Skip to main content
Log in

Cytokine shifts and tolerance in experimental autoimmune encephalomyelitis

  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Cytokines play an important role in the pathogenesis of both multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Effective treatments for both diseases have been shown to alter cytokines in the central nervous system and in activated mononuclear cells. EAE is an animal model that mimics many aspects of multiple sclerosis, and has been widely used to study the mechanisms of disease and therapeutic approaches to multiple sclerosis. Cytokines play an important role in regulation of disease expression in EAE, and in tolerance to disease induction. In this review, we will summarize the current findings on the role of cytokine shifts in the induction of tolerance in EAE. In addition, we will discuss modulation of EAE by altered expression of members of the cytokine-regulated Jak/STAT intracellular signaling pathway.

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.

Similar content being viewed by others

References

  1. Brosran CF, Camella B, Battistini L, et al: Cytokine localization in multiple sclerosis lesions: correlation with adhesion molecule expression and reactive nitrogen species. Neurology 1995;45(6 Suppl 6):S16-S21.

    Google Scholar 

  2. Balashov KE, Smith DR, Khoury SJ, et al.: Increased interleukin 12 production in progressive multiple sclerosis: induction by activated CD4+T cells via CD40 ligand. Proc Natl Acad Sci USA 1997;94(2):599–603.

    PubMed  CAS  Google Scholar 

  3. Comabella M, Balashov K, Issazadeh S, et al.: Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy. J Clin Invest 1998;102(4):671–678.

    PubMed  CAS  Google Scholar 

  4. Balashov KE, Comabella M, Ohashi T, et al.: Defective regulation of 1FN gamma and IL-12 by endogenous IL-10 in progressive MS. Neurology 2000;55(2):192–198.

    PubMed  CAS  Google Scholar 

  5. Karni A, Koldzic DN, Bharanidharan P, et al.: IL-18 is linked to raised 1FN-gamma in multiple sclerosis and is induced by activated CD4(+) T cells via CD40-CD40 ligand interactions. J Neuroimmunol 2002;125(1–2):134–140.

    PubMed  CAS  Google Scholar 

  6. Khademi M, Wallstrom E, Andersson M, et al.: Reduction of both pro- and anti-inflammatory cytokines after 6 months of interferon beta-1a treatment of multiple sclerosis. J Neuroimmunol 2000;103(2):202–210.

    PubMed  CAS  Google Scholar 

  7. Lunemann JD, Aktas O, Gniadek P, et al.: Down-regulation of transforming growth factor-betal in interferon-betala-treated MS patients. Neurology 2001;57(6):1132–1134.

    PubMed  CAS  Google Scholar 

  8. Wandinger KP, Sturzebecber CS, Bielekova B, et al.: Complex immunomodulatory effects of interferon-beta in multiple sclerosis include the upregulation of T helper 1-associated marker genes. Ann Neurol 2001;50(3):349–357.

    PubMed  CAS  Google Scholar 

  9. Dhib-Jalbut S: Mechanisms of action of interferons and glatiramer acetate in multiple sclerosis. Neurology 2002;58(8 Suppl 4):S3-S9.

    PubMed  CAS  Google Scholar 

  10. Yong VW: Differential mechanisms of action of interferon-beta and glatiramer aetate in MS. Neurology 2002;59(6):802–808.

    PubMed  CAS  Google Scholar 

  11. 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):967–976.

    PubMed  CAS  Google Scholar 

  12. Karp CL, van Boxel-Dezaire AH, Byrnes AA, et al.: Interferon-beta in multiple sclerosis: altering the balance of interleukin-12 and interleukin-10? Curr Opin Neurol 2001;14(3):361–368.

    PubMed  CAS  Google Scholar 

  13. Weiner HL, Cohen JA: Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects. Mult Scler 2002;8(2):142–154.

    PubMed  CAS  Google Scholar 

  14. Zhang J, Markovic-Plese S, Lacet B, et al.: Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. J Exp Med, 1994;179(3):973–984.

