4.731. [DOI] [PubMed] [Google Scholar]
  • 7.Sormani MP, Bruzzi P, Comi G, Filippi M. The distribution of the magnetic resonance imaging response to glatiramer acetate in multiple sclerosis. Mult Scler. 2005;11:447–449. doi: 10.1191/1352458505ms1178oa. [DOI] [PubMed] [Google Scholar]
  • 8.Neuhaus O, Farina C, Wekerle H, Hohlfeld R. Mechanisms of action of glatiramer acetate in multiple sclerosis. Neurology. 2001;56:702–708. doi: 10.1212/wnl.56.6.702. [DOI] [PubMed] [Google Scholar]
  • 9.Farina C, Weber MS, Meinl E, Wekerle H, Hohlfeld R. Glatiramer acetate in multiple sclerosis: update on potential mechanisms of action. Lancet Neurol. 2005;4:567–575. doi: 10.1016/S1474-4422(05)70167-8. [DOI] [PubMed] [Google Scholar]
  • 10.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 U S A. 1994;91:4872–4876. doi: 10.1073/pnas.91.11.4872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Teitelbaum D, Fridkis-Hareli M, Amon R, Sela M. Copolymer 1 inhibits chronic relapsing experimental allergic encephalomyelitis induced by proteolipid protein (PLP) peptides in mice and inter-feres with PLP-specific T cell responses. J Neuroimmunol. 1996;64:209–217. doi: 10.1016/0165-5728(95)00180-8. [DOI] [PubMed] [Google Scholar]
  • 12.Neuhaus O, Farina C, Yassouridis A, 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 U S A. 2000;97:7452–7457. doi: 10.1073/pnas.97.13.7452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Dhib-Jalbut S. Mechanisms of action of interferons and glatiramer acetate in multiple sclerosis. Neurology. 2002;58(Suppl 4):S3–9. doi: 10.1212/wnl.58.8_suppl_4.s3. [DOI] [PubMed] [Google Scholar]
  • 14.Duda PW, Schmied MC, Cook SL, Krieger JI, Hafler DA. Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J Clin Invest. 2000;105:967–976. doi: 10.1172/JCI8970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.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 U S A. 2000;97:11472–11477. doi: 10.1073/pnas.97.21.11472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.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 U S A. 1997;94:10821–10826. doi: 10.1073/pnas.94.20.10821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Chen M, Gran B, Costello K, Johnson K, Martin R, Dhib-Jalbut S. Glatiramer acetate induces a Th2-biased response and cross reactivity with myelin basic protein in patients with MS. Mult Scler. 2001;7:209–219. doi: 10.1177/135245850100700401. [DOI] [PubMed] [Google Scholar]
  • 18.Ziemssen T, Kumpfel T, Klinkert WE, 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. 2002;125:2381–2391. doi: 10.1093/brain/awf252. [DOI] [PubMed] [Google Scholar]
  • 19.Weber MS, Starck M, Wagenpfeil S, Meinl E, Hohlfeld R, Farina C. Multiple sclerosis: glatiramer acetate inhibits monocyte reactivity in vitro and in vivo. Brain. 2004;127:1370–1378. doi: 10.1093/brain/awh163. [DOI] [PubMed] [Google Scholar]
  • 20.Kim HJ, Ifergan I, Antel JP, et al. Type 2 monocyte and microglia differentiation mediated by glatiramer acetate therapy in patients with multiple sclerosis. J Immunol. 2004;172:7144–7153. doi: 10.4049/jimmunol.172.11.7144. [DOI] [PubMed] [Google Scholar]
  • 21.Vieira PL, Heystek HC, Wormmeester J, Wierenga EA, Kapsenberg ML. Glatiramer acetate (copolymer-1, copaxone) promotes Th2 cell development and increased IL-10 production through modulation of dendritic cells. J Immunol. 2003;170:4483–4488. doi: 10.4049/jimmunol.170.9.4483. [DOI] [PubMed] [Google Scholar]
  • 22.Stasiolek M, Bayas A, Kruse N, et al. Impaired maturation and altered regulatory function of plasmacytoid dendritic cells in multiple sclerosis. Brain. 2006;129:1293–1305. doi: 10.1093/brain/awl043. [DOI] [PubMed] [Google Scholar]
