Skip to main content
Log in

Therapeutic Approaches in Multiple Sclerosis

Lessons from Failed and Interrupted Treatment Trials

  • Therapy Review
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

The therapy for multiple sclerosis (MS) has changed dramatically over the past decade. Recent immunobiological findings and current pathophysiological concepts together with advances in biotechnology, improvements in clinical trial design and development of magnetic resonance imaging have led to a variety of evaluable therapeutic approaches in MS. However, in contrast to the successfully introduced and established immunomodulatory therapies (e.g. interferon-β and glatiramer acetate), there have been a remarkable number of therapeutic failures as well. Despite convincing immunological concepts, impressive data from animal models and promising results from phase I/II studies, the drugs and strategies investigated showed no benefit or even turned out to have unexpectedly severe adverse effects.

Although to date there is no uniformly accepted model for MS, there is agreement on the significance of inflammatory events mediated by autoreactive T cells in the CNS. These can be modified therapeutically at the individual steps of a hypothetical pathogenetic cascade. Crucial corners like: (i) the prevalence and peripheral activation of CNS-autoreactive T cells in the periphery; (ii) adhesion and penetration of T cells into the CNS; (iii) local activation and proliferation and; (iv) de-and remyelination processes can be targeted through their putative mediators. Like a ‘specificity pyramid’, therapeutic approaches therefore cover from general immunosuppression up to specific targeting of T-cell receptor peptide major histocompatibility (MHC) complex.

We discuss in detail clinical MS trials that failed or were discontinued for other reasons. These trials include cytokine modulators [tumour necrosis factor (TNF)-α antagonists, interleukin-10, interleukin-4, transforming growth factor-β2], immunosuppressive agents (roquinimex, gusperimus, sulfasalazine, cladribine), inducers of remyelination [intravenous immunoglobulins (IVIg)], antigen-derived therapies [oral tolerance, altered peptide ligands (APL), MHC-Peptide blockade], T cell and T-cell receptor directed therapies (T cell vaccination, T-cell receptor peptide vaccination), monoclonal antibodies against leucocyte differentiation molecules (anti-CD3, anti-CD4), and inactivation of circulating T cells (extracorporeal photopheresis).

The main conclusions that can be drawn from these ‘negative’ experiences are as follows. Theoretically promising agents may paradoxically increase disease activity (lenercept, infliximab), be associated with unforeseen adverse effects (e.g. roquinimex) or short-term favourable trends may reverse with prolonged follow-up (e.g. sulfasalzine). One should not be too enthusiastic about successful trials in animal models (TNFα blockers; oral tolerance; remyelinating effect of IVIg) nor be irritated by non-scientific media hype (deoxyspergualine; bone marrow transplantation). More selectivity can imply less efficacy (APL, superselective interventions like T-cell receptor vaccination) and antigen-related therapies can stimulate rather than inhibit encephalitogenic cells. Failed strategies are of high importance for a critical revision of assumed immunopathological mechanisms, their neuroimaging correlates, and for future trial design. Since failed trials add to our growing understanding of multiple sclerosis, ‘misses’ are nearly as important to the scientific process as the ‘hits’.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Table I
Table II

Similar content being viewed by others

References

  1. Hohlfeld R, Wiendl H. The ups and downs of multiple sclerosis therapeutics. Ann Neurol 2001; 49(3): 281–4

    Article  PubMed  CAS  Google Scholar 

  2. Noseworthy JH, Lucchinetti C, Rodriguez M, et al. Multiple sclerosis. N Engl J Med 2000; 343(13): 938–52

    Article  PubMed  CAS  Google Scholar 

  3. Hohlfeld R. Biotechnological agents for the immunotherapy of multiple sclerosis: Principles, problems and perspectives. Brain 1997; 120: 865–916

    Article  PubMed  Google Scholar 

  4. Weilbach FX, Gold R. Disease modifying treatments for multiple sclerosis: what is on the horizon? CNS Drugs 1999; 11(2): 133–57

    Article  CAS  Google Scholar 

  5. Miller DH, Albert PS, Barkhof F, et al. Guidelines for the use of magnetic resonance techniques in monitoring the treatment of multiple sclerosis. US National MS Society Task Force. Ann Neurol 1996; 39: 6–16

    Article  PubMed  CAS  Google Scholar 

  6. Fazekas F, Barkhof F, Filippi M, et al. The contribution of magnetic resonance imaging to the diagnosis of multiple sclerosis. Neurology 1999; 53: 448–56

    Article  PubMed  CAS  Google Scholar 

  7. Noseworthy JH, Wolinsky JS, Lublin FD, et al. Linomide in relapsing and secondary progressive MS: part I: trial design and clinical results. North American Linomide Investigators [see comments]. Neurology 2000; 54(9): 1726–33

