Aktuelle Neurologie 2002; 29(7): 345-351
DOI: 10.1055/s-2002-33657
Arzneimitteltherapie
© Georg Thieme Verlag Stuttgart · New York

Immuntherapie der multiplen Sklerose mit Glatiramerazetat (Copaxone®)

Wirkmechanismen und Ergebnisse aus TherapiestudienImmunotherapy of Multiple Sclerosis with Glatiramer AcetateMechanisms of Action and Results from Therapeutic TrialsR.  Gold1 , F.  Heidenreich2, 3 , L.  Kappos4
  • 1Klinische Forschungsgruppe für multiple Sklerose und Neuroimmunologie, Neurologische Universitätsklinik Würzburg
  • 2Neurologische Klinik mit Klinischer Neurophysiologie, Medizinische Hochschule Hannover
  • 3Neurologische Klinik, Henriettenstiftung Hannover
  • 4Neurologisch-Neurochirurgische Poliklinik, Neurologische Universitätsklinik, Kantonsspital Basel
Further Information

Publication History

Publication Date:
26 September 2002 (online)

Zusammenfasssung

Glatiramerazetat (GLAT; früher: Copolymer-1; Handelsname Copaxone®) hat von den modernen Immuntherapeutika bei multipler Sklerose (MS) die längste immunologische Vorgeschichte. Seine Wirkmechanismen werden auch heute noch nicht vollständig verstanden. In verschiedenen experimentellen Modellen gelang es durch GLAT akute und chronische Verläufe der experimentellen autoimmunen Enzephalomyelitis (EAE) zu therapieren. Zelluläre Untersuchungen an Tier und Mensch legen nahe, dass ein wesentliches Wirkprinzip in der Verschiebung der Immunantwort von sog. T-Helfer-1(TH1)-Mustern zu TH2-Mechanismen liegt. In kontrollierten klinischen Studien konnte die Wirkung von GLAT bei schubförmiger MS klinisch und kernspintomographisch nachgewiesen werden. Wir fassen in diesem Übersichtsartikel die vorliegenden Ergebnisse zu GLAT zusammen und diskutieren seinen Stellenwert bei der modernen MS-Therapie.

Abstract

Amongst immunomodulatory drugs used in multiple sclerosis (MS), glatiramer acetate (GLAT; former name: Copolymer-1; trademark Copaxone) has the longest history. Even today its mechanisms of action are only incompletely understood. GLAT has shown therapeutic efficacy in diverse models of experimental autoimmune encephalomyelitis (EAE). At the cellular level GLAT induces a shift from TH1 to TH2 cytokines. Therapeutic efficacy in relapsing-remitting MS patients has been proven by controlled clinical studies. Here we review current aspects of GLAT therapy and discuss its role in immunomodulatory treatment of MS.

