Glatiramer Acetate in Treatment of Multiple Sclerosis: A Toolbox of Random Co-Polymers for Targeting Inflammatory Mechanisms of both the Innate and Adaptive Immune System?
Multiple sclerosis is a disease of the central nervous system, resulting in the demyelination of neurons, causing mild to severe symptoms. Several anti-inflammatory treatments now play a significant role in ameliorating the disease. Glatiramer acetate (GA) is a formulation of random polypeptide copolymers for the treatment of relapsing-remitting MS by limiting the frequency of attacks. While evidence suggests the influence of GA on inflammatory responses, the targeted molecular mechanisms remain poorly understood. Here, we review the multiple pharmacological modes-of-actions of glatiramer acetate in treatment of multiple sclerosis. We discuss in particular a newly discovered interaction between the leukocyte-expressed integrin α Mβ 2 (also called Mac-1, complement receptor 3, or CD11b/CD18) and perspectives on the GA co-polymers as an influence on the function of the innate immune system.
References
[1]
Charcot, J. Histologie de la sclerose en plaques. Gaz. Hop 1868, 41, 554–555.
[2]
Kachuck, N.J. Sustained release oral fampridine in the treatment of multiple sclerosis. Expert Opin. Pharmacother 2009, 10, 2025–2035.
[3]
Compston, A.; Coles, A. Multiple sclerosis. Lancet 2008, 372, 1502–1517.
[4]
Sadovnick, A.D.; Ebers, G.C. Epidemiology of multiple sclerosis: A critical overview. Can. J. Neurol. Sci 1993, 20, 17–29.
[5]
Calabresi, P.A. Diagnosis and management of multiple sclerosis. Am. Family Phys 2004, 70, 1935–1944.
[6]
Rosati, G. The prevalence of multiple sclerosis in the world: An update. Neurol. Sci.: Off. J. Ital. Neurol. Soc. Ital. Soc. Clin. Neurophysiol 2001, 22, 117–139.
[7]
Stys, P.K.; Zamponi, G.W.; van Minnen, J.; Geurts, J.J. Will the real multiple sclerosis please stand up? Nat. Rev. Neurosci 2012, 13, 507–514.
[8]
Compston, A. Genetic epidemiology of multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 1997, 62, 553–561.
[9]
Ota, K.; Matsui, M.; Milford, E.L.; Mackin, G.A.; Weiner, H.L.; Hafler, D.A. T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature 1990, 346, 183–187.
[10]
Frohman, E.M.; Racke, M.K.; Raine, C.S. Multiple sclerosis—the plaque and its pathogenesis. N. Engl. J. Med 2006, 354, 942–955.
[11]
Ascherio, A.; Munger, K.L. Environmental risk factors for multiple sclerosis. Part I: The role of infection. Ann. Neurol 2007, 61, 288–299.
[12]
Ascherio, A.; Munger, K.L. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Ann. Neurol 2007, 61, 504–513.
Palacios, N.; Alonso, A.; Bronnum-Hansen, H.; Ascherio, A. Smoking and increased risk of multiple sclerosis: Parallel trends in the sex ratio reinforce the evidence. Ann. Epidemiol 2011, 21, 536–542.
[15]
Mohr, D.C.; Hart, S.L.; Julian, L.; Cox, D.; Pelletier, D. Association between stressful life events and exacerbation in multiple sclerosis: A meta-analysis. BMJ 2004, 328, doi:10.1136/bmj.38041.724421.55.
[16]
Harkiolaki, M.; Holmes, S.L.; Svendsen, P.; Gregersen, J.W.; Jensen, L.T.; McMahon, R.; Friese, M.A.; van Boxel, G.; Etzensperger, R.; Tzartos, J.S.; et al. T cell-mediated autoimmune disease due to low-affinity crossreactivity to common microbial peptides. Immunity 2009, 30, 348–357.
DeLorenze, G.N.; Munger, K.L.; Lennette, E.T.; Orentreich, N.; Vogelman, J.H.; Ascherio, A. Epstein-Barr virus and multiple sclerosis: Evidence of association from a prospective study with long-term follow-up. Arch. Neurol 2006, 63, 839–844.
[19]
Haahr, S.; Hollsberg, P. Multiple sclerosis is linked to Epstein-Barr virus infection. Rev. Med. Virol 2006, 16, 297–310.