    Article  PubMed  CAS  Google Scholar 

  8. Wolinsky JS, Narayana PA, Noseworthy JH, et al. Linomide in relapsing and secondary progressive MS: part II: MRI results. MRI Analysis Center of the University of Texas-Houston, Health Science Center, and the North American Linomide Investigators [see comments]. Neurology 2000; 54(9): 1734–41

    Article  PubMed  CAS  Google Scholar 

  9. Noseworthy JH, O’Brien P, Erickson BJ, et al. The Mayo-Clinic Canadian cooperative trial of sulfasalazine in active multiple sclerosis. Neurology 1998; 51(5): 1342–52

    Article  PubMed  CAS  Google Scholar 

  10. Kappos L, Radü EW, Haas J, et al. European multicenter trial +/−deoxyspergualine (dsg) versus placebo: results of the first interim analysis [abstract]. J Neurol 1994; 241:Suppl. 2: S27

    Google Scholar 

  11. Kappos L, Radu EW, Dellas S, et al. Deoxyspergualine in the treatment of active MS: final analysis of the European multicenter study. Neurology 1996; 46Suppl. 2: A410–1

    Google Scholar 

  12. Rice GP, Filippi M, Comi G. Cladribine and progressive ms: clinical and mri outcomes of a multicenter controlled trial. Cladribine MRI Study Group. Neurology 2000; 54(5): 1145–55

    Article  PubMed  CAS  Google Scholar 

  13. Filippi M, Rovaris M, Rice GP, et al. The effect of cladribine on T(1) ‘black hole’ changes in progressive MS. J Neurol Sci 2000; 176(1): 42–4

    Article  PubMed  CAS  Google Scholar 

  14. Filippi M, Rovaris M, Iannucci G, et al. Whole brain volume changes in patients with progressive MS treated with cladribine. Neurology 2000; 55(11): 1714–8

    Article  PubMed  CAS  Google Scholar 

  15. Arnason BGW, Jacobs G, Hanlon M, et al. TNF neutralization in MS -results of a randomized, placebo controlled multicenter study. Neurology 1999; 53: 457–65

    Article  CAS  Google Scholar 

  16. Van Oosten BW, Barkhof F, Truyen L, et al. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody CA2. Neurology 1996; 47(6): 1531–4

    Article  PubMed  Google Scholar 

  17. Calabresi PA, Fields NS, Maloni HW, et al. Phase-1 trial of transforming-growth-factor-beta-2 in chronic progressive MS. Neurology 1998; 51(1): 289–92

    Article  PubMed  CAS  Google Scholar 

  18. Noseworthy JH, O’Brien PC, Petterson TM, et al. A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis. Neurology 2001; 56(11): 1514–22

    Article  PubMed  CAS  Google Scholar 

  19. Noseworthy JH, O’Brien PC, Weinshenker BG, et al. IV immunoglobulin does not reverse established weakness in MS: A double-blind, placebo-controlled trial. Neurology 2000; 55(8): 1135–43

    Article  PubMed  CAS  Google Scholar 

  20. Stangel M, Boegner F, Klatt CH, et al. Placebo controlled pilot trial to study the remyelinating potential of intravenous immunoglobulins in multiple sclerosis. J Neurol Neurosurg Psychiatry 2000; 68: 89–92

    Article  PubMed  CAS  Google Scholar 

  21. Weiner HL, Mackin GA, Matsui M, et al. Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science 1993; 259: 1321–4

    Article  PubMed  CAS  Google Scholar 

  22. Francis G, Evans A, Panitch H. MRI results of a phase III trial of oral myelin in relapsing-remitting multiple sclerosis [abstract]. Ann Neurol 1997; 42: 467

    Google Scholar 

  23. Panitch H, Francis G, Oral Myelin Study Group. Clinical results of a phase III trial of oral myelin in relapsing-remitting multiple sclerosis [abstract]. Ann Neurol 1997; 42: 459

    Google Scholar 

  24. Bielekova B, Goodwin B, Richert N, et al. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: Results of a phase II clinical trial with an altered peptide ligand. Nat Med 2000; 6(10): 1167–75

    Article  PubMed  CAS  Google Scholar 

  25. Kappos L, Comi G, Panitch H, et al. Induction of a non-encephalitogenic type 2 T-helper cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo controlled, randomized phase II trial. Nat Med 2000; 6(10): 1176–82

    Article  PubMed  CAS  Google Scholar 

  26. Goodkin DE, Shulman M, Winkelhake J, et al. A phase I trial of solubilized DR2:MBP84-102 (AG284) in multiple sclerosis. Neurology 2000; 54(7): 1414–20

