Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis and their application for new therapeutic strategies

  • R. Martin
Conference paper


The etiology of multiple sclerosis (MS), a demyelinating disorder of the central nervous system (CNS), is not yet known. Immunological, clinical and pathological studies suggest, however, that T lymphocytes directed against myelin antigens are involved in the pathogenesis of MS. The examination of an experimental animal model for MS, experimental allergic encephalomyelitis (EAE), demonstrated that myelin basic protein- (MBP) or proteol-ipidprotein- (PLP) specific T cells mediate the destruction of CNS myelin. In recent years, elegant studies in EAE showed that encephalitogenic T cells recognize short peptides of MBP or PLP in the context of MHC/HLA-class II molecules, express a restricted number of T cell receptor (TCR) molecules and secrete interferon-y and tumor necrosis factor-α/β. Understanding the pathogenetic steps of demyelination at the molecular level led to highly specific immunotherapies of EAE targeting each individual molecule. MBP-and PLP-specific T cells with similar properties could also be isolated from MS patients and control individuals. Due to their heterogeneity in terms of specificity, function and TCR usage, it was difficult, however, to draw definite conclusions from these results, so far. The recent approval of interferon-β, a cytokine that antagonizes a number of the effects of interferon-γ, for the treatment of MS has raised great interest in examining novel strategies for immunotherapies in MS. The basic concepts as well as the current candidates for such new immunotherapies will be outlined in this brief article.


Multiple Sclerosis Experimental Autoimmune Encephalomyelitis Myelin Basic Protein Experimental Allergic Encephalomyelitis Myelin Antigen 
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  1. Acha-Orbea H, Mitchell L, et al (1988) Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell 54: 263–273PubMedCrossRefGoogle Scholar
  2. Acha-Orbea H, Steinman L, et al (1989) T cell receptors in murine autoimmune diseases. Annu Rev Immunol 7: 371–406PubMedCrossRefGoogle Scholar
  3. Aharoni R, Teitelbaum D, et al (1991) Immunomodulation of experimental allergic encephalomyelitis by antibodies to the antigen-la complex. Nature 351: 147–150PubMedCrossRefGoogle Scholar
  4. Alegretta M, Albertini RJ, et al (1994) Homologies between T cell receptor junctional sequences unique to multiple sclerosis and T cells mediating experimental allergic encephalomyelitis. J Clin Invest 94: 105–109CrossRefGoogle Scholar
  5. Ando DG, Clayton J, et al (1989) Encephalitogenic T cells in the B10.PL model of experimental allergic encephalomyelitis (EAE) are of the Th-1 lymphokine subtype. Cell Immunol 124: 132–143PubMedCrossRefGoogle Scholar
  6. Archelos JJ, Jung S, et al (1993) Inhibition of experimental autoimmune encephalomyelitis by an antibody to the intercellular adhesion molecule ICAM-1. Ann Neurol 34: 145–154PubMedCrossRefGoogle Scholar
  7. Baron JL, Madri JA, et al (1993) Surface expression of α4 integrin by CD4 T cells is required for their entry into brain parenchyma. J Exp Med 177: 57–68PubMedCrossRefGoogle Scholar
  8. Ben Nun A, Cohen IR (1982) Experimental autoimmune encephalomyelitis (EAE) mediated by T cell line: process of selection of lines and characterization of the T cells. J Immunol 129: 303–308Google Scholar
  9. Ben Nun A, Wekerle H, et al (1981) Vaccination against autoimmune encephalomyelitis with T-lymphocyte line cells reactive against myelin basic protein. Nature 293: 60–61CrossRefGoogle Scholar