[20]
Christensen, T. HERVs in neuropathogenesis. J. Neuroimmune Pharmacol 2010, 5, 326–335.
[21]
Sharma, P.; Azebi, S.; England, P.; Christensen, T.; Moller-Larsen, A.; Petersen, T.; Batsche, E.; Muchardt, C. Citrullination of Histone H3 Interferes with HP1-Mediated Transcriptional Repression. PLoS Genet 2012, 8, e1002934.
[22]
Harauz, G.; Ishiyama, N.; Hill, C.M.; Bates, I.R.; Libich, D.S.; Fares, C. Myelin basic protein-diverse conformational states of an intrinsically unstructured protein and its roles in myelin assembly and multiple sclerosis. Micron 2004, 35, 503–542.
[23]
Harauz, G.; Musse, A.A. A tale of two citrullines—structural and functional aspects of myelin basic protein deimination in health and disease. Neurochem. Res 2007, 32, 137–158.
[24]
Musse, A.A.; Harauz, G. Molecular “negativity” may underlie multiple sclerosis: Role of the myelin basic protein family in the pathogenesis of MS. Int. Rev. Neurobiol 2007, 79, 149–172.
[25]
Carrillo-Vico, A.; Leech, M.D.; Anderton, S.M. Contribution of myelin autoantigen citrullination to T cell autoaggression in the central nervous system. J. Immunol 2010, 184, 2839–2846.
[26]
Sawcer, S.; Hellenthal, G.; Pirinen, M.; Spencer, C.C.; Patsopoulos, N.A.; Moutsianas, L.; Dilthey, A.; Su, Z.; Freeman, C.; Hunt, S.E.; et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011, 476, 214–219.
[27]
Jersild, C.; Svejgaard, A.; Fog, T. HL-A antigens and multiple sclerosis. Lancet 1972, 1, 1240–1241.
[28]
Naito, S.; Namerow, N.; Mickey, M.R.; Terasaki, P.I. Multiple sclerosis: Association with HL-A3. Tissue Antigen 1972, 2, 1–4.
[29]
Ramagopalan, S.V.; Maugeri, N.J.; Handunnetthi, L.; Lincoln, M.R.; Orton, S.M.; Dyment, D.A.; Deluca, G.C.; Herrera, B.M.; Chao, M.J.; Sadovnick, A.D.; et al. Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet 2009, 5, e1000369.
[30]
Friese, M.A.; Jakobsen, K.B.; Friis, L.; Etzensperger, R.; Craner, M.J.; McMahon, R.M.; Jensen, L.T.; Huygelen, V.; Jones, E.Y.; Bell, J.I.; et al. Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis. Nat. Med 2008, 14, 1227–1235.
[31]
Madsen, L.S.; Andersson, E.C.; Jansson, L.; krogsgaard, M.; Andersen, C.B.; Engberg, J.; Strominger, J.L.; Svejgaard, A.; Hjorth, J.P.; Holmdahl, R.; et al. A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor. Nat. Genet 1999, 23, 343–347.
[32]
Lublin, F.D.; Reingold, S.C. 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 1996, 46, 907–911.
[33]
Miller, D.; Barkhof, F.; Montalban, X.; Thompson, A.; Filippi, M. Clinically isolated syndromes suggestive of multiple sclerosis, part 2: Non-conventional MRI, recovery processes, and management. Lancet Neurol 2005, 4, 341–348.
[34]
Miller, D.H. Biomarkers and surrogate outcomes in neurodegenerative disease: Lessons from multiple sclerosis. NeuroRx 2004, 1, 284–294.
[35]
Flachenecker, P.; Hartung, H.P. Course of illness and prognosis of multiple sclerosis. 1: The natural illness course. Nervenarzt 1996, 67, 435–443.
[36]
Moura, A.L.; Teixeira, R.A.; Oiwa, N.N.; Costa, M.F.; Feitosa-Santana, C.; Callegaro, D.; Hamer, R.D.; Ventura, D.F. Chromatic discrimination losses in multiple sclerosis patients with and without optic neuritis using the Cambridge Colour Test. Vis. Neurosci 2008, 25, 463–468.
[37]
Patterson, V.H.; Heron, J.R. Visual field abnormalities in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 1980, 43, 205–209.