    Article  PubMed  CAS  Google Scholar 

  27. Medaer R, Stinissen P, Truyen L, et al. Depletion of myelin-basic-protein autoreactive t cells by T-cell vaccination: pilot trial in multiple sclerosis. Lancet 1995; 346(8978): 807–8

    Article  PubMed  CAS  Google Scholar 

  28. Vandenbark AA, Chou YK, Whitham R, et al. Treatment of multiple sclerosis with T-cell receptor peptides: results of a double-blind pilot trial. Nat Med 1996; 2: 1109–15

    Article  PubMed  CAS  Google Scholar 

  29. Rostami AM, Sater RA, Bird SJ, et al. A double-blind, placebo-controlled trial of extracorporeal photopheresis in chronic progressive multiple sclerosis. Mult Scler 1999; 5: 198–203

    PubMed  CAS  Google Scholar 

  30. Aggarwal BB, Natarjan K. Tumor necrosis factor: developments during the last decade. Eur Cytokine Netw 1996; 7: 93–124

    PubMed  CAS  Google Scholar 

  31. Beutler BA. The role of tumor necrosis factor in health and disease. J Rheumatol 1999; 26Suppl. 57: 16–21

    Google Scholar 

  32. Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 2001; 104(4): 487–501

    Article  PubMed  CAS  Google Scholar 

  33. Selmaj K, Raine CS, Cannella B, et al. Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions. J Clin Invest 1991; 87: 949–54

    Article  PubMed  CAS  Google Scholar 

  34. Cannella B, Raine CS. The adhesion molecule and cytokine profile of multiple sclerosis lesions. Ann Neurol 1995; 37: 424–35

    Article  PubMed  CAS  Google Scholar 

  35. Klinkert WEF, Kojima K, Lesslauer W, et al. TNF-alpha receptor fusion protein prevents experimental auto-immune encephalomyelitis and demyelination in Lewis rats: an overview. J Neuroimmunol 1997; 72: 163–8

    Article  PubMed  CAS  Google Scholar 

  36. Körner H, Lemckert FA, Chaudhri G, et al. Tumor necrosis factor blockade in actively induced experimental autoimmune encephalomyelitis prevents clinical disease despite activated T cell infiltration to the central nervous system. Eur J Immunol 1997; 27: 1973–81

    Article  PubMed  Google Scholar 

  37. Beck J, Rondot P, Catinot L, et al. Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestation in multiple sclerosis: do cytokines trigger off exacerbations? Acta Neurol Scand 1988; 78: 318–23

    Article  PubMed  CAS  Google Scholar 

  38. Sharief MK, Hentges R. Association between tumor necrosis factor alpha and disease progression in patients with multiple sclerosis. N Engl J Med 1991; 325: 467–72

    Article  PubMed  CAS  Google Scholar 

  39. Chofflon M, Juillard C, Juillard P, et al. Tumor necrosis factor alpha production as a possible predictor of relapse in patients with multiple sclerosis. Eur Cytokine Netw 1992; 3: 523–31

    PubMed  CAS  Google Scholar 

  40. Rudick RA, Ransohoff RM. Cytokine secretion by multiple sclerosis monocytes. Relationship to disease activity. Arch Neurol 1992; 49: 265–70

    Article  PubMed  CAS  Google Scholar 

  41. Imamura K, Suzumura A, Hayashi F, et al. Cytokine production by peripheral blood monocytes/macrophages in multiple sclerosis patients. Acta Neurol Scand 1993; 87: 281–5

    Article  PubMed  CAS  Google Scholar 

  42. Rieckmann P, Albrecht M, Kitze B, et al. Tumor-necrosis-factor-alpha messenger-RNA expression in patients with relapsing-remitting multiple-sclerosis is associated with disease-activity. Ann Neurol 1995; 37(1): 82–8

    Article  PubMed  CAS  Google Scholar 

  43. Van Oosten BW, Barkhof F, Scholten PET, et al. Increased production of tumor necrosis factor alpha, and not of interferon gamma, preceding disease activity in patients with multiple sclerosis. Arch Neurol 1998; 55(6): 793–8

    Article  PubMed  Google Scholar 

  44. Elliott MJ, Maini RN, Feldmann M, et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibody to tumor necrosis factor alpha. Arthritis Rheum 1993; 36: 1681–90

    Article  PubMed  CAS  Google Scholar 

  45. Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor: fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999; 340: 253–9

    Article  PubMed  CAS  Google Scholar 

  46. Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999; 354(9194): 1932–9

    Article  PubMed  CAS  Google Scholar 

  47. Lovell DJ, Giannini EH, Reiff A, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study group. N Engl J Med 2000; 342(11): 763–9