  10. Brocke S, Gaur A, et al (1993) Induction of relapsing paralysis in experimental by bacterial superantigen. Nature 365: 642–644PubMedCrossRefGoogle Scholar
  11. Broome Powell M, Mitchell D, et al (1990) Lymphotoxin and tumor necrosis factor-alpha production by myelin basic protein-specific T cell clones correlates with encephalito-genicity. Int Immunol 2: 539–544CrossRefGoogle Scholar
  12. Brostoff SW, Mason DW (1984) Experimental allergic encephalomyelitis: successful treatment in vivo with a monoclonal antibody that recognizes T helper cells. J Immunol 133: 1938–1942PubMedGoogle Scholar
  13. Burns FR, Li X, et al (1989) Both rat and mouse T cell receptors specific for the encephalitogenic determinant of myelin basic protein use similar Vα and Vβ chain genes even though the major histocompatibility complex and encephalitogenic determinants being recognized are different. J Exp Med 169: 27–39PubMedCrossRefGoogle Scholar
  14. Cannella B, Cross AH, et al (1993) Anti-adhesion molecule therapy in experimental autoimmune encephalomyelitis. J Neuroimmunol 46: 43–55PubMedCrossRefGoogle Scholar
  15. Chluba J, Steeg C, et al (1989) T cell receptor β chain usage in myelin basic protein-specific rat T lymphocytes. Eur J Immunol 19: 279–284PubMedCrossRefGoogle Scholar
  16. Chou YK, Vainiene M, et al (1989) Response of human T lymphocyte lines to myelin basic protein: association of dominant epitopes with HLA-class II restriction molecules. J Neurol Sci 23: 207–216Google Scholar
  17. Critchfield JM, Racke MK, et al (1994) T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis. Science 263: 1139–1143PubMedCrossRefGoogle Scholar
  18. Cross AH, Cannella B, et al (1990) Homing to central nervous system vasculature by antigen specific lymphocytes. I. Localization of 14C-labeled cells during acute, chronic and relapsing experimental allergic encephalomyelitis. Lab Invest 63: 162–170PubMedGoogle Scholar
  19. Cross AH, O’Mara T, et al (1993) Chronologic localization of myelin-reactive cells in the lesions of relapsing EAE: implications for the study of multiple sclerosis. Neurology 43: 1028–1033PubMedGoogle Scholar
  20. Fritz RB, McFarlin DE (1989) Encephalitogenic epitopes of myelin basic protein. Chem Immunol 46: 101–125PubMedCrossRefGoogle Scholar
  21. Fritz RB, Skeen MJ, et al (1985) Major histocompatibility complex-linked control of the murine immune response to myelin basic protein. J Immunol 134: 2328–2332PubMedGoogle Scholar
  22. Giegerich G, Pette M, et al (1992) Diversity of T cell receptor alpha and beta chain genes expressed by human T cells specific for similar myelin basic protein peptide/major histocompatibility complexes. Eur J Immunol 22: 753–758PubMedCrossRefGoogle Scholar
  23. Goverman J, Woods A, et al (1993) Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell 72: 551–560PubMedCrossRefGoogle Scholar
  24. Gregerson DS, Obritsch WF, et al (1993) Oral tolerance in experimental autoimmune uveoretinitis. Distinct mechanisms of resistance are induced by low dose vs high dose feeding protocols. J Immunol 151: 5751–5761PubMedGoogle Scholar
  25. Hartung H-P (1993) Immune-mediated demyelination. Ann Neurol 33: 563–567PubMedCrossRefGoogle Scholar
  26. Higgins PJ, Weiner HJ (1988) Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein and its fragments. J Immunol 140: 440–445PubMedGoogle Scholar
  27. Hohlfeld R (1989) Neurological autoimmune disease and the trimolecular complex of T lymphocytes. Ann Neurol 25: 531–538PubMedCrossRefGoogle Scholar