    PubMed  CAS  Google Scholar 

  15. Hafler DA, Kent SC, Pietrusewicz MJ, et al.: Oral administration of myelin induces antigen-specific TGF-beta 1 secreting T cells in patients with multiple sclerosis. Ann N Y Acad Sci 1997;835(1):120–131.

    PubMed  CAS  Google Scholar 

  16. Fukaura H Kent SC, Pietrusewicz MJ, et al.: Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factor-betal-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients. J Clin Invest 1996;98(1):70–77.

    PubMed  CAS  Google Scholar 

  17. Minguela A, Torio A, Marin L, et al.: Implication of Th1-Th2, and Th3 cytokines in liver graftacceptance. Transplant Proc 1999;31(1–2):519–520.

    PubMed  CAS  Google Scholar 

  18. Powell MB, Mitchell D, Ledennan J, et al.: Lymphotoxin and tumor necrosis factor-alpha production by myelin basic protein-specific T cell clones correlates with encephalitogenicity Int Immunol 1990;2(6):539–544.

    PubMed  CAS  Google Scholar 

  19. Zamvil SS, Nelson PA, Mitchell DJ, et al.: Encephalitogenic T cell clones specific for myelin basic protein. Anunusual bias inantigen recognition. J Exp Med 1985;162(6):2107–2124.

    PubMed  CAS  Google Scholar 

  20. Khoury SJ, Hancock WW, Weiner HL: Oral tolerance to myel in basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with down regulation of inflammatory cytokines and differential upregulation of transforming growth factor beta, interleukin 4, and prostaglandin E expression in the brain. J Exp Med 1992;176(5):1355–1364.

    PubMed  CAS  Google Scholar 

  21. Issazadeh S, Navikas V, Schaub M, et al.: Kinetics of expression of costimulatory molecules and their ligands in murine relapsing experimental autoimmune encephalomyelitis in vivo. J Immunol 1998;161(3):1104–1112.

    PubMed  CAS  Google Scholar 

  22. Issazadeh S, Ljungdahl A, Hojeberg B, et al.: Cytokine production in the central nervous system of Lewis rats with experimental autoimmune encephalomyelitis: dynamics of mRNA expression for interleukin-10, interleukin-12, cytolysin, tumor necrosis factor alpha and tumor necrosis factor beta. J Neuroimmunol 1995;61(2):205–212.

    PubMed  CAS  Google Scholar 

  23. Chen Y, Kuchroo VK, Inobe J, et al.: Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 1994;265(5176):1237–1240.

    PubMed  CAS  Google Scholar 

  24. Kuchroo VK, Das MP, Brown JA, et al.: B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy. Cell 1995;80(5):707–718.

    PubMed  CAS  Google Scholar 

  25. Cua DJ, Hinton DR, Stohlman SA: Self-antigen-induced Th2 responses in experimental allergic encephalomyelitis (EAE)-resistant mice. Th2-mediated suppression of autoimmune disease. J Immunol 1995;155(8):4052–4059.

    PubMed  CAS  Google Scholar 

  26. Khoruts A, Miller SD, Jenkirs MK: Neuroantigen-specific Th2 cells are in efficient suppressors of experimental autoimmune encephalomyelitis induced by effector Th1 cells. J Immunol, 1995;155(10):5011–5017.

    PubMed  CAS  Google Scholar 

  27. Lafaille JJ, Keere FV, Hsu AL, et al.: Myelin basic protein-specific T helper 2 (Th2) cells cause experimental autoimmune encephalomyelitis in immunodeficient hosts rather than protect them from the disease. J Exp Med 1997;186(2):307–312.

    PubMed  CAS  Google Scholar 

  28. Wensky A, Marcondes MC, Lafaille JJ: The role of IFN-gamma in the production of Th2 subpopulations: implications for variable Th2-mediated pathologies in autoimmunity. J Immunol, 2001;167(6):3074–3081.