    Article  PubMed  CAS  Google Scholar 

  48. Feldmann M, Maini RN. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 2001; 19: 163–96

    Article  PubMed  CAS  Google Scholar 

  49. Croxford JL, Triantaphyllopoulos KA, Neve RM, et al. Gene therapy for chronic relapsing experimental allergic encephalomyelitis using cells expressing a novel soluble p75 dimeric TNF receptor. J Immunol 2000; 164(5): 2776–81

    PubMed  CAS  Google Scholar 

  50. Sean Riminton D, Korner H, Strickland DH, et al. Challenging cytokine redundancy: inflammatory cell movement and clinical course of experimental autoimmune encephalomyelitis are normal in lymphotoxin-deficient, but not tumor necrosis factor-deficient, mice. J Exp Med 1998; 187(9): 1517–28

    Article  Google Scholar 

  51. Kassiotis G, Kollias G. Uncoupling the proinflammatory from the immunosuppressive properties of tumor necrosis factor (tnf) at the p55 tnf receptor level: implications for pathogenesis and therapy of autoimmune demyelination. J Exp Med 2001; 193(4): 427–34

    Article  PubMed  CAS  Google Scholar 

  52. Liu J, Marino MW, Wong G, et al. TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination. Nat Med 1998; 4: 78–83

    Article  PubMed  CAS  Google Scholar 

  53. Eugster HP, Frei K, Bachmann R, et al. Severity of symptoms and demyelination in mog-induced EAE depends on TNFR1. Eur J Immunol 1999; 29: 626–32

    Article  PubMed  CAS  Google Scholar 

  54. Probert L, Eugster HP, Akassoglou K, et al. TNFR1 signalling is critical for the development of demyelination and the limitation of T-cell responses during immune-mediated CNS disease. Brain 2000; 123 (Pt 10): 2005–19

    Article  PubMed  Google Scholar 

  55. Grewal IS, Grewal KD, Wong FS, et al. Local expression of transgene encoded TNF alpha in islets prevents autoimmune diabetes in nonobese diabetic (NOD) mice by preventing the development of auto-reactive islet-specific T cells. J Exp Med 1996; 184(5): 1963–74

    Article  PubMed  CAS  Google Scholar 

  56. Weishaupt A, Gold R, Hartung T, et al. Role of TNF-alpha in high-dose antigen therapy in experimental autoimmune neuritis: inhibition of TNF-alpha by neutralizing antibodies reduces T-cell apoptosis and prevents liver necrosis. J Neuropathol Exp Neurol 2000; 59(5): 368–76

    PubMed  CAS  Google Scholar 

  57. Campbell IK, O’Donnell K, Lawlor KE, et al. Severe inflammatory arthritis and lymphadenopathy in the absence of TNF. J Clin Invest 2001; 107: 1519–27

    Article  PubMed  CAS  Google Scholar 

  58. Cope AP. Regulation of autoimmunity by proinflammatory cytokines. Curr Opin Immunol 1998; 10(6): 669–76

    Article  PubMed  CAS  Google Scholar 

  59. Stavnezer J. Regulation of antibody production and class switching by TFG-β. J Immunol 1995; 155: 1647–51

    PubMed  CAS  Google Scholar 

  60. Schluesener HJ, Lider O. Transforming growth factors β1 and β2: cytokines with identical immunosuppressive effects and a potential role in the regulation of autoimmune T cell function. J Neuroimmunol 1989; 24: 249–58

    Article  PubMed  CAS  Google Scholar 

  61. Johns LD, Flanders KC, Ranges GE, et al. Successful treatment of experimental allergic encephalomyelitis with transforming growth factor-β1. J Immunol 1991; 147: 1792–6

    PubMed  CAS  Google Scholar 

  62. Kuruvilla AP, Shah R, Hochwald GM, et al. Protective effect of transforming growth factor-β1 on experimental autoimmune diseases in mice. Proc Natl Acad Sci U S A 1991; 88: 2918–21

    Article  PubMed  CAS  Google Scholar 

  63. Racke MK, Bonomo A, Scott DE, et al. Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. J Exp Med 1994; 180: 1961–6

    Article  PubMed  CAS  Google Scholar 

  64. Stevens DB, Gould KE, Swanborg RH. Transforming growth factor-β1 inhibits tumor necrosis factor-alpha/lymphotoxin production and adoptive transfer of disease by effector cells of autoimmune encephalomyelitis. J Neuroimmunol 1994; 51: 77–83

    Article  PubMed  CAS  Google Scholar 

  65. Fabry Z, Topham DJ, Fee D, et al. TGF-β2 decreases migration of lymphocytes in vitro and homing of cells into the central nervous system in vivo. J Immunol 1995; 155: 325–32

