Skip to main content

The Role of Interferons in Experimental Autoimmune Encephalomyelitis

  • Chapter
Book cover Experimental Models of Multiple Sclerosis

Abstract

Interferons, despite their common name, comprise a group of cytokines with quite different molecular structures, cellular receptors, biological effects, functions and applications. We here review studies directed at defining the role played by these molecules when they are produced endogenously or administered exogenously in the course of experimental autoimmune encephalomyelitis (EAE), a model disease considered relevant for the pathogenesis of multiple sclerosis (MS).

Studies on the role of Type II interferon, i.e. interferon-γ (IFN-γ), are almost unanimously indicative of a beneficial role, though this is in contrast to clinical observations pertaining to the role of IFN-γ in MS. Possible explanations for this discrepancy are considered in this review.

Interferon-β (IFN-β), one of the Type I interferons, also exerts a beneficial effect in EAE. In this case there is good correspondence with clinical observations, and studies in the animal model have contributed to providing possible explanations for these beneficial effects.

Our review also covers a limited number of studies on the apparently beneficial effect of treatment with another Type I interferon, namely IFN-τ, originally discovered as a pregnancy recognition hormone in sheep.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Reference List

  1. De Maeyer, E. and J. De Maeyer-Guignard, 1998. Type I interferons. nt.Rev.Immunol. 17:53–73.

    Google Scholar 

  2. Stark, G.R., I.M. Kerr, B.R.G. Williams, R.H. Silverman, and R.D. Schreiber. 1998. How cells respond to interferons. Annu.Rev.Biochem. 67:227–264.

    PubMed  CAS  Google Scholar 

  3. Domanski. P. and O.R. Colamonici. 1996. The type I interferon receptor. The long and short of it. Cytokine Growth Factor Rev. 7:143–151.

    PubMed  CAS  Google Scholar 

  4. Wheelock, E.F. 1965. Interferon-like virus inhibitor induced in human leukocytes by phytohemagglutinin. Science 141:30–311.

    Google Scholar 

  5. Farrar. M.A. and R.D. Schreiber. 1993. The molecular cell biology of interferon-γ and its receptor. Annu.Rev.Immunol. 11:571–611.

    PubMed  CAS  Google Scholar 

  6. Billiau, A. 1996. Interferon-γ: biology and role in pathogenesis. Adv.Immunol. 62:61–130.

    PubMed  CAS  Google Scholar 

  7. Young, H.A. and K.J. Hardy. 1995. Role of interferon-γ in immune cell regulation. J.Leukocyte Biol. 58:373–381.

    PubMed  CAS  Google Scholar 

  8. Gresser, I. and F. Belardelli. 2002. Endogenous type 1 interferons as a defence against tumors. Cytokine Growth Factor Rev. 13:111–118.

    PubMed  CAS  Google Scholar 

  9. Bogdan, C. 2000. The function of type I interferons in antimicrobial immunity. Curr.Opin.Immunol. 12:419–424.

    PubMed  CAS  Google Scholar 

  10. Zamvil, S.S. and L. Steinman. 1990. The Tlymphocyte in experimental allergic encephalomyelitis. Annu.Rev.Immunol. 8:579–621.

    PubMed  CAS  Google Scholar 

  11. Martin, R., H.F. McFarland, and D.E. McFarlin. 1992. Immunological aspects of demyelinating diseases. Annu.Rev.Immunol. 10:153–187.

    PubMed  CAS  Google Scholar 

  12. Benveniste, E.N. 1992. Inflammatory cytokines within the central nervous system: sources, function, and mechanism of action. Am.J.Physiol. 263:C1–C16.

    PubMed  CAS  Google Scholar 

  13. Benveniste, E.N. and D.J. Benos. 1995. TNF-α-and IFN-γ-mediated signal transduction pathways: effects on glial gene expression and function. FASEB J 9:1577–1584.

    PubMed  CAS  Google Scholar 

  14. Sethna, M.P. and L.A. Lampson. 1991. Immune modulation within the brain:recruitment of inflammatory cells and increased major histocompatibility antigen expression following intracerebral injection of interferon-γ. J.Neuroimmunol. 34:121–132.

    PubMed  CAS  Google Scholar 

  15. Hartung, H.P., S. Jung, G. Stoll, J. Zielasek, B. Schmidt, J. Archelos, and K. Toyka. 1992. Inflammatory mediators in demyelinating disorders of the CNS and PNS. J.Neuroimmunol. 40:197–210.

    PubMed  CAS  Google Scholar 

  16. Opdenakker, G. and J. Van Damme. 1994. Cytokine-regulated proteases in autoimmune diseases. Immunol.Today 15:103–107.

    PubMed  CAS  Google Scholar 

  17. Hartung, H.P., J.J. Archelos, J. Zielasek, R. Gold, M. Koltzenburg, K.H. Reiners, and K.V. Toyka. 1995. Circulating adhesion molecules and inflammatory mediators in demyelination: a review. Neurology 45:S22–S32.

    PubMed  CAS  Google Scholar 

  18. Hughes, C.C.W., D.K. Male, and P.L. Lantos. 1988. Adhesion of lymphocytes to cerebral microvascular cells: effects of interferon-γ, tumor necrosis factor and interleukin-1. Immunology 64:677–681.

    PubMed  CAS  Google Scholar 

  19. Issekutz, T.B. 1990. Effects of six different cytokines on lymphocyte adherence to microvascular endothelium and in vivo lymphocyte migration in the rat. J.Immunol 144:2140–2146.