    PubMed  CAS  Google Scholar 

  29. Issazadeh S, Mustafa M, Ljungdahl A, et al.: Interferon gamma, interleukin 4 and transforming growth factor beta in experimental autoimmune encephalomyelitis in Lewis rats: dynamics of cellular mRNA expression in the central nervous system and lymphoid cells. J Neurosci Res 1995;40(5):579–590.

    PubMed  CAS  Google Scholar 

  30. Begolka WS, Vanderlugt CL, Rahbe SM, et al.: Differential expression of inflammatory cytokines parallels progression of central nervous system pathology in two clinically distinct models of multiples clerosis. J Immunol 1998;161(8):4437–4446.

    PubMed  CAS  Google Scholar 

  31. Renno T, Taupin V, Bourbonniere L, et al.: Interferon-gamma in progression to chronic demyelination and neurological deficit following acute EAE. Mol Cell Neurosci 1998;12(6):376–389.

    PubMed  CAS  Google Scholar 

  32. Ferber IA, Brocke S, Taylor-Edwards C, et al.: Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol 1996;156(1):5–7.

    PubMed  CAS  Google Scholar 

  33. Lublin FD, Knobler RL, Kalman B, et al.: Monoclonal anti-gamma interferon antibodies enhance experimental allergic encephalomyelitis. Autoimmunity, 1993; 16(4):267–274.

    PubMed  CAS  Google Scholar 

  34. Krakowski M, Owens T: Interferon-gamma confers resistance to experimental allergic encephalomyelitis. Eur J Immunol 1996;26(7):1641–1646.

    PubMed  CAS  Google Scholar 

  35. Konieczny BT, Dai Z, Elwood ET, et al.: IFN-gamma is critical for long-term allograft survival induced by blocking the CD28 and CD40 ligand T cell costimulation pathways. J Immunol 1998;160(5):2059–2064.

    PubMed  CAS  Google Scholar 

  36. Hassan AT, Dai Z, Konieczny BT, et al.: Regulation of alloantigen-mediated T-cell proliferation by endogenous interferon-gamma: implications for long-term allograft acceptance. Transplantation 1999;68(1):124–129.

    PubMed  CAS  Google Scholar 

  37. Badovinac VP, Tvinnereim AR, Harty JT: Regulation of antigen-specific CD8+ T cell homeostasis by perforin and interferon-gamma. Science 2000;290(5495):1354–1358.

    PubMed  CAS  Google Scholar 

  38. Chu CQ, Wittmer S, Dalton DK: Failure to suppress the expansion of the activated CD4T cell population in interferon gamma-deficient mice leads to exacerbation of experimental autoimmune encephalomyelitis. J Exp Med 2000;192(1):123–128.

    PubMed  CAS  Google Scholar 

  39. Willenborg DO, Fordham SA, Staykova MA, et al.: IFN-gamma is critical to the control of murine autoimmune encephalomyelitis and regulates both in the periphery and in the target tissue: a possible role for nitric oxide. J Immunol 1999;163(10):5278–5286.

    PubMed  CAS  Google Scholar 

  40. Liu Y, Janeway CA Jr: Interferon gamma plays a critical role in induced cell death of effector T cell: a possible third mechanism of self-tolerance. J Exp Med 1990;172(6):1735–1739.

    PubMed  CAS  Google Scholar 

  41. van der Veen RC, Dietlin TA, Dixon Gray J, et al.: Macrophage-derived nitric oxide inhibits the proliferation of activated T helper cells and is induced during antigenic stimulation of resting T cells. Cell Immunol 2000;199(1):43–49.

    PubMed  Google Scholar 

  42. Sallusto F, Lenig D, Mackay CR, et al.: Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J Exp Med 1998; 187(6):875–883.

    PubMed  CAS  Google Scholar 

  43. Vanguri P, Farber JM: IFN and virus-inducible expression of an immediate early gene, crg-2/IP-10, and a delayed gene, I-A alpha in astrocytes and microglia. J Immunol 1994;152(3):1411–1418.

    PubMed  CAS  Google Scholar 

  44. Tran EH, Prince EN, Owens T: IFN-gamma shapes immune invasion of the central nervous system via regulation of chemokines. J Immunol 2000;164(5):2759–2768.