    PubMed  CAS  Google Scholar 

  66. Wahl SM. Transforming growth factor β: the good, the bad, and the ugly. J Exp Med 1994; 180: 1587–90

    Article  PubMed  CAS  Google Scholar 

  67. Moore KW, de Waal Malefyt R, Coffman RL, et al. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001; 19: 683–765

    Article  PubMed  CAS  Google Scholar 

  68. Rott O, Fleischer B, Cash E. Interleukin-10 prevents experimental allergic encephalomyelitis in rats. Eur J Immunol 1994; 24: 1434–40

    Article  PubMed  CAS  Google Scholar 

  69. Crisi GM, Santambrogio L, Hochwald GM, et al. Staphylococcus enterotoxin B and tumor-necrosis factor-alpha induced relapses of experimental allergic encephalomyelitis: protection by transforming growth factor-β and interleukin-10. Eur J Immunol 1995; 25: 3035–40

    Article  PubMed  CAS  Google Scholar 

  70. Cannella B, Gao YL, Brosnan C, et al. Il-10 fails to abrogate experimental autoimmune encephalomyelitis. J Neurosci Res 1996; 45: 735–46

    Article  PubMed  CAS  Google Scholar 

  71. Owens T, Wekerle H, Antel J. Genetic models for CNS inflammation. Nat Med 2001; 7(2): 161–6

    Article  PubMed  CAS  Google Scholar 

  72. Porrini AM, Gambi D, Reder AT. Interferon effects on interleukin-10 secretion: mononuclear cell response to interleukin-10 is normal in multiple sclerosis patients. J Neuroimmunol 1995; 61: 27–34

    Article  PubMed  CAS  Google Scholar 

  73. Rudick RA, Ransohoff RM, Peppier R, et al. Interferon beta induces interleukin-10 expression: relevance to multiple sclerosis. Ann Neurol 1996; 40(4): 618–27

    Article  PubMed  CAS  Google Scholar 

  74. Salmaggi A, Dufour A, Eoli M, et al. Low serum interleukin-10 levels in multiple sclerosis: further evidence for decreased systemic immunosuppression? J Neurol 1996; 243: 13–7

    Article  PubMed  CAS  Google Scholar 

  75. Chernoff AE, Granowitz EV, Shapiro L, et al. A randomized controlled trial of Il-10 in humans: inhibition of inflammatory cytokine production and immune responses. J Immunol 1995; 154: 5292–499

    Google Scholar 

  76. Paul WE, Seder RA. Lymphocyte responses and cytokines. Cell 1994; 76(2): 241–51

    Article  PubMed  CAS  Google Scholar 

  77. de Vries JE, Carballido JM, Aversa G. Receptors and cytokines involved in allergic Th2 cell responses. J Allergy Clin Immunol 1999; 103 (5 Pt 2): S492–6

    Article  PubMed  Google Scholar 

  78. Manabe A, Coustan-Smith E, Kumagai M, et al. Interleukin-4 induces programmed cell death (apoptosis) in cases of high-risk acute lymphoblastic leukemia. Blood 1994; 83(7): 1731–7

    PubMed  CAS  Google Scholar 

  79. Srivannaboon K, Shanafelt AB, Todisco E, et al. Interleukin-4 variant (BAY 36-1677) selectively induces apoptosis in acute lymphoblastic leukemia cells. Blood 2001; 97(3): 752–8

    Article  PubMed  CAS  Google Scholar 

  80. Bettelli E, Das MP, Howard ED, et al. IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10-and IL-4-deficient and transgenic mice. J Immunol 1998; 161(7): 3299–306

    PubMed  CAS  Google Scholar 

  81. Falcone M, Rajan AJ, Bloom BR, et al. A critical role for IL-4 in regulating disease severity in experimental allergic encephalomyelitis as demonstrated in IL-4-deficient C57BL/6 mice and BALB/c mice. J Immunol 1998; 160(10): 4822–30

    PubMed  CAS  Google Scholar 

  82. Vandenbroeck K, Martino G, Marrosu M, et al. Occurrence and clinical relevance of an interleukin-4 gene polymorphism in patients with multiple sclerosis. J Neuroimmunol 1997; 76(1–2): 189–92

    Article  PubMed  Google Scholar 

  83. Neuhaus O, Farina C, Yassouridis A, et al. Multiple sclerosis: comparison of co-polymer-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(13): 7452–7

    Article  PubMed  CAS  Google Scholar 

  84. Duda PW, Schmied MC, Cook SL, et al. Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J Clin Invest 2000; 105(7): 967–76