    PubMed  CAS  Google Scholar 

  20. Oppenheimer-Marks, N. and M. Ziff. 1988. Migration of lymphocytes through endothelial cell monolayers: augmentation by interferon-γ. Cell.Immunol. 114:307–323.

    PubMed  CAS  Google Scholar 

  21. Simmons, R.D. and D.O. Willenborg. 1990. Direct injection of cytokines into the spinal cord causes autoimmune encephalomyelitis-like inflammation. J.Neurol.Sci. 100:37–42.

    PubMed  CAS  Google Scholar 

  22. Huynh, H.K. and K. Dorovini-Zis. 1993. Effects of interferon-γ on primary cultures of human brain microvessel endothelial cells. Am.J.Pathol. 142:1265–1278.

    PubMed  CAS  Google Scholar 

  23. Hickey, W.F. 1999. Leukocyte traffic in the central nervous system: the participants and their roles. Seminars Immunol. 11:125–137.

    CAS  Google Scholar 

  24. Cannella, B., A.H. Cross, and C.S. Raine. 1990. Upregulation and coexpression of adhesion molecules correlate with relapsing autoimmune demyelination in the central nervous system. J.Exp.Med. 172:1521–1523.

    PubMed  CAS  Google Scholar 

  25. Lindsey, J.W. and L. Steinman. 1993. Competitive PCR quantification of CD4, CD8, ICAM-1, VCAM-1, and MHC class II mRNA in the central nervous system during development and resolution of experimental allergic encephalomyelitis. J.Neuroimmunol. 48:227–234.

    PubMed  CAS  Google Scholar 

  26. Steffen, B.J., E.C. Butcher, and B. Engelhardt. 1994. Evidence for involvement of ICAM-1 and VCAM-1 in lymphocyte interaction with endothelium in experimental autoimmune encephalomyelitis in the central nervous system in the SJL/J mouse. Am.J.Pathol. 145:189–201.

    PubMed  CAS  Google Scholar 

  27. McCarron, R.M., L. Wang, M.K. Racke, D.E. McFarlin, and M. Spatz. 1993. Cytokine-regulated adhesion between encephalitogenic Tlymphocytes and cerebrovascular endothelial cells. J.Neuroimmunol. 43:23–30.

    PubMed  CAS  Google Scholar 

  28. Fabry, Z., M.M. Waldschmidt, D. Hendrickson, J. Keiner, L. Love-Homan, F. Takei, and M.N. Hart. 1992. Adhesion molecules on murine brain microvascular endothelial cells: expression and regulation of ICAM-1 and Lgp 55. J.Neuroimmunol. 36:1–11.

    PubMed  CAS  Google Scholar 

  29. Yu, C.L., D.O. Haskard, D. Cavender, A. Johnson, and M. Ziff. 1985. Human γ interferon increases the binding of Tlymphocytes to endothelial cells. Clin.Exp.Immunol. 62:554–560.

    PubMed  CAS  Google Scholar 

  30. Barten, D.M. and N.H. Ruddle. 1994. Vascular adhesion molecule-1 modulation by tumor necrosis factor in experimental allergic encephalomyelitis. J.Neuroimmunol. 51:123–133.

    PubMed  CAS  Google Scholar 

  31. Kennedy, K.J. and W.J. Karpus. 1999. Role of chemokines in the regulation of Th1/Th2 and autoimmune encephalomyelitis. J.Clin.Immunol 19:273–279.

    PubMed  CAS  Google Scholar 

  32. Ransohoff, R.M. 1999. Mechanisms of inflammation in MS tissue: adhesion molecules and chemokines. J.Neuroimmunol. 98:57–68.

    PubMed  CAS  Google Scholar 

  33. Glabinski, A.R., S. O’Bryant, K. Selmaj, and R.M. Ransohoff. 2000. CXC chemokine receptors expression during chronic relapsing experimental autoimmune encephalomyelitis. Ann.NY Acad.Sci 917:135–144.

    PubMed  CAS  Google Scholar 

  34. Marfaing-Koka, A., O. Devergne, G. Gorgone, A. Portier, T.J. Schall, P. Galanaud, and D. Emilie. 1995. Regulation of the production of the RANTES chemokine by endothelial cells: Synergistic induction by IFN-γ plus TNF-α and inhibition by IL-4 and IL-13. J.Immunol. 154:1870–1878.

    PubMed  CAS  Google Scholar 

  35. Janabi, N., I. Hau, and M. Tardieu. 1999. Negative feedback between prostaglandin and α-and (β-chemokine synthesis in human microglial cells and astrocytes. J.Immunol 162:1701–1706.

    PubMed  CAS  Google Scholar 

  36. Glabinski, A.R., M. Krakowski, Y. Han, T. Owens, and R.M. Ransohoff. 1999. Chemokine expression in GKO mice (lacking interferon-γ) with experimental autoimmune encephalomyelitis. J.Neurovirology 5:95–101.

    CAS  Google Scholar 

  37. Valente, A.J., J.F. Xie, M.A. Abramova, U.O. Wenzel, H.E. Abboud, and D.T. Graves. 1998. A complex element regulates IFN-γ-stimulated monocyte chemoattractant protein-1 gene transcription. J.Immunol. 161:3719–3728.