  28. Howell MD, Winters ST, et al (1989) Vaccination against experimental allergic autoimmune encephalomyelitis with T cell receptor peptides. Science 246: 668–670PubMedCrossRefGoogle Scholar
  29. Jacobs CA, Baker PE, et al (1991) Experimental autoimmune encephalomyelitis is exacerbated by IL-1α and suppressed by soluble IL-1 receptors. J Immunol 146:2983–2989PubMedGoogle Scholar
  30. Jung S, Schluesener HJ, et al (1993) Modulation of EAE by vaccination with T cell receptor peptides: Vß8 T cell receptor peptide-specific CD4+ lymphocytes lack direct imunoregulatory activity. J Neuroimmunol 45: 15–22PubMedCrossRefGoogle Scholar
  31. Kawano Y-I, Sasamoto Y, et al (1991) Trials of vaccination against experimental autoimmune uveoretinitis with a T-Cell receptor peptide. Curr Eye Res 10: 789–795PubMedCrossRefGoogle Scholar
  32. Kennedy MK, Tan L-J, et al (1990) Inhibition of murine relapsing experimental autoimmune encephalomyelitis by immune tolerance to proteolipid protein and its encephalitogenic peptides. J Immunol 144: 909–915PubMedGoogle Scholar
  33. Kerlero de Rosbo N, Milo R, et al (1993) Reactivity to myelin antigens in multiple sclerosis. Peripheral blood lymphocytes respond predominantly to myelin oligodendrocyte glycoprotein. J Clin Invest 92: 2602–2608CrossRefGoogle Scholar
  34. Kotzin BL, Karuturi S, et al (1991) Preferential T-cell receptor Vβ-chain variable gene use in myelin basic protein-reactive T-cell clones from patients with multiple sclerosis. Proc Natl Acad Sci USA 88: 9161–9165PubMedCrossRefGoogle Scholar
  35. Kuruvilla AP, Shah R, et al (1991) Protective effect of transforming growth factor β1 on experimental autoimmune diseases in mice. Proc Natl Acad Sci USA 88: 2918–2921PubMedCrossRefGoogle Scholar
  36. Lamont AG, Sette A, et al (1990) Inhibition of experimental autoimmune encephalomyelitis induction in SJL/J mice by using a peptide with high affinity for IAS molecules. J Immunol 145: 1687–1693:PubMedGoogle Scholar
  37. Linington C, Bradl M, et al (1988) Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein. Am J Pathol 130: 443–454PubMedGoogle Scholar
  38. Mackin GA, Dawson DM, et al (1992) Treatment of multiple sclerosis with cyclophosphamide. In: Rudick RA, Goodkin DE (eds) Treatment of multiple sclerosis. Springer, London, pp 199–216Google Scholar
  39. Martin R, Howell MD, et al (1991) A myelin basic protein peptide is recognized by cytotoxic T cells in the context of four HLA-DR types associated with multiple sclerosis. J Exp Med 173: 19–24PubMedCrossRefGoogle Scholar
  40. Martin R, Jaraquemada D, et al (1990) Fine specificity and HLA restriction of myelin basic protein-specific cytotoxic T cell lines from multiple sclerosis patients and healthy individuals. J Immunol 145: 540–548PubMedGoogle Scholar
  41. Martin R, McFarland HF, et al (1992a) Immunological aspects of demyelinating diseases. Annu Rev Immunol 10: 153–187PubMedCrossRefGoogle Scholar
  42. Martin R, Utz U, et al (1992b) Diversity in fine specificity and T cell receptor usage of the human CD4+ cytotoxic T cell response specific for the immunodominant myelin basic protein peptide 87–106. J Immunol 148: 135–1366Google Scholar
  43. McCarron RM, Wang L, et al (1993) Cytokine-regulated adhesion between encepha-litogenic T lymphocytes and cerebrovascular endothelial cells. J Neuroimmunol 43: 23–30PubMedCrossRefGoogle Scholar