  • 23.Stuve O, Youssef S, Weber MS, et al. Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity. J Clin Invest. 2006;116:1037–1044. doi: 10.1172/JCI25805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Fridkis-Hareli M, Strominger JL. Promiscuous binding of synthetic copolymer 1 to purified HLA-DR molecules. J Immunol. 1998;160:4386–4397. [PubMed] [Google Scholar]
  • 25.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 U S A. 1992;89:137–141. doi: 10.1073/pnas.89.1.137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Aharoni R, Schlegel PG, Teitelbaum D, et al. Studies on the mechanism and specificity of the effect of the synthetic random copolymer GLAT on graft-versus-host disease. Immunol Lett. 1997;58:79–87. doi: 10.1016/S0165-2478(97)00032-1. [DOI] [PubMed] [Google Scholar]
  • 27.Webb C, Teitelbaum D, Herz A, Amon R, Sela M. Molecular requirements involved in suppression of EAE by synthetic basic copolymers of amino acids. Immunochemistry. 1976;13:333–337. doi: 10.1016/0019-2791(76)90344-X. [DOI] [PubMed] [Google Scholar]
  • 28.Wiesemann E, Klatt J, Sonmez D, Blasczyk R, Heidenreich F, Windhagen A. Glatiramer acetate (GA) induces IL-13/IL-5 secretion in naive T cells. J Neuroimmunol. 2001;119:137–144. doi: 10.1016/S0165-5728(01)00379-4. [DOI] [PubMed] [Google Scholar]
  • 29.Farina C, Wagenpfeil S, Hohlfeld R. Immunological assay for assessing the efficacy of glatiramer acetate (Copaxone) in multiple sclerosis: a pilot study. J Neurol. 2002;249:1587–1592. doi: 10.1007/s00415-002-0904-0. [DOI] [PubMed] [Google Scholar]
  • 30.Lisak RP, Zweiman B, Blanchard N, Rorke LB. Effect of treatment with Copolymer 1 (Cop-1) on the in vivo and in vitro manifestations of experimental allergic encephalomyelitis (EAE) J Neurol Sci. 1983;62:281–293. doi: 10.1016/0022-510X(83)90205-8. [DOI] [PubMed] [Google Scholar]
  • 31.Aharoni R, Teitelbaum D, Sela M, Amon R. Bystander suppression of experimental autoimmune encephalomyelitis by T cell lines and clones of the Th2 type induced by copolymer 1. J Neuroimmunol. 1998;91:135–146. doi: 10.1016/S0165-5728(98)00166-0. [DOI] [PubMed] [Google Scholar]
  • 32.Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057–1061. doi: 10.1126/science.1079490. [DOI] [PubMed] [Google Scholar]
  • 33.Brunkow ME, Jeffery EW, Hjerrild KA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lympho-proliferative disorder of the scurfy mouse. Nat Genet. 2001;27:68–73. doi: 10.1038/83784. [DOI] [PubMed] [Google Scholar]
  • 34.Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4:330–336. doi: 10.1038/ni904. [DOI] [PubMed] [Google Scholar]
  • 35.Bacchetta R, Passerini L, Gambineri E, et al. Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J Clin Invest. 2006;116:1713–1722. doi: 10.1172/JCI25112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Sakaguchi S, Fukuma K, Kuribayashi K, Masuda T. Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J Exp Med. 1985;161:72–87. doi: 10.1084/jem.161.1.72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Kukreja A, Cost G, Marker J, et al. Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest. 2002;109:131–140. doi: 10.1172/JCI13605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004;199:971–979. doi: 10.1084/jem.20031579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Putheti P, Soderstrom M, Link H, Huang YM. Effect of glatiramer acetate (Copaxone) on CD4+CD25high T regulatory cells and their IL-10 production in multiple sclerosis. J Neuroimmunol. 2003;144:125–131. doi: 10.1016/j.jneuroim.2003.08.001. [DOI] [PubMed] [Google Scholar]