    PubMed  CAS  Google Scholar 

  38. Popko, B., J.G. Corbin, K.D. Baerwald, J. Dupree, and A.M. Garcia. 1997. The effects of interferon-γ on the central nervous system. Mol.Neurobiol. 14:19–35.

    PubMed  CAS  Google Scholar 

  39. Merrill, J.E., LJ. Ignarro, M.P. Sherman, J. Melinek, and T.E. Lane. 1993. Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. J.Immunol. 151:2132–2141.

    PubMed  CAS  Google Scholar 

  40. Sherman, M.P., J.M. Griscavage, and LJ. Ignarro. 1992. Nitric oxide-mediated neuronal injury in multiple sclerosis. Med.Hypotheses 39:143–146.

    PubMed  CAS  Google Scholar 

  41. Li, Y., J. Atashi, C. Hayes, E. Reap, S. Hunt,III, and B. Popko. 1995. Morphological and molecular response of the MOCH-1 oligodendrocyte cell line to serum and interferon-γ: Possible implications for demyelinating disorders. J.Neurosci.Res. 40:189–198.

    PubMed  CAS  Google Scholar 

  42. Vartanian, T., Y. Li, M. Zhao, and K. Stefansson. 1995. Interferon-γ-induced oligodendrocyte cell death: implications for the pathogenesis of multiple sclerosis. Mol.Med. 1:732–743.

    PubMed  CAS  Google Scholar 

  43. Horwitz, M.S., C.F. Evans, D.B. McGavern, M. Rodriguez, and M.B.A. Oldstone. 1997. Primary demyelination in transgenic mice expressing interferon-γ. Nature Med. 3:1037–1041.

    PubMed  CAS  Google Scholar 

  44. Corbin, J.G., D. Kelly, E.M. Rath, K.D. Baerwald, K. Suzuki, and B. Popko. 1996. Targeted CNS expression of interferon-γ in transgenic mice leads to hypomyelination, reactive gliosis, and abnormal cerebellar development. Mol.Cell.Neurosci. 7:354–370.

    PubMed  CAS  Google Scholar 

  45. Renno, T., V. Taupin, L. Bourbonniere, G. Verge, E. Tran, R. De Simone, M. Krakowski, M. Rodriguez, A. Peterson, and T. Owens. 1998. Interferon-γ in progression to chronic demyelination and neurological deficit following acute EAE. Mol.Cell.Neurosci. 12:376–389.

    PubMed  CAS  Google Scholar 

  46. Seder, R.A. and W.E. Paul. 1994. Acquisition of lympokine-producing phenotypes by CD4+ T cells. Annu.Rev.Immunol. 12:635–673.

    PubMed  CAS  Google Scholar 

  47. Chomarat, P., M.-C. Rissoan, J. Banchereau, and P. Miossec. 1993. Interferon γ inhibits interleukin 10 production by monocytes. J.Exp.Med. 177:523–527.

    PubMed  CAS  Google Scholar 

  48. Ando, D.G., J. Clayton, D. Kono, J.L. Urban, and E.E. Sercarz. 1989. Encephalitogenic T cells in the B10.PL model of experimental allergic encephalomyelitis (EAE) are of the Th-1 lymphokine subtype. Cell.Immunol. 132–143.

    Google Scholar 

  49. McDonald, A.H. and R.H. Swanborg. 1988. Antigen-specific inhibition of immune interferon production by suppressor cells of autoimmune encephalomyelitis. J.Immunol. 140:1132–1138.

    PubMed  CAS  Google Scholar 

  50. Raine, C.S. 1994. The Dale E. McFarlin memorial lecture: The immunology of multiple sclerosis. Ann.Neurol. 36:S61–S72.

    PubMed  CAS  Google Scholar 

  51. Juedes. A.E. and N.H. Ruddle. 2001. Resident and infiltrating central nervous system APCs regulate the emergence and resolution of experimental autoimmune encephalomyelitis. J.Immunol. 166:5168–5175.

    PubMed  CAS  Google Scholar 

  52. Neumann, H., H. Schmidt, E. Wilharm, L. Behrens, and H. Wekerle. 1997. Interferon γ gene expression in sensory neurons: evidence for autocrine gene regulation. J.Exp.Med. 186:2023–2031.

    PubMed  CAS  Google Scholar 

  53. Adorini, L. 1999. Interleukin-12, a key cytokine in Th1-mediated autoimmune diseases. Cell.Mol.Life Sci. 55:1610–1625.

    PubMed  CAS  Google Scholar 

  54. Dinarello, C.A. 1999. Interleukin-18. Methods 19:121–132.

    PubMed  CAS  Google Scholar 

  55. Nakanishi, K., T. Yoshimoto, H. Tsutsui, and H. Okamura. 2001. Interleukin-18 regulates both Th1 and Th2 responses. Annu.Rev.Immunol. 19:423–474.

    PubMed  CAS  Google Scholar 

  56. Leonard, J.P., K.E. Waldburger, and S.J. Goldman. 1995. Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J.Exp.Med. 181:381–386.

    PubMed  CAS  Google Scholar 

  57. Heremans, H., C. Dillen, M. Groenen, E. Martens, and A. Billiau. 1996. Chronic relapsing experimental autoimmune encephalomyelitis (CREAE) in mice: enhancement by monoclonal antibodies against IFN-γ. Eur.J.Immunol. 26:2393–2398.