    PubMed  CAS  Google Scholar 

  45. Chitnis T, Najafian N, Benou C, et al.: Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis. J Clin Invest 2001;108(5):739–747.

    PubMed  CAS  Google Scholar 

  46. Issazadeh S, Lorentzen JC, Mustafa MI, et al.: Cytokines in relapsing experimental autoimmune encephalomyelitis in DA rats: persistent mRNA expression of proinflammatory cytokines and absent expression of interleukin-10 and transforming growth factor-beta. J Neuroimmunol, 1996;69(1–2):103–115.

    PubMed  CAS  Google Scholar 

  47. Kuroda Y, Shimamoto Y: Human tumor necrosis factor-alpha augments experimental allergic encephalomyelitis in rats. J Neuroimmunol 1991;34(2–3):159–164.

    PubMed  CAS  Google Scholar 

  48. Selmaj K, Raine CS, Cross AH: Anti-tumor necrosis factor therapy abrogates autoimmune demyelination. Ann Neurol 1991;30(5):694–700.

    PubMed  CAS  Google Scholar 

  49. Ruddle NH, Bergman CM, McGrath KM, et al.: An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J Exp Med 1990;172(4):1193–1200.

    PubMed  CAS  Google Scholar 

  50. Probert L, Akassoglou K, Pasparakis M, et al.: Spontaneous inflammatory demyelinating disease in transgenic mice showing centralnervous system-specific expression of tumor necrosis factor alpha. Proc Natl Acad Sci USA 1995;92(24):11294–11298.

    PubMed  CAS  Google Scholar 

  51. Selmaj KW, Raine CS: Tumor necrosis factor mediates myelinandoligodendrocyte damage in vitro. Ann Neurol 1988;23(4):339–346.

    PubMed  CAS  Google Scholar 

  52. Akassoglou K, Bauer J, Kassiotis G, et al.: Oligodendrocyte apoptosis and primary demyelination induced by local TNF/p55 TNF receptor signaling in the central nervous system of transgenic mice: models for multiple sclerosis with primary oligodendrogliopathy. Am J Pathol 1998;153(3):801–813.

    PubMed  CAS  Google Scholar 

  53. Liu J, Marino MW, Wong G, et al.: TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination. Nat Med 1998;4(1):78–83.

    PubMed  CAS  Google Scholar 

  54. Frei K, Eugster HP, Bopst M, et al.: Tumor necrosis factor alpha and lymphotoxin alpha are not required for induction of acute experimental autoimmune encephalomyelitis. J Exp Med 1997;185(12):2177–2182.

    PubMed  CAS  Google Scholar 

  55. Bachmann R, Eugster HP, Frei K, et al.: Impairment of TNF-receptor-1 signaling but not fas signaling diminishes T-cell apoptosis in myelin oligodendrocyte glycoprotein peptide-induced chronic demyelinating autoimmune encephalomyelitis in mice. Am J Pathol 1999;154(5):1417–1422.

    PubMed  CAS  Google Scholar 

  56. Suvannavejh GC, Lee HO, Padilla J, et al.: Divergent roles for p55 and p75 tumor necrosis factor receptors in the pathogenes is of MOG(35–55)-induced experimental autoimmune encephalomyelitis. Cell Immunol 2000; 205(1):24–33.

    PubMed  CAS  Google Scholar 

  57. Selmaj K, Papierz W, Glabinski A, et al.: Prevention of chronic relapsing experimental autoimmune encephalomyelitis by soluble tumor necrosis factor receptor I. J Neuroimmunol 1995;56(2):135–141.

    PubMed  CAS  Google Scholar 

  58. Korner 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(8):1973–1981.

    PubMed  CAS  Google Scholar 

  59. Speiser DE, Sebzda E, Ohteki T, et al.: Tumor necrosis factor receptor p55 mediates deletion of peripheral cytotoxic T lymphocytes in vivo. Eur J Immunol 1996; 26(12):3055–3060.