Literatur

  • 1 Teitelbaum H, Meshorer A, Hirshfeld T. et al . Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide.  Eur J Immunol. 1971;  1 242-248
  • 2 Lassmann H, Bruck W, Lucchinetti C. Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy.  Trends Mol Med. 2001;  7 115-121
  • 3 Gold R, Hartung H-P, Toyka K V. Animal models for autoimmune demyelinating disorders of the nervous system.  Mol Med Today. 2000;  6 88-91
  • 4 Johnson K P, Brooks B R, Cohen J A. 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. 1995;  45 1268-1276
  • 5 Teitelbaum D, Webb C, Meshorer A. et al . Suppression by several synthetic polypeptides of experimental allergic encephalomyelitis induced in guinea pigs and rabbits with bovine and human basic encephalitogen.  Eur J Immunol. 1973;  3 273-279
  • 6 Teitelbaum D, Webb C, Bree M. et al . Suppression of experimental allergic encephalomyelitis in Rhesus monkeys by a synthetic basic copolymer.  Clin Immunol Immunopathol. 1974;  3 256-262
  • 7 Keith A B, Arnon R, Teitelbaum D. et al . The effect of Cop 1, a synthetic polypeptide, on chronic relapsing experimental allergic encephalomyelitis in guinea pigs.  J Neurol Sci. 1979;  42 267-274
  • 8 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. 1988;  85 9724-9728
  • 9 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
  • 10 Falk K, Rötzschke O, Santambrogio L. et al . Induction and suppression of an autoimmune disease by oligomerized T cell epitopes: Enhanced in vivo potency of encephalitogenic peptides.  J Exp Med. 2000;  191 717-730
  • 11 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
  • 12 Miller A, Shapiro S, Gershtein R. et al . Treatment of multiple sclerosis with Copolymer-1 (Copaxone®): implicating mechanisms of Th1 to Th2/Th3 immune-deviation.  J Neuroimmunol. 1998;  92 113-121
  • 13 Weiner H L. Oral tolerance with copolymer 1 for the treatment of multiple sclerosis (comment).  Proc Natl Acad Sci USA. 1999;  96 3333-3335
  • 14 Maron R, Slavin A J, Hoffmann E. et al . Oral tolerance to copolymer 1 in myelin basic protein (MBP) TCR transgenic mice: cross-reactivity with MBP-specific TCR and differential induction of anti-inflammatory cytokines.  Int Immunol. 2002;  14 131-138
  • 15 Mosmann T R, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more.  Immunol Today. 1996;  17 138-146
  • 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 USA. 1997;  94 10821-10826
  • 17 Fridkis-Hareli M, Teitelbaum D, Gurevich E. et al . Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen-presenting cells - specificity and promiscuity.  Proc Natl Acad Sci USA. 1994;  91 4872-4876
  • 18 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. USA;  97 7452-7457
  • 19 Duda P W, Schmied M C, Cook S L. et al . Glatiramer acetate (Copaxone®) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis.  J Clin Invest. 2000;  105 967-976
  • 20 Wiesemann E, Klatt J, Sonmez D. et al . Glatiramer acetate (GA) induces IL-13/IL-5 secretion in naive T cells.  J Neuroimmunol. 2001;  119 137-144
  • 21 Gran B, Tranquill L R, Chen M. et al . Mechanisms of immunomodulation by glatiramer acetate.  Neurology. 2000;  55 1704-1714
  • 22 Bornstein M B, Miller A, Slagle S. et al . A pilot trial of Cop I in exacerbating-remitting multiple sclerosis.  N Engl J Med. 1987;  317 408-414
  • 23 Johnson K P, Brooks B R, Cohen J A. 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.  Neurology. 1998;  50 701-708
  • 24 Johnson K P, Brooks B R, Ford C C. 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
  • 25 Mancardi G L, Sardanelli F, Parodi R C. et al . Effect of copolymer-1 on serial gadolinium-enhanced MRI in relapsing remitting multiple sclerosis.  Neurology. 1998;  50 1127-1133
  • 26 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.  Ann Neurol. 2001;  49 290-297
  • 27 Filippi M, Rovaris M, Rocca M A. et al . Glatiramer acetate reduces the proportion of new MS lesions evolving into „black holes”.  Neurology. 2001;  57 731-733
  • 28 Bornstein M B, Miller A, Slagle S. et al . A placebo-controlled, double-blind, randomized, two-center, pilot trial of Cop 1 in chronic progressive multiple sclerosis.  Neurology. 1991;  41 533-539
  • 29 Bornstein M B, Johnson K P. Treatment of multiple sclerosis with copolymer I. In: Rudick RA, Goodkin DE (eds) Treatment of multiple sclerosis. Trial design, results and future perspectives. Heidelberg; Springer-Verlag 1996: 173-198
  • 30 Windhagen A, Maniak S, Marckmann S. et al . Lymphadenopathy in patients with multiple sclerosis undergoing treatment with glatiramer acetate.  J Neurol Neurosurg Psychiatry. 2001;  70 415-416
  • 31 Buttner U, Chofflon M, Hess K. et al . Escalating immunomodulatory therapy of multiple sclerosis - 1. Supplement.  Nervenarzt. 2001;  72 150-157

Prof. Dr. Ralf Gold

Neurologische Universitätsklinik

Josef-Schneider-Straße 11

97080 Würzburg

Email: r.gold@mail.uni-wuerzburg.de

    >