    PubMed  CAS  Google Scholar 

  58. Heremans, H., C. Dillen, and A. Billiau. 1996. Role of IFN-γ and IL-12 in a model for chronic relapsing EAE in Biozzi mice. Eur.Cytokine Network 7:458. (Abstr.)

    Google Scholar 

  59. Segal, B.M. and E.M. Shevach. 1996. IL-12 unmasks latent autoimmune disease in resistant mice. J.Exp.Med. 184:771–775.

    PubMed  CAS  Google Scholar 

  60. Wildbaum. G., S. Youssef, N. Grabie, and N. Karin. 1998. Neutralizing antibodies to IFN-γ-inducing factor prevent experimental autoimmune encephalomyelitis. J.Immunol. 161:6368–6374.

    PubMed  CAS  Google Scholar 

  61. Kennedy, M.K., D.S. Torrance, K.S. Picha, and K.M. Mohler. 1992. 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. 149:2496–2505.

    PubMed  CAS  Google Scholar 

  62. Merrill, J.E., D.H. Kono, J. Clayton, D.G. Ando, D.R. Hinton, and F.M. Hofman. 1992. Inflammatory leukocytes and cytokines in the peptide-induced disease of experimental allergic encephalomyelitis in SJL/J and B10.PL mice. Proc.Natl.Acad.Sci.USA 89:574–578.

    PubMed  CAS  Google Scholar 

  63. Mustafa, M., P. Diener, B. Höjeberg, P. Van der Meide, and T. Olsson. 1991. T cell immunity and interferon-γ secretion during experimental allergic encephalomyelitis in Lewis rats. J.Neuroimmunol. 31:165–177.

    PubMed  CAS  Google Scholar 

  64. Baker, D., J.K. O’Neill, and J.L. Turk. 1991. Cytokines in the central nervous system of mice during chronic relapsing experimental allergic encephalomyelitis. Cell.Immunol. 134:505–510.

    PubMed  CAS  Google Scholar 

  65. Renno, T., J.-Y. Lin, C. Piccirillo, J. Antel, and T. Owens. 1994. Cytokine production by cells in cerebrospinal fluid during Experimental Allergic Encephalomyelitis in SJL/J mice. J.Neuroimmunol. 49:1–7.

    PubMed  CAS  Google Scholar 

  66. Stoll, G., S. Müller, B. Schmidt, P. Van der Meide, S. Jung, K.V. Toyka, and H. P. Hartung. 1993. Localization of interferon-γ and la-antigen in T cell line-mediated experimental autoimmune encephalomyelitis. Am.J.Pathol. 142:1866–1875.

    PubMed  CAS  Google Scholar 

  67. Young, H.A. and K.J. Hardy. 1990. Interferon-γ: producer cells, activation stimuli, and molecular genetic regulation. Pharmac.Ther. 45:137–151.

    CAS  Google Scholar 

  68. Khoury. S.J., W.W. Hancock, and H.L. Weiner. 1992. Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor β interleukin 4, and prostaglandin E expression in the brain. J.Exp.Med. 176:1355–1364.

    PubMed  CAS  Google Scholar 

  69. Tanuma, N., M.L. Shin, T. Shin, T. Koga, K. Kogure, and Y. Matsumoto. 1999. Differential role of TNF-α and IFN-γ in the brain of rats with chronic relapsing autoimmune encephalomyelitis. J.Neuroimmunol. 96:73–79.

    PubMed  CAS  Google Scholar 

  70. Begolka, W.S., C.L. Vanderlugt, S.M. Rahbe, and S.D. Miller. 1998. Differential expression of inflammatory cytokines parallels progression of central nervous system pathology in two clinically distinct models of multiple sclerosis. J.Immunol. 161:4437–4446.

    PubMed  CAS  Google Scholar 

  71. Juedes, A.E., P. Hjelström, C.M. Bergman, A.L. Neild, and N.H. Ruddle. 2000. Kinetics and cellular origin of cytokines in the central nervous system: insight into mechanisms of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. J.Immunol. 164:419–426.

    PubMed  CAS  Google Scholar 

  72. Vass, K., K. Heininger, B. Schäfer, C.Linington, and H. Lassman. 1992. Interferon-γ potentiates antibody-mediated demyelination in vivo. Ann.Neurol. 32:198–206.

    PubMed  CAS  Google Scholar 

  73. Panitch, H.S., R.L. Hirsch, J. Schindler, and K.P. Johnson. 1987. Treatment of multiple sclerosis with γ interferon: exacerbations associated with activation of the immune system. Neurology 37:1097–1102.

    PubMed  CAS  Google Scholar 

  74. Panitch, H.S., A.S. Haley, R.L. Hirsch, and K.P. Johnson. 1987. Exacerbations of multiple sclerosis in patients treated with γ interferon. Lancet i:893–895.

    Google Scholar 

  75. Panitch, H.S. 1992. Interferons in multiple sclerosis. Drugs 44:946–962.

    PubMed  CAS  Google Scholar 

  76. Billiau, A., H. Heremans, F. Vandekerckhove, R. Dijkmans, H. Sobis, E. Meulepas, and H. Carton. 1988. Enhancement of experimental allergic encephalomyelitis in mice by antibodies against IFN-γ. J.Immunol. 140:1506–1510.

    PubMed  CAS  Google Scholar 

  77. Duong, T.T., J.St. Louis, J.J. Gilbert, F.D. Finkelman, and G.H. Strejan. 1992. Effect of anti-interferon-γ and anti-interleukin-2 monoclonal antibody treatment on the development of actively and passively induced experimental allergic encephalomyelitis in the SJL/J mouse. J.Neuroimmunol. 36:105–115.