[38]
Leray, E.; Yaouanq, J.; le Page, E.; Coustans, M.; Laplaud, D.; Oger, J.; Edan, G. Evidence for a two-stage disability progression in multiple sclerosis. Brain 2010, 133, 1900–1913.
[39]
Bronnum-Hansen, H.; Koch-Henriksen, N.; Stenager, E. Trends in survival and cause of death in Danish patients with multiple sclerosis. Brain 2004, 127, 844–850.
[40]
Weinshenker, B.G. Natural history of multiple sclerosis. Ann. Neurol 1994, 36, S6–S11.
[41]
Beiske, A.G.; Pedersen, E.D.; Czujko, B.; Myhr, K.M. Pain and sensory complaints in multiple sclerosis. Eur. J. Neurol 2004, 11, 479–482.
[42]
Feinstein, A. Multiple sclerosis and depression. Mult. Scler 2011, 17, 1276–1281.
[43]
Andersson, M.; Alvarez-Cermeno, J.; Bernardi, G.; Cogato, I.; Fredman, P.; Frederiksen, J.; Fredrikson, S.; Gallo, P.; Grimaldi, L.M.; Gronning, M.; et al. Cerebrospinal fluid in the diagnosis of multiple sclerosis: A consensus report. J. Neurol. Neurosurg. Psychiatry 1994, 57, 897–902.
[44]
Polman, C.H.; Reingold, S.C.; Edan, G.; Filippi, M.; Hartung, H.P.; Kappos, L.; Lublin, F.D.; Metz, L.M.; McFarland, H.F.; O’Connor, P.W.; et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann. Neurol 2005, 58, 840–846.
[45]
McDonald, W.I.; Compston, A.; Edan, G.; Goodkin, D.; Hartung, H.P.; Lublin, F.D.; McFarland, H.F.; Paty, D.W.; Polman, C.H.; Reingold, S.C.; et al. Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann. Neurol 2001, 50, 121–127.
[46]
Whiting, P.; Harbord, R.; Main, C.; Deeks, J.J.; Filippini, G.; Egger, M.; Sterne, J.A. Accuracy of magnetic resonance imaging for the diagnosis of multiple sclerosis: systematic review. BMJ 2006, 332, 875–884.
[47]
Miller, D.M.; Weinstock-Guttman, B.; Bethoux, F.; Lee, J.C.; Beck, G.; Block, V.; Durelli, L.; LaMantia, L.; Barnes, D.; Sellebjerg, F.; et al. A meta-analysis of methylprednisolone in recovery from multiple sclerosis exacerbations. Mult. Scler 2000, 6, 267–273.
[48]
Martinelli Boneschi, F.; Rovaris, M.; Capra, R.; Comi, G. Mitoxantrone for multiple sclerosis. Cochrane Database Syst. Rev. 2005, doi:10.1002/14651858.CD002127.pub2.
[49]
Swinburn, W.R.; Liversedge, L.A. Long-term treatment of multiple sclerosis with azathioprine. J. Neurol. Neurosurg. Psychiatry 1973, 36, 124–126.
[50]
Casetta, I.; Iuliano, G.; Filippini, G. Azathioprine for multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 2009, 80, 131–132.
Goodkin, D.E.; Rudick, R.A.; VanderBrug Medendorp, S.; Greene, T.; Schwetz, K.M.; Fischer, J.; Daughtry, M.M.; Ross, J.; Van Dyke, C. Low-dose (7.5 mg) oral methotrexate for chronic progressive multiple sclerosis. Design of a randomized, placebo-controlled trial with sample size benefits from a composite outcome variable including preliminary data on toxicity. Online J. Curr. Clin. Trials 1992, 19. 1343611
[53]
Weitz-Schmidt, G.; Welzenbach, K.; Brinkmann, V.; Kamata, T.; Kallen, J.; Bruns, C.; Cottens, S.; Takada, Y.; Hommel, U. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat. Med 2001, 7, 687–692.
[54]
Kallen, J.; Welzenbach, K.; Ramage, P.; Geyl, D.; Kriwacki, R.; Legge, G.; Cottens, S.; Weitz-Schmidt, G.; Hommel, U. Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a I-domain. J. Mol. Biol 1999, 292, 1–9.
[55]
Katznelson, S.; Kobashigawa, J.A. Dual roles of HMG-CoA reductase inhibitors in solid organ transplantation: lipid lowering and immunosuppression. Kidney Int. Suppl 1995, 52, S112–S115.