    Article  PubMed  CAS  Google Scholar 

  85. Gran B, Tranquill LR, Chen M, et al. Mechanisms of immunomodulation by glatiramer acetate. Neurology 2000; 55(11): 1704–14

    Article  PubMed  CAS  Google Scholar 

  86. Farina C, 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 (Pt 4): 705–19

    Article  PubMed  CAS  Google Scholar 

  87. Shanafelt AB, Forte CP, Kasper JJ, et al. An immune cell-selective interleukin 4 agonist. Proc Natl Acad Sci U S A 1998; 95(16): 9454–8

    Article  PubMed  CAS  Google Scholar 

  88. Townsend MJ, McKenzie AN. Unravelling the net? Cytokines and diseases. J Cell Sci 2000; 113 (Pt 20): 3549–50

    PubMed  Google Scholar 

  89. Lassmann H, Bruck W, Lucchinetti C. Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med 2001; 7(3): 115–21

    Article  PubMed  CAS  Google Scholar 

  90. Arimilli S, Ferlin W, Solvason N, et al. Chemokines in autoimmune diseases. Immunol Rev 2000; 177: 43–51

    Article  PubMed  CAS  Google Scholar 

  91. Gonzalo J, Gonzalez-Garcia A, Kalland T, et al. Linomide, a novel immunomodulator that prevents death in four models of septic shock. Eur J Immunol 1993; 23: 2372–4

    Article  PubMed  CAS  Google Scholar 

  92. Karussis DM, Lehmann D, Slavin S, et al. Inhibition of acute, experimental autoimmune encephalomyelitis by the synthetic immunomodulator linomide. Ann Neurol 1993; 34: 654–60

    Article  PubMed  CAS  Google Scholar 

  93. Karussis DM, Lehmann D, Slavin S, et al. Treatment of chronic relapsing experimental autoimmune encephalomyelitis with the synthetic immunomodulator linomide (quinoline-3-carboxamide). Proc Natl Acad Sci U S A 1993; 90: 6400–4

    Article  PubMed  CAS  Google Scholar 

  94. Schwid SR, Noseworthy JH. Targeting immunotherapy in multiple sclerosis: a near hit and a clear miss. Neurology 1999; 53: 444–5

    Article  PubMed  CAS  Google Scholar 

  95. Peppercorn MA. Sulfasalazine: pharmacology, clinical use, toxicity, and related new drug development. Ann Intern Med 1984; 101: 377–86

    PubMed  CAS  Google Scholar 

  96. Hoult JR. Pharmacological and biochemical actions of sulfasalazine. Drugs 1986; 32: 18–26

    Article  PubMed  CAS  Google Scholar 

  97. Prosiegel M, Neu I, Ruhenstroth-Bauer G, et al. Suppression of experimental autoimmune encephalitis by sulfasalazine. N Engl J Med 1989; 321: 545–6

    PubMed  CAS  Google Scholar 

  98. Prosiegel M, Neu I, Vogl S, et al. Suppression of experimental autoimmune encephalomyelitis by sulfasalazine. Acta Neurol Scand 1990; 81: 237–8

    Article  PubMed  CAS  Google Scholar 

  99. Kappos L. Multiple sclerosis trials [letter; comment]. Lancet 1999; 353(9171): 2242–3

    Article  PubMed  CAS  Google Scholar 

  100. Rudge P. Are clinical trials of therapeutic agents for MS long enough? Lancet 1999; 353(9158): 1033–4

    Article  PubMed  CAS  Google Scholar 

  101. Amemiya H. 15-Deoxyspergualin: a newly developed immunosuppressive agent and its mechanism of action and clinical effect: a review. Japan Collaborative Transplant Study Group for NKT-01. Artif Organs 1996; 20(8): 832–5

    Article  PubMed  CAS  Google Scholar 

  102. Jung S, Toyka KV, Hartung HP. Impact of 15-deoxyspergualin on effector cells in experimental autoimmune diseases of the nervous system in the Lewis rat. Clin Exp Immunol 1994; 98(3): 494–502

    Article  PubMed  CAS  Google Scholar 

  103. Yamamura T, Da-Lin Y, Satoh J, et al. Suppression of experimental allergic encephalomyelitis by 15-deoxyspergualin. J Neurol Sci 1987; 82(1–3): 101–10

    Article  PubMed  CAS  Google Scholar 

  104. Beutler E. Cladribine (2-chlorodeoxyadenosine). Lancet 1992; 340: 952–6

    Article  PubMed  CAS  Google Scholar 

  105. Sipe JC, Romine JS, Koziol JA, et al. Cladribine in treatment of chronic progressive multiple sclerosis [see comments]. Lancet 1994; 344(8914): 9–13