    PubMed  CAS  Google Scholar 

  78. Duong, T.T., F.D. Finkelman, B. Singh, and G.H. Strejan. 1994. Effect of anti-interferon-γ monoclonal antibody treatment on the development of experimental allergic encephalomyelitis in resistant mouse strains. J.Neuroimmunol. 53:101–107.

    PubMed  CAS  Google Scholar 

  79. Voorthuis, J.A.C., B.M.J. Uitdehaag, C.J.A. De Groot, P.H. Goede, P.H. Van der Meide, and C.D. Dijkstra. 1990. Suppression of experimental allergic encephalomyelitis by intraventricular administration of interferon-γ in rats. Clin.Exp.Immunol. 81:183–188.

    PubMed  CAS  Google Scholar 

  80. Lublin, F.D., R.L. Knobler, B. Kalman, M. Goldhaber, J. Marini, M. Perrault, C. D’Imperio, J. Joseph, S.S. Alkan, and R. Korngold. 1993. Monoclonal anti-γ interferon antibodies enhance experimental allergic encephalomyelitis. Autoimmunity 16:264–374.

    Google Scholar 

  81. Billiau, A. 1996. Interferon-γ in autoimmunity. Cytokine Growth Factor Rev. 7:25–34.

    PubMed  CAS  Google Scholar 

  82. Ferber, I.A., S. Brocke, C. Taylor-Edwards, W. Ridgway, C. Dinisco, L. Steinman, D. Dalton, and C.G. Fathman. 1996. Mice with a disrupted IFN-γ gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J.Immunol. 156:5–7.

    PubMed  CAS  Google Scholar 

  83. Krakowski, M. and T. Owens. 1996. Interferon-γ confers resistance to experimental allergic encephalomyelitis. Eur. J.Immunol. 26:1641–1646.

    PubMed  CAS  Google Scholar 

  84. Willenborg, D.O., S. Fordham, C.C.A. Bernard, W.B. Cowden, and I.A. Ramshaw. 1996. IFN-γ plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. J.Immunol. 157:3223–3227.

    PubMed  CAS  Google Scholar 

  85. Willenborg, D.O., S.A. Fordham, M.A. Staykova, I.A. Ramshaw, and W.B. Cowden. 1999. IFN-γ 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. 163:5278–5286.

    PubMed  CAS  Google Scholar 

  86. Furlan, R., E. Brambilla, F. Ruffini, P.L. Poliani, A. Bergami, P.C. Marconi, D.M. Franciotta, G. Penna, G. Comi, L. Adorini, and G. Martino. 2001. Intrathecal delivery of IFN-γ protects C57BL/6 mice from chronic-progressive experimental autoimmune encephalomyelitis by increasing apoptosis of central nervous system-infiltrating lympocytes. J.Immunol. 167:1821–1829.

    PubMed  CAS  Google Scholar 

  87. Dalton, D.K., S. Pitts-Meek, S. Keshav, I.S. Figari, A. Bradley, and T.A. Stewart. 1993. Multiple defects of immune cell function in mice with disrupted interferon-γ genes. Science 259:1739–1742.

    PubMed  CAS  Google Scholar 

  88. van der Veen, R.C., T.A. Dietlin, J.D. Gray, and W. Gilmore. 2000. Macrophage-derived nitric oxide inhibits the proliferation of activated T helper cells and is induced during antigenic stimulation of resting T cells. Cell.Immunol. 199:43–49.

    PubMed  Google Scholar 

  89. Tran, E.H., E.N. Prince, and T. Owens. 2000. IFN-γ shapes immune invasion of the central nervous system via regulation of chemokines. J.Immunol. 164:2759–2768.

    PubMed  CAS  Google Scholar 

  90. Chu, C.-Q., S. Wittmer, and D.K. Dalton. 2000. Failure to suppress the expansion of the activated CD4 T cell population in interferon γ-deficient mice leads to exacerbation of experimental autoimmune encephalomyelitis. J.Exp.Med. 192:123–128.

    PubMed  CAS  Google Scholar 

  91. Metzger, Z., J.T. Hoffeld, and J.J. Oppenheim. 1980. Macrophage-mediated suppression. I. evidence for participation of both hydrogen peroxide and prostaglandin in suppression of murine lymphocyte proliferation. J.Immunol. 124:983–988.

    PubMed  CAS  Google Scholar 

  92. Twardzik, D.R., J.A. Mikovits, J.E. Ranchalis, A.F. Purchio, L. Ellingswaorth, and F.W. Ruscetti. 1990. γ-Interferon-induced activation of latent transforming growth-factor-fi by human monocytes. Ann.NY Acad.Sci. 593:276–284.

    PubMed  CAS  Google Scholar 

  93. Karpus, W.J. and R.H. Swanborg. 1991. CD4+ suppressor cells inhibit the function of effector cells of experimental autoimmune encephalomyelitis through a mechanism involving transforming growth factor-β. J.Immunol 146:1163–1168.

    PubMed  CAS  Google Scholar 

  94. Smith, K.J., R. Kapoor, and P.A. Felts. 1999. Demyelination: the role of reactive oxygen and nitrogen species. Brain Pathol. 9:69–92.