[56]
Wang, J.; Xiao, Y.; Luo, M.; Luo, H. Statins for multiple sclerosis. Cochrane Database Syst. Rev. 2011, 12, CD008386.
[57]
Cortese, I.; Chaudhry, V.; So, Y.T.; Cantor, F.; Cornblath, D.R.; Rae-Grant, A. Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2011, 76, 294–300.
[58]
Achiron, A.; Kishner, I.; Sarova-Pinhas, I.; Raz, H.; Faibel, M.; Stern, Y.; Lavie, M.; Gurevich, M.; Dolev, M.; Magalashvili, D.; et al. Intravenous immunoglobulin treatment following the first demyelinating event suggestive of multiple sclerosis: A randomized, double-blind, placebo-controlled trial. Arch. Neurol 2004, 61, 1515–1520.
[59]
Bohn, A.B.; Nederby, L.; Harbo, T.; Skovbo, A.; Vorup-Jensen, T.; Krog, J.; Jakobsen, J.; Hokland, M.E. The effect of IgG levels on the number of natural killer cells and their Fc receptors in chronic inflammatory demyelinating polyradiculoneuropathy. Eur. J. Neurol 2011, 18, 919–924.
[60]
Kappos, L. European Study Group on interferon beta-1b in secondary progressive MS. Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. Lancet 1998, 352, 1491–1497.
[61]
Jacobs, L.D.; Beck, R.W.; Simon, J.H.; Kinkel, R.P.; Brownscheidle, C.M.; Murray, T.J.; Simonian, N.A.; Slasor, P.J.; Sandrock, A.W. CHAMPS Study Group. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N. Engl. J. Med. 2000, 343, 898–904.
[62]
Comi, G.; Filippi, M.; Barkhof, F.; Durelli, L.; Edan, G.; Fernandez, O.; Hartung, H.; Seeldrayers, P.; Sorensen, P.S.; Rovaris, M.; et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: A randomised study. Lancet 2001, 357, 1576–1582.
[63]
Yednock, T.A.; Cannon, C.; Fritz, L.C.; Sanchez-Madrid, F.; Steinman, L.; Karin, N. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 1992, 356, 63–66.
[64]
Steinman, L.; Zamvil, S.S. Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis. Trends Immunol 2005, 26, 565–571.
[65]
Polman, C.H.; O’Connor, P.W.; Havrdova, E.; Hutchinson, M.; Kappos, L.; Miller, D.H.; Phillips, J.T.; Lublin, F.D.; Giovannoni, G.; Wajgt, A.; et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med 2006, 354, 899–910.
[66]
Miller, D.H.; Soon, D.; Fernando, K.T.; MacManus, D.G.; Barker, G.J.; Yousry, T.A.; Fisher, E.; O’Connor, P.W.; Phillips, J.T.; Polman, C.H.; et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology 2007, 68, 1390–1401.
[67]
Sorensen, P.S.; Ross, C.; Clemmesen, K.M.; Bendtzen, K.; Frederiksen, J.L.; Jensen, K.; Kristensen, O.; Petersen, T.; Rasmussen, S.; Ravnborg, M.; et al. Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis. Lancet 2003, 362, 1184–1191.
[68]
Calabresi, P.A.; Giovannoni, G.; Confavreux, C.; Galetta, S.L.; Havrdova, E.; Hutchinson, M.; Kappos, L.; Miller, D.H.; O’Connor, P.W.; Phillips, J.T.; et al. The incidence and significance of anti-natalizumab antibodies: Results from AFFIRM and SENTINEL. Neurology 2007, 69, 1391–1403.
[69]
Bloomgren, G.; Richman, S.; Hotermans, C.; Subramanyam, M.; Goelz, S.; Natarajan, A.; Lee, S.; Plavina, T.; Scanlon, J.V.; Sandrock, A.; et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N. Engl. J. Med 2012, 366, 1870–1880.
[70]
Tavazzi, E.; Ferrante, P.; Khalili, K. Progressive multifocal leukoencephalopathy: An unexpected complication of modern therapeutic monoclonal antibody therapies. Clin. Microbiol. Infect 2011, 17, 1776–1780.
[71]
Vorup-Jensen, T. On the roles of polyvalent binding in immune recognition: Perspectives in the nanoscience of immunology and the immune response to nanomedicines. Adv. Drug Deliv. Rev. 2012. in press.