  44. McFarland HF, Frank JA, et al (1992) Using gadolinium-enhanced magnetic resonance imaging lesions to monitor disease activity in multiple sclerosis. Ann Neurol 32: 758–766PubMedCrossRefGoogle Scholar
  45. McFarlin DE, McFarland HF (1982a) Multiple sclerosis, part 1. N Engl J Med 307: 1183–1188PubMedCrossRefGoogle Scholar
  46. McFarlin DE, McFarland HF (1982b) Multiple sclerosis, part 2. N Engl J Med 307: 1246–1251PubMedCrossRefGoogle Scholar
  47. Meinl E, Weber F, et al (1993) Myelin basic protein-specific T lymphocyte repertoire in multiple sclerosis. Complexity of the response and dominance of nested epitopes due to recruitment of multiple T cell clones. J Clin Invest 92: 2633–2643PubMedCrossRefGoogle Scholar
  48. Metzler B, Wraith DC (1993) Inhibition of experimental autoimmune encephalomyelitis by inhalation but not oral administration of the encephalitogenic peptide: influence of MHC binding affinity. Int Immunol 5: 1159–1165PubMedCrossRefGoogle Scholar
  49. Offner H, Hashim GA, et al (1991) T cell receptor peptide therapy triggers autoregulation of experimental encephalomyelitis. Science 251: 430–432PubMedCrossRefGoogle Scholar
  50. Offner H, Buenafe AC, et al (1993) Where, when, and how to detect biased expression of disease-relevant Vβ genes in rats with experimental autoimmune encephalomyelitis. J Immunol 151: 506–517PubMedGoogle Scholar
  51. Oksenberg JR, Panzara MA, et al (1993) Selection for T-cell receptor Vβ-Dβ-Jβ gene rearrangements with specificity for a myelin basic protein peptide in brain lesions of multiple sclerosis. Nature 362: 68–70PubMedCrossRefGoogle Scholar
  52. Olsson T, Wei Zhi W, et al (1990) Autoreactive T lymphocytes in multiple sclerosis determined by antigen-induced secretion of interferon-03B3. J Clin Invest 86: 981–985PubMedCrossRefGoogle Scholar
  53. Olsson T, Sun J, et al (1992) Increased numbers of T cells recognizing multiple myelin basic protein epitopes in multiple sclerosis. Eur J Immunol 22: 1083–1087PubMedCrossRefGoogle Scholar
  54. Ota K, Matsui M, et al (1990) T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature 346: 183–187PubMedCrossRefGoogle Scholar
  55. Paty DW, Li DKB, et al (1993) Interferon beta-lb is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43: 662–667PubMedGoogle Scholar
  56. Pette M, Fujita K, et al (1990a) Myelin basic protein-specific T lymphocyte lines from MS patients and healthy individuals. Neurology 40: 1770–1776PubMedGoogle Scholar
  57. Pette M, Fujita K, et al (1990b) Myelin autoreactivity in multiple sclerosis: recognition of myelin basic protein in the context of HLA-DR2 products by T lymphocytes of multiple sclerosis patients and healthy donors. Proc Natl Acad Sci USA 87: 7968–7972PubMedCrossRefGoogle Scholar
  58. Pettinelli CB, McFarlin DE (1981) Adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice after in vivo activation of lymph node cells by myelin basic protein: requirement for Lyt-1+2- T lymphocytes. J Immunol 127: 1420–1423PubMedGoogle Scholar
  59. Prineas JW (1985) The neuropathology of multiple sclerosis. In: Vinken PJ, Bruyn GW, Klawans HL, Koetsier JC (eds) Demyelinating diseases. Elsevier, Amsterdam New York, pp 213–257 (Handbook of Clinical Neurology 3, 47)Google Scholar
  60. Racke MK, Dhib-Jalbut S, et al (1991) Prevention and treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-β1. J Immunol 146: 3012–3017PubMedGoogle Scholar
  61. Racke MK, Martin R, et al (1992) Copolymer-1-induced inhibition of antigen-specific T cell activation: interference with antigen presentation. J Neuroimmunol 37: 75–84PubMedCrossRefGoogle Scholar