    PubMed  CAS  Google Scholar 

  95. Willenborg, D.O., M.A. Staykova, and W.B. Cowden. 1999. Our shifting understanding of the role of nitric oxide in autoimmune encephalomyelitis: a review. J.Neuroimmunol. 100:21–35.

    PubMed  CAS  Google Scholar 

  96. Fenyk-Melody, J.E., A.E. Garrison, S.R. Brunnert, J.R. Weidner, F. Shen, B.A. Shelton, and J.S. Mudgett. 1998. Experimental autoimmune encephalomyelitis is exacerbated in mice lacking the NOS2 gene. J.Immunol. 160:2940–2946.

    PubMed  CAS  Google Scholar 

  97. Sahrbacher, U.C., F. Lechner, H.P. Eugster, K. Frei, H. Lassmann, and A. Fontana. 1998. Mice with an inactivation of the inducible nitric oxide synthase gene are susceptible to experimental autoimmune encephalomyelitis. Eur.J.Immunol. 28:1332–1338.

    PubMed  CAS  Google Scholar 

  98. Albina, J.E., J.A. Abate, and W.L.J. Henry. 1991. Nitric oxide production is required for murine resident peritoneal macrophages to suppress mitogen-stimulated T cell proliferation Role of IFN-γ in the induction of nitric oxide-synthesizing pathway. J.Immunol. 147:144–148.

    PubMed  CAS  Google Scholar 

  99. Mills, C.D. 1991. Molecular basis of suppressor macrophages. Arginine metabolism via the nitric oxide synthetase pathway. J.Immunol. 146:2719–2723.

    PubMed  CAS  Google Scholar 

  100. Krenger, W., G. Falzarano, J. Delmonte, Jr., K.M. Snyder, J.C.H. Byon, and J.L.M. Ferrara. 1996. Interferon-γ suppresses T-cell proliferation to mitogen via the nitric oxide pathway during experimental acute graft-versus-host disease. Blood 88:1113–1121.

    PubMed  CAS  Google Scholar 

  101. Sicher, S.C., M.A. Vazquez, and C.Y. Lu. 1994. Inhibition of macrophage Ia expression by nitric oxide. J.Immunol. 153:1293–130.

    PubMed  CAS  Google Scholar 

  102. Schmied, M., H. Breitschopf, R. Gold, H. Zischer, G. Rothe, and H. Wekerle. 1993. Apoptosis of T lymphocytes in experimental autoimune encephalomyelitis. Evidence for programmed cell death as a mechanism to control inflammation in the brain. Am.J.Pathol. 143:446–452.

    PubMed  CAS  Google Scholar 

  103. Bonetti, B., J. Pohl, Y.L. Gao, and C.S. Raine. 1997. Cell death during autoimmune demyelination: effector but not target cells are eliminated by apoptosis. J.Immunol. 159:5733–5741.

    PubMed  CAS  Google Scholar 

  104. Pender, M.P., K.B. Nguyen, P.A. McCombe, and J.F. Kerr. 1991. Apoptosis in the nervous system in experimental allergic encephalomyelitis. J.Neurol.Sci. 104:81–87.

    PubMed  CAS  Google Scholar 

  105. Bauer, J., M. Bradl, W.F. Hickey, S. Forss-Petter, H. Breitschopf, C. Linington, H. Wekerle, and H. Lassmann. 1998. T-cell apoptosis in inflammatory brain lesions. Destruction of T cells does not depend on antigen recognition. Am.J.Pathol. 153:715–724.

    PubMed  CAS  Google Scholar 

  106. Liu, Y. and C.A. Jr. Janeway. 1990. Interferon γ plays a critical role in induced cell death of effector T cell: a possible third mechanism of self-tolerance. J.Exp.Med. 172:1735–1739.

    PubMed  CAS  Google Scholar 

  107. Novelli, F., F. Di Pierro, P.F. Di Celle, S. Bertini, P. Affaticati, G. Garotta, and G. Forni. 1994. Environmental signals influencing expression of the IFN-γ receptor on human T cells control whether IFN-g promotes proliferation or apoptosis. J.Immunol. 152:496–504.

    PubMed  CAS  Google Scholar 

  108. Dalton, D.K., L. Haynes, C.-Q. Chu, S.L. Swain, and S. Wittmer. 2000. Interferon γ eliminates responding CD4 T cells during mycobacterial infection by inducing apoptosis of activated CD4 T cells. J.Exp.Med. 192:117–122.

    PubMed  CAS  Google Scholar 

  109. Ren, Y. and J. Savill. 1998. Apoptosis: the importance of being eaten. Cell Death Differentiation 5:563–568.

    CAS  Google Scholar 

  110. Platt, N., R.P. da Silva, and S. Gordon. 1998. Recognizing death: the phagocytosis of apoptitic cells. Trends Cell Biol. 8:368–372.

    Google Scholar 

  111. Nguyen, K.B. and M.P. Pender. 1998. Phagocytosis of apoptotic lymphocytes by oligodendrocytes in experimental autoimmune encephalomyelitis. Acta Neuropathol. 95:40–46.

    PubMed  CAS  Google Scholar 

  112. Ren, Y. and J. Savill. 1995. Proinflammatory cytokines potentiate thrombospondin-mediated phagocytosis of neutrophils undergoing apoptosis. J.Immunol, 154:2366–2374.