[72]
Krumbholz, M.; Derfuss, T.; Hohlfeld, R.; Meinl, E. B cells and antibodies in multiple sclerosis pathogenesis and therapy. Nat. Rev. Neurol. 2012, doi:10.1038/nrneurol.2012.203.
[73]
Bornstein, M.B.; Miller, A.; Slagle, S.; Weitzman, M.; Crystal, H.; Drexler, E.; Keilson, M.; Merriam, A.; Wassertheil-Smoller, S.; Spada, V.; et al. A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N. Engl. J. Med 1987, 317, 408–414.
[74]
Miller, A.; Spada, V.; Beerkircher, D.; Kreitman, R.R. Long-term (up to 22 years), open-label, compassionate-use study of glatiramer acetate in relapsing-remitting multiple sclerosis. Mult. Scler 2008, 14, 494–499.
[75]
Ford, C.; Goodman, A.D.; Johnson, K.; Kachuck, N.; Lindsey, J.W.; Lisak, R.; Luzzio, C.; Myers, L.; Panitch, H.; Preiningerova, J.; 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 2010, 16, 342–350.
[76]
Ford, C.C.; Johnson, K.P.; Lisak, R.P.; Panitch, H.S.; Shifronis, G.; Wolinsky, J.S. A prospective open-label study of glatiramer acetate: Over a decade of continuous use in multiple sclerosis patients. Mult. Scler 2006, 12, 309–320.
[77]
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 2001, 49, 290–297.
[78]
Johnson, K.P.; Brooks, B.R.; Cohen, J.A.; Ford, C.C.; Goldstein, J.; Lisak, R.P.; Myers, L.W.; Panitch, H.S.; Rose, J.W.; Schiffer, R.B. The Copolymer 1 Multiple Sclerosis Study Group. 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.
[79]
Martinelli Boneschi, F.; Rovaris, M.; Johnson, K.P.; Miller, A.; Wolinsky, J.S.; Ladkani, D.; Shifroni, G.; Comi, G.; Filippi, M. 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 2003, 9, 349–355.
[80]
La Mantia, L.; Munari, L.M.; Lovati, R. Glatiramer acetate for multiple sclerosis. Cochrane Database Syst. Rev. 2010, doi:10.1002/14651858.CD004678.pub2.
[81]
Korczyn, A.D.; Nisipeanu, P. Safety profile of copolymer 1: Analysis of cumulative experience in the United States and Israel. J. Neurol 1996, 243, S23–S26.
[82]
Copaxone 20mg/mL, Solution For Injection, Pre-Filled Syringe, Available online: http://www.medicines.org.uk/emc/medicine/17516/SPC , accessed on 5 November 2012.
[83]
Johnson, K.P.; Brooks, B.R.; Ford, C.C.; Goodman, A.; Guarnaccia, J.; Lisak, R.P.; Myers, L.W.; Panitch, H.S.; Pruitt, A.; Rose, J.W.; 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 2000, 6, 255–266.
Katchalski, E.; Grossfeld, I.; Frankel, M. Poly-lysine. J. Am. Chem. Soc 1947, 69, 2564.
[91]
Katchalski, E.; Sela, M. Synthesis and chemical properties of poly-alpha-amino acids. Adv. Protein Chem 1958, 13, 243–492.
[92]
Pauling, L.; Corey, R.B.; Branson, H.R. The structure of proteins; two hydrogen-bonded helical configurations of the polypeptide chain. Proc. Natl. Acad. Sci. USA 1951, 37, 205–211.
[93]
Perutz, M.F. New X-ray evidence on the configuration of polypeptide chains. Nature 1951, 167, 1053–1054.
[94]
Rich, A.; Crick, F.H. The structure of collagen. Nature 1955, 176, 915–916.
[95]
Engel, J.; Kurtz, J.; Katchalski, E.; Berger, A. Polymers tripeptides as collagen models. II. Conformational changes of poly(l-prolyl-glycyl-l-prolyl) in solution. J. Mol. Biol 1966, 17, 255–272.
[96]
Levin, Y.; Berger, A.; Katchalski, E. Hydrolysis and transpeptidation of lysine peptides by trypsin. Biochem. J 1956, 63, 308–316.