    Article  PubMed  CAS  Google Scholar 

  106. Beutler E, Sipe JC, Romine JS, et al. The treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci U S A 1996; 93: 1716–20

    Article  PubMed  CAS  Google Scholar 

  107. Sipe JC, Romine JS, Koziol J, et al. Cladribine improves relapsing-remitting MS: a double blind placebo controlled study. Neurology 1997; 48Suppl. 2: A340

    Google Scholar 

  108. Romine JS, Sipe JC, Koziol JA, et al. A double-blind, placebo-controlled, randomized trial of cladribine in relapsing-remitting multiple sclerosis. Proc Assoc Am Physician 1999; 111(1): 35–44

    Article  CAS  Google Scholar 

  109. Stangel M, Hartung HP, Marx P, et al. Intravenous immunoglobulin treatment of neurological autoimmune disorders. J Neurol Sci 1998; 153: 203–14

    Article  PubMed  CAS  Google Scholar 

  110. Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 2001; 291(5503): 484–6

    Article  PubMed  CAS  Google Scholar 

  111. Rodriguez M, Lennon VA. Immunoglobulins promote remyelination in the central nervous system. Ann Neurol 1990; 27: 12–7

    Article  PubMed  CAS  Google Scholar 

  112. Warrington AE, Asakura K, Bieber AJ, et al. Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis. Proc Natl Acad Sci U S A 2000; 97(12): 6820–5

    Article  PubMed  CAS  Google Scholar 

  113. Van Engelen BG, Hommes OR, Pinckers A, et al. Improved vision after intravenous immunoglobulin in stable demyelinating optic neuritis [letter]. Ann Neurol 1992; 32: 834–5

    Article  PubMed  Google Scholar 

  114. Larroche C, Chanseaud Y, Garciadelapenalefebvre P, et al. Mechanisms of intravenous immunoglobulin action in autoimmune disorders. Biodrugs 2002; 16(1): 47–55

    Article  PubMed  CAS  Google Scholar 

  115. Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001; 345(10): 747–55

    Article  PubMed  CAS  Google Scholar 

  116. Kekow J, Reinhold D, Pap T, et al. Intravenous immunoglobulins and transforming growth factor beta. Lancet 1998; 351(9097): 184–5

    Article  PubMed  CAS  Google Scholar 

  117. Van Schaik IN, Vermeulen M, Brand A. Intravenous immunoglobulins and transforming growth factor beta. Lancet 1998; 351(9111): 1288

    Article  PubMed  Google Scholar 

  118. Stangel M, Compston A, Scolding MJ. Polyclonal immunoglobulins for intravenous use do not influence the behaviour of cultured oligodendrocytes. J Neuroimmunol 1999; 96: 228–33

    Article  PubMed  CAS  Google Scholar 

  119. Weiner HL, Friedmann A, Miller A, et al. Oral tolerance: immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. Ann Rev Immunol 1994; 12: 809–37

    Article  CAS  Google Scholar 

  120. Chen Y, Kuchroo VK, Inobe JI, et al. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 1994; 265: 1237–40

    Article  PubMed  CAS  Google Scholar 

  121. Teitelbaum D, Arnon R, Sela M. Immunomodulation of experimental autoimmune encephalomyelitis by oral administration of copolymer-I. Proc Natl Acad Sci U S A 1999; 96: 3842–7

    Article  PubMed  CAS  Google Scholar 

  122. Tian J, Olcott A, Hanssen L, et al. Antigen-based immunotherapy for autoimmune disease: from animal models to humans? Immunol Today 1999; 20(4): 190–5

    Article  PubMed  CAS  Google Scholar 

  123. Sloan-Lancaster J, Allen PM. Altered peptide ligand induced partial T cell activation: molecular mechanisms and role in T cell biology. Ann Rev Immunol 1996; 14: 1–27

    Article  CAS  Google Scholar 

  124. Windhagen A, Scholz C, Höllsbert P, et al. Modulation of cytokine patterns of human autoreactive T cell clones by a single amino acid substitution of their peptide ligand. Immunity 1995; 2: 373–80

    Article  PubMed  CAS  Google Scholar 

  125. Sloan-Lancaster J, Evavold BD, Allen PM. Induction of T-cell anergy by altered T-cell-receptor ligand on live antigen-presenting cells. Nature 1993; 363: 156–9

    Article  PubMed  CAS  Google Scholar 

  126. Smilek DE, Wraith DC, Hodgkinson S, et al. A single amino acid change in a myelin basic protein peptide confers the capacity to prevent rather than induce experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 1991; 88: 9633–7

    Article  PubMed  CAS  Google Scholar 

  127. Nicholson LB, Greer JM, Sobel RA, et al. An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis. Immunity 1995; 3: 397–405