  • 40.Hong J, Li N, Zhang X, Zheng B, Zhang JZ. Induction of CD4+CD25+ regulatory T cells by copolymer-I through activation of transcription factor Foxp3. Proc Natl Acad Sci U S A. 2005;102:6449–6454. doi: 10.1073/pnas.0502187102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Karandikar NJ, Crawford MP, Yan X, et al. Glatiramer acetate (Copaxone) therapy induces CD8(+) T cell responses in patients with multiple sclerosis. J Clin Invest. 2002;109:641–649. doi: 10.1172/JCI14380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Farina C, Then Bergh F, Albrecht H, et al. Treatment of multiple sclerosis with Copaxone (COP): Elispot assay detects COP-induced interleukin-4 and interferon-gamma response in blood cells. Brain. 2001;124:705–719. doi: 10.1093/brain/124.4.705. [DOI] [PubMed] [Google Scholar]
  • 43.Tennakoon DK, Mehta RS, Ortega SB, Bhoj V, Racke MK, Karandikar NJ. Therapeutic induction of regulatory, cytotoxic CD8+ T cells in multiple sclerosis. J Immunol. 2006;176:7119–7129. doi: 10.4049/jimmunol.176.11.7119. [DOI] [PubMed] [Google Scholar]
  • 44.Biegler BW, Yan SX, Ortega SB, Tennakoon DK, Racke MK, Karandikar NJ. Glatiramer acetate (GA) therapy induces a focused, oligoclonal CD8+ T-cell repertoire in multiple sclerosis. J Neuroimmunol. 2006;180:159–171. doi: 10.1016/j.jneuroim.2006.07.015. [DOI] [PubMed] [Google Scholar]
  • 45.Teitelbaum D, Brenner T, Abramsky O, Aharoni R, Sela M, Arnon R. Antibodies to glatiramer acetate do not interfere with its biological functions and therapeutic efficacy. Mult Scler. 2003;9:592–599. doi: 10.1191/1352458503ms963oa. [DOI] [PubMed] [Google Scholar]
  • 46.Farina C, Vargas V, Heydari N, Kumpfel T, Meinl E, Hohlfeld R. Treatment with glatiramer acetate induces specific IgG4 antibodies in multiple sclerosis patients. J Neuroimmunol. 2002;123:188–192. doi: 10.1016/S0165-5728(01)00490-8. [DOI] [PubMed] [Google Scholar]
  • 47.Brenner T, Amon R, Sela M, et al. Humoral and cellular immune responses to Copolymer 1 in multiple sclerosis patients treated with Copaxone. J Neuroimmunol. 2001;115:152–160. doi: 10.1016/S0165-5728(01)00250-8. [DOI] [PubMed] [Google Scholar]
  • 48.Ure DR, Rodriguez M. Polyreactive antibodies to glatiramer acetate promote myelin repair in murine model of demyelinating disease. Faseb J. 2002;16:1260–1262. doi: 10.1096/fj.01-1023fje. [DOI] [PubMed] [Google Scholar]
  • 49.Li Q, Milo R, Panitch H, Swoveland P, Bever CT. Glatiramer acetate blocks the activation of THP-1 cells by interferon-gamma. Eur J Pharmacol. 1998;342:303–310. doi: 10.1016/S0014-2999(97)01509-4. [DOI] [PubMed] [Google Scholar]
  • 50.Hussien Y, Sanna A, Soderstrom M, Link H, Huang YM. Glatiramer acetate and IFN-beta act on dendritic cells in multiple sclerosis. J Neuroimmunol. 2001;121:102–110. doi: 10.1016/S0165-5728(01)00432-5. [DOI] [PubMed] [Google Scholar]
  • 51.Jung S, Siglienti I, Grauer O, Magnus T, Scarlato G, Toyka K. Induction of IL-10 in rat peritoneal macrophages and dendritic cells by glatiramer acetate. J Neuroimmunol. 2004;148:63–73. doi: 10.1016/j.jneuroim.2003.11.014. [DOI] [PubMed] [Google Scholar]
  • 52.Sanna A, Fois ML, Arru G, et al. Glatiramer acetate reduces lymphocyte proliferation and enhances IL-5 and IL-13 production through modulation of monocyte-derived dendritic cells in multiple sclerosis. Clin Exp Immunol. 2006;143:357–362. doi: 10.1111/j.1365-2249.2006.02997.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Weber MS, Prod’homme T, Youssef S, et al. Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat Med. 2007;13:935–943. doi: 10.1038/nm1620. [DOI] [PubMed] [Google Scholar]