[97]
Arnon, R.; Sela, M. Studies on the chemical basis of the antigenicity of proteins. 2. Antigenic specificity of polytyrosyl gelatins. Biochem. J 1960, 75, 103–109.
[98]
Sela, M.; Arnon, R. Studies on the chemical basis of the antigenicity of proteins. 1. Antigenicity of polypeptidyl gelatins. Biochem. J 1960, 75, 91–102.
[99]
Sela, M.; Arnon, R. Studies on the chemical basis of the antigenicity of proteins. 3. The role of rigidity in the antigenicity of polypeptidyl gelatins. Biochem. J 1960, 77, 394–399.
[100]
Arnon, R.; Maron, E.; Sela, M.; Anfinsen, C.B. Antibodies reactive with native lysozyme elicited by a completely synthetic antigen. Proc. Natl. Acad. Sci. USA 1971, 68, 1450–1455.
[101]
Shaw, C.M.; Alvord, E.C., Jr; Fahlberg, W.J.; Kies, M.W. Specificity of encephalitogen-induced inhibition of experimental “allergic” encephalomyelitis in the guinea pig. J. Immunol. 1962, 89, 54–61.
[102]
Teitelbaum, D.; Meshorer, A.; Hirshfeld, T.; Arnon, R.; Sela, M. Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide. Eur. J. Immunol 1971, 1, 242–248.
[103]
Teitelbaum, D.; Gan, R.; Meshorer, A.; Hirsfeld, T.; Arnon, R.; Sela, M. Therapeutic Copolymer. U.S. Patent 3,849,550, March 1971.
[104]
Katchalski-Katzir, E. Synthesis, physicochemical and biological properties of poly-alpha-amino acids--the simplest of protein models. Acta Biochim. Polon 1996, 43, 217–226.
[105]
Fridkis-Hareli, M.; Santambrogio, L.; Stern, J.N.; Fugger, L.; Brosnan, C.; Strominger, J.L. Novel synthetic amino acid copolymers that inhibit autoantigen-specific T cell responses and suppress experimental autoimmune encephalomyelitis. J. Clin. Invest 2002, 109, 1635–1643.
Berkowitz, S.A.; Engen, J.R.; Mazzeo, J.R.; Jones, G.B. Analytical tools for characterizing biopharmaceuticals and the implications for biosimilars. Nat. Rev. Drug Discov 2012, 11, 527–540.
[109]
Guerrini, M.; Beccati, D.; Shriver, Z.; Naggi, A.; Viswanathan, K.; Bisio, A.; Capila, I.; Lansing, J.C.; Guglieri, S.; Fraser, B.; et al. Oversulfated chondroitin sulfate is a contaminant in heparin associated with adverse clinical events. Nat. Biotechnol 2008, 26, 669–675.
[110]
Kishimoto, T.K.; Viswanathan, K.; Ganguly, T.; Elankumaran, S.; Smith, S.; Pelzer, K.; Lansing, J.C.; Sriranganathan, N.; Zhao, G.; Galcheva-Gargova, Z.; et al. Contaminated heparin associated with adverse clinical events and activation of the contact system. N. Engl. J. Med 2008, 358, 2457–2467.
[111]
Liu, H.; Zhang, Z.; Linhardt, R.J. Lessons learned from the contamination of heparin. Nat. Prod. Rep 2009, 26, 313–321.
[112]
Fridkis-Hareli, M.; Stern, J.N.; Fugger, L.; Strominger, J.L. Synthetic peptides that inhibit binding of the myelin basic protein 85–99 epitope to multiple sclerosis-associated HLA-DR2 molecules and MBP-specific T-cell responses. Human Immunol 2001, 62, 753–763.
[113]
Teitelbaum, D.; Aharoni, R.; Sela, M.; Arnon, R. Cross-reactions and specificities of monoclonal antibodies against myelin basic protein and against the synthetic copolymer 1. Proc. Natl. Acad. Sci. USA 1991, 88, 9528–9532.
[114]
Fridkis-Hareli, M.; Strominger, J.L. Promiscuous binding of synthetic copolymer 1 to purified HLA-DR molecules. J. Immunol 1998, 160, 4386–4397.
[115]
Fridkis-Hareli, M.; Aharoni, R.; Teitelbaum, D.; Arnon, R.; Sela, M.; Strominger, J.L. Binding of random copolymers of three amino acids to class II MHC molecules. Int. Immunol 1999, 11, 635–641.