    PubMed  CAS  Google Scholar 

  60. Bright JJ, Musuro BF, Du C, et al.: Expression of IL-12 in CNS and lymphoid organs of mice with experimental allergic encephalitis. J Neuroimmunol 1998;82(1): 22–30.

    PubMed  CAS  Google Scholar 

  61. Jander S, Stoll G.: Differential induction of interleukin-12, interleukin-18, and interleukin-1 beta converting enzyme mRNA in experimental autoimmune encephalomyelitis of the Lewis rat. J Neuroimmunol 1998; 91(1–2):93–99.

    PubMed  CAS  Google Scholar 

  62. Smith T, Hewson AK, Kingsley CI, et al.: Interleukin-12 induces relapse in experimental allergic encephalomyelitis in the Lewis rat. Am J Pathol 1997;150(6):1909–1917.

    PubMed  CAS  Google Scholar 

  63. Leonard JP, Waldburger KE, Goldman SJ: Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J Exp Med 1995;181(1):381–386.

    PubMed  CAS  Google Scholar 

  64. Segal BM, Shevach EM: IL-12 unmasks latent autoimmune disease in resistant mice. J Exp Med 1996;184(2):771–775.

    PubMed  CAS  Google Scholar 

  65. Waldburger KE, Hastings RC, Schaub RG, et al.: Adoptive transfer of experimental allergic encephalomyelitis after in vitro treatment with recombinant murine interleukin-12. Preferential expansion of interferon-gamma-producing cells and increased expression of macrophage-associated inducible nitric oxide synthase as immunomodulatory mechanisms. Am J Pathol 1996;148(2):375–382.

    PubMed  CAS  Google Scholar 

  66. Leonard JP, Waldburger KE, Goldman SJ: Regulation of experimental autoimmune encephalomyelitis by interleukin-12. Ann NY Acad Sci 1996;795:216–226.

    PubMed  CAS  Google Scholar 

  67. Campbell IL, Stalder AK, Akwa Y, et al.: Transgenic models to study the actions of cytokines in the central nervous system. Neuroimmunomodulation, 1998; 5(3–4):126–135.

    PubMed  CAS  Google Scholar 

  68. Segal BM, Dwyer BK, Shevach EM: An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J Exp Med 1998; 187(4):537–546.

    PubMed  CAS  Google Scholar 

  69. Gran B, Zhang GX, Yu S., et al.: IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. J Immunol 2002;169(12):7104–7110.

    PubMed  CAS  Google Scholar 

  70. Cua DJ, Sherlock J, Chen Y, et al.: Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003; 421(6924):744–748.

    PubMed  CAS  Google Scholar 

  71. Okamura H, Tsuti H, Komatsu T, et al.: Cloning of a new cytokine that induces IFN-gamma production by T cells [see comments]. Nature 1995;378(6552):88–91.

    PubMed  CAS  Google Scholar 

  72. Ushio S, Namba M, Okura T, et al.: Cloning of the cDNA for human IFN-gamma-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the protein. J Immunol 1996;156(11):4274–4279.

    PubMed  CAS  Google Scholar 

  73. Tone M, Thompson SA, Tone Y, et al.: Regulation of IL-18 (IFN-gamma-inducing factor) gene expression. J Immunol 1997;159(12):6156–6163.

    PubMed  CAS  Google Scholar 

  74. Matsumoto S, Tsuji-Takayama K, Aizawa Y, et al.: Interleukin-18 activates NF-kappa B in murine T helper type 1 cells. Biochem Biophys Res Commun 1997; 234(2):454–457.

    PubMed  CAS  Google Scholar 

  75. Jacobson NG, Szabo SJ, Weber-Nordt RM, et al.: Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat) 3 and Stat 4. J Exp Med 1995; 181(5):1755–1762.

    PubMed  CAS  Google Scholar 

  76. Chang JT, Segal BM, Nakanishi K, et al.: The costimulatory effector IL-18 on the induction of antigen-specific IFN-gamma production by resting T cells is IL-12 dependent and is mediated by up-regulation of the IL-12 receptor beta 2 subunit. Eur J Immunol 2000; 30(4):1113–1119.