  62. Raine CS (1983) Multiple sclerosis and chronic relapsing EAE: comparative ultrastructural neuropathology. In: Hallpike JF, Adams CW, Tourtellotte WW (eds) Multiple sclerosis. Williams & Wilkins, Baltimore, pp 413–478Google Scholar
  63. Raine CS, Scheinberg LC (1988) On the immunopathology of plaque development and repair in multiple sclerosis. J Neuroimmunol 20: 189–201PubMedCrossRefGoogle Scholar
  64. Raine CS, Cannella B, et al (1990) Homing to central nervous system vasculature by antigen-specific lymphocytes. II. Lymphocyte/endothelial cell adhesion during the initial stages of autoimmune demyelination. Lab Invest 63: 476–489PubMedGoogle Scholar
  65. Richert JR, Driscoll BG, et al (1979) Adoptive transfer of experimental allergic encephalomyelitis: incubation of rat spleen cells with specific antigen. J Immunol 122: 494–496PubMedGoogle Scholar
  66. Richert JR, Robinson ED, et al (1989) Human cytotoxic T-cell recognition of a synthetic peptide of myelin basic protein. Ann Neurol 26: 342–346PubMedCrossRefGoogle Scholar
  67. Rivers TM, Sprunt DH, et al (1933) Observations on attempts to produce acute disseminated encephalomyelitis in monkeys. J Exp Med 58: 39–53PubMedCrossRefGoogle Scholar
  68. Ruddle NH, Bergman CM, et al (1990) An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J Exp Med 172: 1193–1200PubMedCrossRefGoogle Scholar
  69. Sadovnick AD, Armstrong H, et al (1993) A population-based study of multiple sclerosis in twins: update. Ann Neurol 33: 281–285PubMedCrossRefGoogle Scholar
  70. Salvetti M, Ristori G, et al (1993) Predominant and stable T cell responses to regions of myelin basic protein can be detected in individual patients with multiple sclerosis. Eur J Immuol 23: 1232–1239CrossRefGoogle Scholar
  71. Schiffenbauer J, Johnson HM, et al (1993) Staphylococcal enterotoxins can reactivate experimental allergic encephalomyelitis. Proc Natl Acad Sci USA 90: 8543–8546PubMedCrossRefGoogle Scholar
  72. Schmied M, Breitschopf H, et al (1993) Apoptosis of T lymphocytes in experimental autoimmune encephalomyelitis: evidence for programmed cell death as a mechanism to control inflammation in the brain. Am J Pathol 143: 446–452PubMedGoogle Scholar
  73. Sercarz EE, Lehmann PV, et al (1993) Dominance and crypticity of T cell antigenic determinants. Annu Rev Immunol 11: 729–766PubMedCrossRefGoogle Scholar
  74. Sharma SD, Nag B (1993) Antigen-specific therapy of experimental allergic encephalomyelitis by soluble class II major histocompatibility complex-peptide complexes. Proc Natl Acad Sci USA 88: 11465–11469CrossRefGoogle Scholar
  75. Sun D, Gold DP, et al (1992) Characterization of rat encephalitogenic T cells bearing non-Vβ8 T cell receptors. Eur J Immunol 22: 591–594PubMedCrossRefGoogle Scholar
  76. Teitelbaum D, Aharoni R, et al (1988) Specific inhibition of the T-cell response to myelin basic protein by the synthetic copolymer Cop-1. Proc Natl Acad Sci USA 85: 9724–9728PubMedCrossRefGoogle Scholar
  77. The IFN-β Multiple Sclerosis Study Group (1993) Interferon beta-lb is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43: 655–661Google Scholar
  78. Tiwari JL, Terasaki PI (1985) HLA and disease associations. Springer, New York, pp 152–167Google Scholar
  79. Tourtellotte WW (1985) The cerebrospinal fluid in multiple sclerosis. In: Vinken PJ, Bruyn GW, Klawans HL, Koetsier JC (eds) Demyelinating diseases. Elsevier, Amsterdam New York, pp 79–130 (Handbook of Clinical Neurology 3, 47)Google Scholar