[116]
Teitelbaum, D.; Fridkis-Hareli, M.; Arnon, R.; Sela, M. 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 1996, 64, 209–217.
[117]
Ben-Nun, A.; Mendel, I.; Bakimer, R.; Fridkis-Hareli, M.; Teitelbaum, D.; Arnon, R.; Sela, M.; de Rosbo, N.K. The autoimmune reactivity to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis is potentially pathogenic: effect of copolymer 1 on MOG-induced disease. J. Neurol 1996, 243, S14–S22.
[118]
Ibarra, A.; Avendano, H.; Cruz, Y. Copolymer-1 (Cop-1) improves neurological recovery after middle cerebral artery occlusion in rats. Neurosci. Lett 2007, 425, 110–113.
[119]
Aharoni, R.; Teitelbaum, D.; Arnon, R.; Sela, M. Copolymer 1 inhibits manifestations of graft rejection. Transplantation 2001, 72, 598–605.
[120]
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 2000, 105, 967–976.
[121]
Berthelot, L.; Miqueu, P.; Pettre, S.; Guillet, M.; Moynard, J.; Wiertlewski, S.; Lefrere, F.; Brouard, S.; Soulillou, J.P.; Laplaud, D.A. Failure of glatiramer acetate to modify the peripheral T cell repertoire of relapsing-remitting multiple sclerosis patients. Clin. Immunol 2010, 135, 33–42.
[122]
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 1997, 94, 10821–10826.
[123]
Kala, M.; Rhodes, S.N.; Piao, W.H.; Shi, F.D.; Campagnolo, D.I.; Vollmer, T.L. B cells from glatiramer acetate-treated mice suppress experimental autoimmune encephalomyelitis. Exp. Neurol 2010, 221, 136–145.
[124]
Racke, M.K.; Lovett-Racke, A.E. Glatiramer acetate treatment of multiple sclerosis: an immunological perspective. J. Immunol 2011, 186, 1887–1890.
[125]
Neuhaus, O.; Farina, C.; Yassouridis, A.; Wiendl, H.; Then Bergh, F.; Dose, T.; Wekerle, H.; Hohlfeld, R. 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 2000, 97, 7452–7457.
[126]
Krogsgaard, M.; Wucherpfennig, K.W.; Cannella, B.; Hansen, B.E.; Svejgaard, A.; Pyrdol, J.; Ditzel, H.; Raine, C.; Engberg, J.; Fugger, L. Visualization of myelin basic protein (MBP) T cell epitopes in multiple sclerosis lesions using a monoclonal antibody specific for the human histocompatibility leukocyte antigen (HLA)-DR2-MBP 85–99 complex. J. Exp. Med 2000, 191, 1395–1412.
[127]
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 1998, 91, 135–146.
[128]
Jee, Y.; Liu, R.; Bai, X.F.; Campagnolo, D.I.; Shi, F.D.; Vollmer, T.L. Do Th2 cells mediate the effects of glatiramer acetate in experimental autoimmune encephalomyelitis? Int. Immunol 2006, 18, 537–544.
[129]
Kipnis, J.; Yoles, E.; Porat, Z.; Cohen, A.; Mor, F.; Sela, M.; Cohen, I.R.; 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 2000, 97, 7446–7451.
[130]
Stapulionis, R.; Oliveira, C.L.P.; Gjelstrup, M.C.; Pedersen, J.S.; Hokland, M.E.; Hoffmann, S.V.; Poulsen, K.; Jacobsen, C.; Vorup-Jensen, T. Structural insight into the function of myelin basic protein as a ligand for integrin alpha(M)beta(2). J. Immunol 2008, 180, 3946–3956.
Gjelstrup, L.C.; Boesen, T.; Kragstrup, T.W.; Jorgensen, A.; Klein, N.J.; Thiel, S.; Deleuran, B.W.; Vorup-Jensen, T. Shedding of large functionally active CD11/CD18 Integrin complexes from leukocyte membranes during synovial inflammation distinguishes three types of arthritis through differential epitope exposure. J. Immunol 2010, 185, 4154–4168.