    PubMed  CAS  Google Scholar 

  77. Yoshimoto T, Takeda K, Tanaka T, et al.: IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-gamma production. J Immunol 1998;161(7):3400–3407.

    PubMed  CAS  Google Scholar 

  78. Xu D, Chan WL, Leung BP, et al.: Selective expression and functions of interleukin 18 receptor on T helper (Th) type 1 but not Th2 cells. J Exp Med 1998;188(8):1485–1492.

    PubMed  CAS  Google Scholar 

  79. Fantuzzi G, Reed DA, Dinarello CA: IL-12-induced IFN-gamma is dependent on caspase-1 processing of the IL-18 precursor. J Clin Invest 1999;104(6):761–767.

    PubMed  CAS  Google Scholar 

  80. Kennedy MK, Torrance DS, Picha KS, et al.: Analysis of cytokine mRNA expression in the central nervous system of mice with experimental autoimmune encephalomyelitis reveals that IL-10 mRNA expression correlates with recovery. J Immunol 1992;149(7):2496–2505.

    PubMed  CAS  Google Scholar 

  81. Okuda Y, Sakoda S, Yanagihara T: The pattern of cytokine gene expression in lymphoid organs and peripheral blood mononuclear cells of mice with experimental allergic encephalomyelitis. J Neuroimmunol 1998;87(1–2):147–155.

    PubMed  CAS  Google Scholar 

  82. Okuda Y, Sakoda S, Bernard CC, et al.: The development of autoimmune encephalomyelitis provoked by myelinoligodendrocyte glycoprotein is associated with an upregulatory of both proinflammatory and immunoregulatory cytokines in the central nervous system. J Interferon Cytokine Res 1998;18(6):415–421.

    PubMed  CAS  Google Scholar 

  83. Mendel I, Katz A, Nozak N, et al.: Interleukin-6 functions in autoimmune encephalomyelitis: a study in genetargeted mice. Eur J Immunol 1998;28(5):1727–1737.

    PubMed  CAS  Google Scholar 

  84. Diab A, Zhu J, Xiao BG, et al.: High IL-6 and low IL-10 in the central nervous system are associated with protracted relapsing EAE in DA rats. J Neuropathol Exp Neurol 1997;56(6):641–650.

    PubMed  CAS  Google Scholar 

  85. Gijbels K, Brocke S, Abrams JS, et al.: Administration of neutralizing antibodies to interleukin-6 (IL-6) reduces experimental autoimmune encephalomyelitis and is associated with elevated levels of IL-6 bioactivity in central nervous system and circulation. Mol Med 1995; 1(7):795–805.

    PubMed  CAS  Google Scholar 

  86. Okuda Y, Sakoda S, Fujimura H, et al.: IL-6 plays a crucial role in the induction phase of myelin oligodendro cyte glucoprotein 35–55 induced experimental autoimmune encephalomyelitis. J Neuroimmunol 1999; 101(2):188–196.

    PubMed  CAS  Google Scholar 

  87. Eugster HP, Frei K, Kopf M, et al.: IL-6-deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. Eur J Immunol 1998; 28(7):2178–2187.

    PubMed  CAS  Google Scholar 

  88. Samoilova EB, Horton JL, Hilliard B, et al.: IL-6-deficientmice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. J Immunol 1998; 161(12):6480–6486.

    PubMed  CAS  Google Scholar 

  89. Karpus WJ, Gould KE, Swanborg RH: CD4+suppressor cells of autoimmune encephalomyelitis respond to T cell receptor-associated determinants on effector cells by interleukin-4 secretion. Eur J Immunol 1992;22(7): 1757–1763.

    PubMed  CAS  Google Scholar 

  90. Racke MK, Bonomo A, Scott DE, et al.: Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. J Exp Med, 1994;180(5): 1961–1966.

    PubMed  CAS  Google Scholar 

  91. 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):3299–3306.