    Article  PubMed  CAS  Google Scholar 

  128. Hafler DA, Weiner HL. Immunosuppression with monoclonal antibodies in multiple sclerosis. Neurology 1988; 38 7Suppl. 2: 42–7

    Google Scholar 

  129. Hafler DA, Ritz J, Schlossman SF, et al. Anti-CD4 and anti-CD2 monoclonal antibody infusions in subjects with multiple sclerosis. Immunosuppressive effects and human anti-mouse responses. J Immunol 1988; 141(1): 131–8

    PubMed  CAS  Google Scholar 

  130. Weinshenker BG, Bass B, Karlik S, et al. An open trial of OKT3 in patients with multiple sclerosis. Neurology 1991; 41(7): 1047–52

    Article  PubMed  CAS  Google Scholar 

  131. Lindsey JW, Hodgkinson S, Mehta R, et al. Repeated treatment with chimeric anti-CD4 antibody in multiple sclerosis. Ann Neurol 1994; 36(2): 183–9

    Article  PubMed  CAS  Google Scholar 

  132. Lindsey JW, Hodgkinson S, Mehta R, et al. Phase 1 clinical trial of chimeric monoclonal anti-CD4 antibody in multiple sclerosis. Neurology 1994; 44 (3 Pt 1): 413–9

    Article  PubMed  CAS  Google Scholar 

  133. Van Oosten BW, Lai M, Barkhof F, et al. A phase II trial of anti-CD4 antibodies in the treatment of multiple sclerosis. Mult Scler 1996; 1(6): 339–42

    PubMed  Google Scholar 

  134. Racadot E, Rumbach L, Bataillard M, et al. Treatment of multiple sclerosis with anti-CD4 monoclonal antibody. A preliminary report on B-F5 in 21 patients. J Autoimmun 1993; 6(6): 771–86

    Article  PubMed  CAS  Google Scholar 

  135. Rep MH, van Oosten BW, Roos MT, et al. Treatment with depleting CD4 monoclonal antibody results in a preferential loss of circulating naive T cells but does not affect IFN-gamma secreting TH1 cells in humans. J Clin Invest 1997; 99(9): 2225–31

    Article  PubMed  CAS  Google Scholar 

  136. Weinberg AD, Bourdette DN, Sullivan TJ, et al. Selective depletion of myelin-reactive T cells with the anti-OX-40 antibody ameliorates autoimmune encephalomyelitis. Nat Med 1996; 2(2): 183–9

    Article  PubMed  CAS  Google Scholar 

  137. Anderson DE, Sharpe AH, Hafler DA. The B7-CD28/CTLA-4 costimulatory pathways in autoimmune disease of the central nervous system. Curr Opin Immunol 1999; 11(6): 677–83

    Article  PubMed  CAS  Google Scholar 

  138. Sperling AI. ICOS costimulation: is it the key to selective immunotherapy? Clin Immunol 2001; 100(3): 261–2

    Article  PubMed  CAS  Google Scholar 

  139. Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T cell lymphoma by extracorporeal photochemistry: Preliminary results. N Engl J Med 1987; 316: 297–303

    Article  PubMed  CAS  Google Scholar 

  140. Vahlquist C, Larsson M, Ernerudh J, et al. Treatment of psoriatic arthritis with extracorporeal photochemotherapy and conventional psoralen-ultraviolet A irradiation. Arthritis Rheum 1996; 39: 1519–23

    Article  PubMed  CAS  Google Scholar 

  141. Schwartz J, Gonzalez J, Palangio M, et al. Extracorporeal photochemotherapy in progressive systemic sclerosis: a follow-up study. Int J Derm 1997; 36: 380–5

    Article  PubMed  CAS  Google Scholar 

  142. Lider O, Reshef T, Beraud E, et al. Anti-idiotype network induced by T cell vaccination against experimental autoimmune encephalomyelitis. Science 1988; 239: 181–3

    Article  PubMed  CAS  Google Scholar 

  143. Khavari P, Edelson RL, Lider O, et al. Specific vaccination against photoinactivated cloned T cells [abstract]. Clin Res 1988; 36: 662A

    Google Scholar 

Download references

Acknowledgements

The Institute for Clinical Neuroimmunology is supported by the Hermann and Lilly Schilling Foundation. The authors have participated in trials and conducted research supported by manufacturers of therapeutic agents mentioned in this article.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Heinz Wiend.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wiend, H., Hohlfeld, R. Therapeutic Approaches in Multiple Sclerosis. BioDrugs 16, 183–200 (2002). https://doi.org/10.2165/00063030-200216030-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00063030-200216030-00003

Keywords

Navigation