[138]
Vorup-Jensen, T.; Carman, C.V.; Shimaoka, M.; Schuck, P.; Svitel, J.; Springer, T.A. Exposure of acidic residues as a danger signal for recognition of fibrinogen and other macromolecules by integrin alphaXbeta2. Proc. Natl. Acad. Sci. USA 2005, 102, 1614–1619.
[139]
Vorup-Jensen, T.; Chi, L.; Gjelstrup, L.C.; Jensen, U.B.; Jewett, C.A.; Xie, C.; Shimaoka, M.; Linhardt, R.J.; Springer, T.A. Binding between the integrin alphaXbeta2 (CD11c/CD18) and heparin. J. Biol. Chem 2007, 282, 30869–30877.
[140]
Davis, G.E. The Mac-1 and p150,95 beta 2 integrins bind denatured proteins to mediate leukocyte cell-substrate adhesion. Exp. Cell. Res 1992, 200, 242–252.
[141]
Whitaker, J.N. Myelin basic protein in cerebrospinal fluid and other body fluids. Mult. Scler 1998, 4, 16–21.
[142]
Constantinescu, R.; Zetterberg, H.; Holmberg, B.; Rosengren, L. Levels of brain related proteins in cerebrospinal fluid: an aid in the differential diagnosis of parkinsonian disorders. Parkinsonism Relat. Disord 2009, 15, 205–212.
[143]
Prineas, J.W.; Graham, J.S. Multiple sclerosis: Capping of surface immunoglobulin G on macrophages engaged in myelin breakdown. Ann. Neurol 1981, 10, 149–158.
[144]
Epstein, L.G.; Prineas, J.W.; Raine, C.S. Attachment of myelin to coated pits on macrophages in experimental allergic encephalomyelitis. J. Neurol. Sci 1983, 61, 341–348.
[145]
Nielsen, H.H.; Ladeby, R.; Fenger, C.; Toft-Hansen, H.; Babcock, A.A.; Owens, T.; Finsen, B. Enhanced microglial clearance of myelin debris in T cell-infiltrated central nervous system. J. Neuropathol. Exp. Neurol 2009, 68, 845–856.
[146]
Ransohoff, R.M.; Kivisakk, P.; Kidd, G. Three or more routes for leukocyte migration into the central nervous system. Nat. Rev. Immunol 2003, 3, 569–581.
[147]
Lobel, E.; Riven-Kreitman, R.; Amselem, A.; Pinchasi, I. Copolymer 1. Drug Fut 1996, 21, 131–134.
[148]
Ziemssen, T.; Neuhaus, O.; Hohlfeld, R. Risk-benefit assessment of glatiramer acetate in multiple sclerosis. Drug Saf 2001, 24, 979–990.
[149]
Weber, M.S.; Prod’homme, T.; Youssef, S.; Dunn, S.E.; Rundle, C.D.; Lee, L.; Patarroyo, J.C.; Stuve, O.; Sobel, R.A.; Steinman, L.; et al. Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat. Med 2007, 13, 935–943.
[150]
Weber, M.S.; 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.
[151]
Clausen, J.; Matzke, J.; Gerhardt, W. Agar-Gel Micro-Electrophoresis of Proteins in the Cerebrospinal Fluid Normal and Pathological Findings. Acta Neurol. Scand. Suppl 1964, 40, 49–56.
[152]
Borlongan, C.V.; Glover, L.E.; Sanberg, P.R.; Hess, D.C. Permeating the blood brain barrier and abrogating the inflammation in stroke: Implications for stroke therapy. Curr. Pharm. Des 2012, 18, 3670–3676.
[153]
Toker, A.; Slaney, C.Y.; Backstrom, B.T.; Harper, J.L. Glatiramer acetate treatment directly targets CD11b(+)Ly6G(-) monocytes and enhances the suppression of autoreactive T cells in experimental autoimmune encephalomyelitis. Scand. J. Immunol 2011, 74, 235–243.
[154]
Lamers, K.J.; Vos, P.; Verbeek, M.M.; Rosmalen, F.; van Geel, W.J.; van Engelen, B.G. Protein S-100B, neuron-specific enolase (NSE), myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) and blood of neurological patients. Brain Res. Bull 2003, 61, 261–264.
[155]
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 2003, 100, 14157–14162.
[156]
Ure, D.R.; Rodriguez, M. Polyreactive antibodies to glatiramer acetate promote myelin repair in murine model of demyelinating disease. FASEB J 2002, 16, 1260–1262.