    PubMed  CAS  Google Scholar 

  92. Shaw MK, Lorens JB, Dhawan A, et al.: Local delivery of interleukin 4 by retrovirus-transduced T lymphocytes ameliorates experimental autoimmune encephalomyelitis. J Exp Med 1997;185(9):1711–1714.

    PubMed  CAS  Google Scholar 

  93. Liblau R, Steinman L, Brocke S: Experimental autoimmune encephalomyelitis in IL-4-deficient mice. Int Immunol 1997;9(5):799–803.

    PubMed  CAS  Google Scholar 

  94. 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):4822–4830.

    PubMed  CAS  Google Scholar 

  95. Inobe J, Slavin AJ, Komagata Y, et al.: IL-4 is a differentiation factor for transforming growth factor-beta secreting Th3: cells and oral administration of IL-4 enhances oral tolerance in experimental allergic encephalomyelitis. Eur J Immunol 1998;28(9): 2780–2790.

    PubMed  CAS  Google Scholar 

  96. Rott O, Fleischer B, Cash E: Interleukin-10 prevents experimental allergic encephalomyelitis in rats. Eur J Immunol 1994;24(6):1434–1440.

    PubMed  CAS  Google Scholar 

  97. Cua DJ, Groux H, Hinton DR, et al.: Transgenic interleukin 10 prevents induction of experimental autoimmune encephalomyelitis. J Exp Med 1999;189(6): 1005–1010.

    PubMed  CAS  Google Scholar 

  98. Cannella B, Gao YL, Brosnan C, et al.: IL-10 fails to abrogate experimental autoimmune encephalomyelitis. J Neurosci Res 1996;45(6):735–746.

    PubMed  CAS  Google Scholar 

  99. Koo GC, Manyak CL, Dasch J, et al.: Suppressive effects of monocytic cells and transforming growth factor-beta on natural killer cell differentiation in autoimmune viable mothealen mutant mice. J Immunol 1991;147(4): 1194–1200.

    PubMed  CAS  Google Scholar 

  100. Stevens DB, Gould KE, Swanborg RH: Transforming growth factor-beta 1 inhibits tumor necrosis factor-alpha/lymphotoxin production and adoptive transfer of disease by effect or cells of autoimmune encephalomyelitis. J Neuroimmunol 1994;51(1):77–83.

    PubMed  CAS  Google Scholar 

  101. Shull MM, Ormsby I, Kier AB, et al.: Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 1992; 359(6397):693–699.

    PubMed  CAS  Google Scholar 

  102. Johns LD, Flanders KC, Ranges GE, et al.: Successful treatment of experimental allergic encephalomyelitis with transforming growth factor-beta 1. J Immunol 1991;147(6):1792–1796.

    PubMed  CAS  Google Scholar 

  103. Kuruvilla AP, Shah R, Hochwald GM, et al.: Protective effect of transforming growth factor beta 1 on experimental autoimmune diseases in mice. Proc Natl Acad Sci USA 1991;88(7):2918–2921.

    PubMed  CAS  Google Scholar 

  104. Santambrogio L, Hochwald GM, Saxena B, et al.: Studies on the mechanisms by which transforming growth factor-beta (TGF-beta) protects against allergic encephalomyelitis. Antagonism between TGF-beta and tumor necrosis factor. J Immunol 1993;151(2): 1116–1127.

    PubMed  CAS  Google Scholar 

  105. Racke MK, Sriaram S, Carlino J, et al.: Long-term treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-beta 2. J Neuroimmunol 1993;46(1–2): p. 175–183.

    PubMed  CAS  Google Scholar 

  106. Thorbecke GJ, Umetsu DT, deKruyff RH, et al.: When engineered to produce latent TGF-beta1, antigen specific T cells down regulate Th1 cell-mediated autoimmune and Th2 cell-mediated allergic inflammatory processes. Cytokine Growth Factor Rev 2000;11(1–2): 89–96.