  • 54.Allie R, Hu L, Mullen KM, Dhib-Jalbut S, Calabresi PA. Bystander modulation of chemokine receptor expression on peripheral blood T lymphocytes mediated by glatiramer therapy. Arch Neurol. 2005;62:889–894. doi: 10.1001/archneur.62.6.889. [DOI] [PubMed] [Google Scholar]
  • 55.Zhang M, Chan CC, Vistica B, Hung V, Wiggert B, Gery I. Copolymer 1 inhibits experimental autoimmune uveoretinitis. J Neuroimmunol. 2000;103:189–194. doi: 10.1016/S0165-5728(99)00239-8. [DOI] [PubMed] [Google Scholar]
  • 56.Gur C, Karussis D, Golden E, Doron S, Ilan Y, Safadi R. Amelioration of experimental colitis by Copaxone is associated with class-II-restricted CD4 immune blocking. Clin Immunol. 2006;118:307–316. doi: 10.1016/j.clim.2005.10.004. [DOI] [PubMed] [Google Scholar]
  • 57.Amon R, Aharoni R. Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications. Proc Natl Acad Sci U S A. 2004;101(Suppl 2):14593–14598. doi: 10.1073/pnas.0404887101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Aharoni R, Teitelbaum D, Amon R. T suppressor hybridomas and interleukin-2-dependent lines induced by copolymer 1 or by spinal cord homogenate down-regulate experimental allergic encephalomyelitis. Eur J Immunol. 1993;23:17–25. doi: 10.1002/eji.1830230105. [DOI] [PubMed] [Google Scholar]
  • 59.Kerschensteiner M, Stadelmann C, Dechant G, Wekerle H, Hohlfeld R. Neurotrophic cross-talk between the nervous and immune systems: implications for neurological diseases. Ann Neurol. 2003;53:292–304. doi: 10.1002/ana.10446. [DOI] [PubMed] [Google Scholar]
  • 60.Kerschensteiner M, Gallmeier E, Behrens L, et al. Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuro-protective role of inflammation? J Exp Med. 1999;189:865–870. doi: 10.1084/jem.189.5.865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Hickey WF, Hsu BL, Kimura H. T-lymphocyte entry into the central nervous system. J Neurosci Res. 1991;28:254–260. doi: 10.1002/jnr.490280213. [DOI] [PubMed] [Google Scholar]
  • 62.Aharoni R, Kayhan B, Eilam R, Sela M, Amon 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 U S A. 2003;100:14157–14162. doi: 10.1073/pnas.2336171100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Kipnis J, Yoles E, Porat Z, et al. T cell immunity to copolymer 1 confers neuroprotection on the damaged optic nerve: possible therapy for optic neuropathies. Proc Natl Acad Sci U S A. 2000;97:7446–7451. doi: 10.1073/pnas.97.13.7446. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Schori H, Kipnis J, Yoles E, et al. Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: implications for glaucoma. Proc Natl Acad Sci U S A. 2001;98:3398–3403. doi: 10.1073/pnas.041609498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Angelov DN, Waibel S, Guntinas-Lichius O, et al. Therapeutic vaccine for acute and chronic motor neuron diseases: implications for amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2003;100:4790–4795. doi: 10.1073/pnas.0530191100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Benner EJ, Mosley RL, Destache CJ, et al. Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson’s disease. Proc Natl Acad Sci U S A. 2004;101:9435–9440. doi: 10.1073/pnas.0400569101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Boska MD, Lewis TB, Destache CJ, et al. Quantitative 1H magnetic resonance spectroscopic imaging determines therapeutic immunization efficacy in an animal model of Parkinson’s disease. J Neurosci. 2005;25:1691–1700. doi: 10.1523/JNEUROSCI.4364-04.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]

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