    PubMed  CAS  Google Scholar 

  113. Chan, A., T. Magnus, and R. Gold. 2001. Phagocytosis of apoptotic inflammatory cells by microglia and modulation by different cytokines: mechanisms for removal of apoptotic cells in the inflamed nervous system. Clia 33:87–95.

    CAS  Google Scholar 

  114. Gusella, G.L., T. Musso, M.C. Bosco, I. Espinoza-Delgado, K. Matsushima, and L. Varesio. 1993. IL-2 up-regulates but IFN-γ suppresses IL-8 expression in human monocytes. J.Immunol. 151:2725–2732.

    PubMed  CAS  Google Scholar 

  115. Asensio, V.C., H. Lassmann, A. Pagenstecher, S.C. Steffensen, S.J. Henriksen, and I. Campbell. 1999. C10 is a novel chemokine expressed in experimental inflammatory demyelinating disorders that promotes recruitment of macrophages to the central nervous system. Am.J.Pathol. 154:1181–1191.

    PubMed  CAS  Google Scholar 

  116. McColl, S.R., M.A. Staykova, A. Wozniak, S. Fordham, J. Bruce, and D.O. Willenborg. 1998. Treatment with anti-granulocyte antibodies inhibits the effector phase of experimental autoimmune encephalomyelitis. J.Immunol. 161:6421–6426.

    PubMed  CAS  Google Scholar 

  117. Liu, Y.J., H. Kanzler, V. Soumelis, and M. Gilliet. 2001. Dendritic cell lineage, plasticity and cross-regulation. Nature Immunol. 2:585–589.

    CAS  Google Scholar 

  118. Asselin-Paturel, C., A. Boonstra, M. Dalod, I. Durand, N. Yessaad, C. Dezutter-Dambuyant, A. Vicari, A. O’Garra, C. Biron, and G. Trinchieri. 2001. Mouse type I interferon producing cells are immature antigen-presenting cells with plasmacytoid morphology. Nature Immunol. 2:1144–1150.

    CAS  Google Scholar 

  119. De Maeyer, E. and J. De Maeyer-Guignard. 1994. Interferons. In The Cytokine Handbook. A. Thompson, editor. Academic Press, 265–288.

    Google Scholar 

  120. Brierley, M.M. and E.N. Fish. 2002. IFN-α/β receptor interactions to biologic outcomes: understanding the circuitry. J.Interferon Cytokine Res. 22:835–845.

    PubMed  CAS  Google Scholar 

  121. Chofflon, M. 2000. Recombinant human interferon β in relapsing-remitting multiple sclerosis: a review of the major clinical trials. Eur.J.Neurol. 7:369–380.

    PubMed  CAS  Google Scholar 

  122. Durelli, L., M.R. Bongioanni, R. Cavallo, B. Ferrero, R. Ferri, E. Verdun, G.B. Bradac, A. Riva, M. Geuna, L. Bergamini, and et al. 1995. Interferon α treatment of relapsing-remitting multiple sclerosis: long-term study of the correlations between clinical and magnetic resonance imaging results and effects on the immune function. Multiple Sclerosis 1:S32–S37.

    PubMed  CAS  Google Scholar 

  123. Myhr, K.M., T. Riise, F.E. Green Lilleas, T.G. Beiske, E.G. Celius, A. Edland, D. Jensen, J.P. Larsen, R. Nilsen, M.W. Nortvedt, A.I. Smievoll, C. Vedeler, and H.I. Nyland. 1999. Interferon-α2a reduces MRI disease activity in relapsing-remitting multiple sclerosis. Neurology 52:1049–1056.

    PubMed  CAS  Google Scholar 

  124. Brod, S.A., J.W. Lindsey, F.S. Vriesendorp, C. Ahn, E. Henninger, P.A. Narayana, and J.S. Wolinsky. 2001. Ingested IFN-α. Neurology 57:845–852.

    PubMed  CAS  Google Scholar 

  125. Abreu, S.L., J. Tondreau, S. Levine, and R. Sowinski. 1983. Inhibition of passive localized experimental allergic encephalomyelitis by interferon. Int.Arch.Allergy Appl.Immunol. 72:30–33.

    PubMed  CAS  Google Scholar 

  126. Abreu, S.L. 1982. Suppression of experimental allergic encephalomyelitis by interferon. Immunol.Commun. 11:1–7.

    PubMed  CAS  Google Scholar 

  127. Hertz, F. and R. Degheni. 1985. Effect of rat and β-human interferons on hyperacute experimental allergic encephalomyelitis in rats. Agents and Actions 16:397–403.

    PubMed  CAS  Google Scholar 

  128. Yu, M., A. Nishiyama, B.D. Trapp, and V.K. Tuohy. 1996. Interferon-β inhibits progression of relapsing-remitting experimental autoimmune encephalomyelitis. J.Neuroimmunol. 64:91–100.

    PubMed  CAS  Google Scholar 

  129. Inada, T. and C.A. Mims. 1986. Infection of mice with lactic dehydrogenase virus prevents development of experimental allergic encephalomyelitis. J.Neuroimmunol. 11:53–56.

    PubMed  CAS  Google Scholar 

  130. Brod, S.A., M. Khan, R.H. Kerman, and M. Pappolla. 1995. Oral administration of human or murine interferon α suppresses relapses and modifies adoptive transfer in experimental autoimmune encephalomyelitis. J.Neuroimmunol. 58:61–69.