    PubMed  CAS  Google Scholar 

  107. Chen LZ, Hochwald GM, Huang C, et al.: Gene therapy in allergic encephalomyelitis using myelin basic protein-specific T cells engineered to express laten transforming growth factor-beta 1. Proc Natl Acad Sci USA 1998;95(21):12516–12521.

    PubMed  CAS  Google Scholar 

  108. Johns LD, Sriram S: Experimental allergic encephalomyelitis: neutralizing antibody to TGF beta 1 enhances the clinical severity of the disease. J Neuroimmunol 1993;47(1):1–7.

    PubMed  CAS  Google Scholar 

  109. Wyss-Coray T, Borrow P, Brooker MJ, et al.: Astroglial overproduction of TGF-beta 1 enhances inflammatory central nervous system disease in transgenic mice. J Neuroimmunol 1997;77(1):45–50.

    PubMed  CAS  Google Scholar 

  110. Cash E, Minty A, Ferrara P, et al.: Macrophage-inactivating IL-13 suppresses experimental autoimmune encephalomyelitis in rats. J Immunol 1994;153(9): 4258–4267.

    PubMed  CAS  Google Scholar 

  111. Kaplan MH, Schindler U, Smiley ST, et al.: Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 1996;4(3):313–319.

    PubMed  CAS  Google Scholar 

  112. Takeda K, Tanaka T, Shi W, et al.: Essential role of State in IL-4 signalling. Nature 1996;380(6575):627–630.

    PubMed  CAS  Google Scholar 

  113. Thierfelder WE, van Deursen JM, Yamamoto K, et al.: Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 1996; 382(6587):171–174.

    PubMed  CAS  Google Scholar 

  114. Kaplan MH, Sun YL, Hoey T, et al.: Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature 1996;382(6587):174–177.

    PubMed  CAS  Google Scholar 

  115. Barbulescu K, Becker C, Schlaak JF, et al.: IL-12 and IL-18 differentially regulate the transcriptional activity of the human IFN-gamma promoter in primary CD4+ T lymphocytes. J Immunol 1998;160(8):3642–3647.

    PubMed  CAS  Google Scholar 

  116. Robinson D, Shibuya K, Mui A, et al.: IGIF does not drive Th1 development but synergizes with IL-12 for interferon-gamma production and activates 1RAK and NFkappaB. Immunity 1997;7(4):571–581.

    PubMed  CAS  Google Scholar 

  117. Chitnis T, Najafian N, Abdallah KA, et al.: CD28-independent induction of experimental autoimmune encephalomyelitis. J Clin Invest 2001;107(5):575–583.

    PubMed  CAS  Google Scholar 

  118. Schaub M, Issazadeh S, Stadlbauer TH, et al.: Costimulatory signal blockade in murine relapsing experimental autoimmune encephalomyelitis. J Neuroimmunol 1999; 96(2):158–166.

    PubMed  CAS  Google Scholar 

  119. Khoury SJ, Galloon L, Verburg RR, et al.: Ex vivo treatment of antigen-presenting cells with CTLA4Ig and encephalito genic peptide prevents experimental autoimmune encephalomyelitis in the Lewis rat. J Immunol 1996;157(8):3700–3705.

    PubMed  CAS  Google Scholar 

  120. Khoury SJ, Akalin E, Chandraker A, et al.: CD28-B7 costimulatory blockade by CTLA4Ig prevents actively induced experimental autoimmune encephalomyelitis and inhibits Th1 but spares Th2 cytokines in the central nervous system. J Immunol 1995;155(10): 4521–4524.

    PubMed  CAS  Google Scholar 

  121. Zhang X, Izikson L, Liu L, et al.: Activation of CD25(+) CD4(+) regulatory T cells by oral antigen administration. J Immunol 2001;167(8):4245–4253.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chitnis, T., Khoury, S.J. Cytokine shifts and tolerance in experimental autoimmune encephalomyelitis. Immunol Res 28, 223–239 (2003). https://doi.org/10.1385/IR:28:3:223

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/IR:28:3:223

Key words

Navigation