  80. Tuohy VK, Sobel RA, et al (1988) Myelin proteolipid protein-induced experimental allergic encephalomyelitis. Variations of disease expression in different strains of mice. J Immunol 140: 1868–1873PubMedGoogle Scholar
  81. Urban JL, Horvath SJ, et al (1989) Autoimmune T cells: immune recognition of normal and variant peptide epitopes and peptide-based therapy. Cell 59: 257–271PubMedCrossRefGoogle Scholar
  82. Utz U, Biddison WE, et al (1993) Skewed T cell receptor repertoire in genetically identical twins with multiple sclerosis correlates with disease. Nature 364: 243–247PubMedCrossRefGoogle Scholar
  83. Utz U, Brooks JA, et al (1994) Heterogeneity of T-cell receptor α-chain complementarity-determining region 3 in myelin basic protein-specific T cells increases with severity of multiple sclerosis. Proc Natl Acad Sci USA 91: 5567–5571PubMedCrossRefGoogle Scholar
  84. Vandenbark AA, Hashim G, et al (1989) Immunization with a synthetic T-cell receptor V-region peptide against experimental autoimmune encephalomyelitis. Nature 341: 541–544PubMedCrossRefGoogle Scholar
  85. Vogt AB, Kropshofer H, et al (1994) Ligand motifs of HLA-DRB5*0101 and DRB1*1501 molecules delineated from sel-peptides. J Immunol 153: 1665–1673PubMedGoogle Scholar
  86. Voskuhl RR, Martin R, et al (1993) T Helper 1 (TH1) functional phenotype of human myelin basic protein-specific T lymphocytes. Autoimmunity 1 5: 137–143CrossRefGoogle Scholar
  87. Waldor MK, Sriram S, et al (1985) Reversal of experimental allergic encephalomyelitis with a monoclonal antibody to a T cell subset marker (L3T4). Science 227: 415–417PubMedCrossRefGoogle Scholar
  88. Weber WEJ, Vandermeeren MMPP, et al (1989) Human myelin basic protein-specific cytolytic T lymphocyte clones are functionally restricted by HLA class II gene products. Cell Immunol 120: 145–153PubMedCrossRefGoogle Scholar
  89. Weiner HL, Mackin GA, et al (1993) Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science 259: 1321–1324PubMedCrossRefGoogle Scholar
  90. Whitacre CC, Gienapp IE, et al (1991) Oral tolerance in experimental autoimmune encephalomyelitis. III. Evidence for clonal anergy. J Immunol 147: 2155–2163PubMedGoogle Scholar
  91. Wraith DC, Smilek DE, et al (1989) Antigen recognition in autoimmune encephalomyelitis and the potential for peptide-mediated immunotherapy. Cell 59: 247–255PubMedCrossRefGoogle Scholar
  92. Wucherpfennig KW, Ota K, et al (1990) Shared human T cell receptor V beta usage to immunodominant regions of myelin basic protein. Science 248: 1016–1019PubMedCrossRefGoogle Scholar
  93. Wucherpfennig KW, Newcombe J, et al (1992) T cell receptor Vα-Vβ repertoire and cytokine gene expression in active multiple sclerosis lesions. J Exp Med 175: 993–1002PubMedCrossRefGoogle Scholar
  94. Wucherpfennig KW, Sette A, et al (1994) Structural requirements for binding of an immunodominant myelin basic protein peptide to DR2 isotypes and for its recognition by human T cell clones. J Exp Med 179: 279–290PubMedCrossRefGoogle Scholar
  95. Yednock TA, Cannon C, et al (1992) Prevention of experimental autoimmune encephalomyelitis by antibodies against α4βl integrin. Nature 356: 63–66PubMedCrossRefGoogle Scholar
  96. Zamvil SS, Steinman L (1990) The T lymphocyte in experimental allergic encephalomyelitis. Annu Rev Immunol 8: 579–621PubMedCrossRefGoogle Scholar

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© Springer-Verlag/Wien 1997

Authors and Affiliations

  • R. Martin
    • 1
  1. 1.Department of NeurologyUniversity of Tübingen Medical SchoolTübingenFederal Republic of Germany

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