    PubMed  CAS  Google Scholar 

  131. Brod, S.A. and D.K. Burns. 1994. Suppression of relapsing experimental autoimmune encephalomyelitis in the SJL/J mouse by oral administration of type I interferons. Neurology 44:1144–1148.

    PubMed  CAS  Google Scholar 

  132. Nelson, P.A., Y. Akselband, S.M. Dearborn, A. Al-Sabbagh, Z.J. Tian, P.A. Gonnella, S.S. Zamvil, Y. Chen, and H.L. Weiner. 1996. Effect of oral β interferon on subsequent immune responsiveness. Ann.NY Acad.Sci 778:145–155.

    PubMed  CAS  Google Scholar 

  133. Abreu, S.L., I. Thampoe, and P. Kaplan. 1986. Interferon in experimental autoimmune encephalomyelitis: intraventricular administration. J.Interferon Res. 6:627–632.

    PubMed  CAS  Google Scholar 

  134. Ruuls, S.R., M.C.D.C. de Labie, K.S. Weber, C.A.D. Botman, R.J. Groenestein, C.D. Dijkstra, T. Olsson, and P.H. Van der Meide. 1996. The length of treatment determines whether IFN-β prevents or aggravates experimental autoimmune encephalomyelitis in Lewis rats. J.Immunol. 157:5721–5731.

    PubMed  CAS  Google Scholar 

  135. Van der Meide, P.H., M.C. de Labie, S.R. Ruuls, R.J. Groenestein, C.A. Botman, T. Olsson, and C.D. Dijkstra. 1998. Discontinuation of treatment with IFN-β leads to exacerbation of experimental autoimmune encephalomyelitis in Lewis rats. Rapid reversal of the antiproliferative activity of IFN-β and excessive expansion of autoreactive T cells as disease promoting mechanisms. J.Neuroimmunol. 84:14–23.

    PubMed  Google Scholar 

  136. Croxford, J.L., K. Triantaphyllopoulos, O.L. Podhajcer, M. Feldmann, D. Baker, and Y. Chernajovsky. 1998. Cytokine gene therapy in experimental allergic encephalomyelitis by injection of plasmid DNA-cationic liposome complex into the central nervous system. J.Immunol. 160:5181–5187.

    PubMed  CAS  Google Scholar 

  137. Brod, S.A. and M. Khan. 1996. Oral administration of IFN-α is superior to subcutaneous administration of IFN-α in the suppression of chronic relapsing experimental autoimmune encephalomyelitis. J.Autommunity 9:11–20.

    CAS  Google Scholar 

  138. Brod, S.A., M. Scott, D.K. Burns, and J.T. Phillips. 1995. Modification of acute experimental autoimmune encephalomyelitis in the Lewis rat by oral administration of type 1 Interferons. J.Interferon Res. 15:115–122.

    CAS  Google Scholar 

  139. Yong, V.W., S. Chabot, O. Stuve, and G. Williams. 1998. Interferon β in the treatment of multiple sclerosis: mechanisms of action. Neurology 51:682–689.

    PubMed  CAS  Google Scholar 

  140. Luca, M.E., L. Visser, C.J. Lucas, and L. Nagelkerken. 1999. IFN-β modulates specific T cell responses in vitro but does not affect experimental autoimmune encephalomyelitis in the SJL mouse. J.Neuroimmunol. 100:190–196.

    PubMed  CAS  Google Scholar 

  141. Noronha, A., A. Toscas, and M.A. Jensen. 1993. Interferon β decreases T cell activation and interferon γ production in multiple sclerosis. J.Neuroimmunol. 46:145–153.

    PubMed  CAS  Google Scholar 

  142. Ling, P.D., M.K. Warren, and S.N. Vogel. 1985. Antagonistic effect of interferon-α/β on the interferon-γ-induced expression of Ia antigen in murine macrophages. J.Immunol. 135:1857–1863.

    PubMed  CAS  Google Scholar 

  143. Ransohoff, R.M., C. Devajyothi, M.L. Estes, G. Babcock, R.A. Rudick, E.M. Frohman, and B.P. Barna. 1991. Interferon-β specifically inhibits interferon-γ-induced class II major histocompatibility complex gene transcription in a human astrocytoma cell line. J.Neuroimmunol. 33:103–112.

    PubMed  CAS  Google Scholar 

  144. Soilu-Hanninen, M., A. Salmi, and R. Salonen. 1995. Interferon-β downregulates expression of VLA-4 antigen and antagonizes interferon-γ-induced expression of HLA-DQ on human peripheral blood monocytes. J.Neuroimmunol. 60:99–106.

    PubMed  CAS  Google Scholar 

  145. Miller, A., N. Lanir, S. Shapiro, M. Revel, S. Honigman, A. Kinarty, and N. Lahat. 1996. Immunoregulatory effects of interferon-β and interacting cytokines on human vascular endothelial cells. Implications for multiple sclerosis and other autoimmune diseases. J.Neuroimmunol. 64:151–161.

    PubMed  CAS  Google Scholar 

  146. Brown, K.A. 2001. Factors modifying the migration of lymphocytes across the blood-brain barrier. Int.Immunopharmacol. 1:2043–2062.

    PubMed  CAS  Google Scholar 

  147. Floris, S., S.R. Ruuls, A. Wierinckx, S.M.A. van der Pol, E. Döpp, P.H. Van der Meide, C.D. Dijkstra, and H.E. De Vries. 2002. Interferon-β directly influences monocyte infiltration into the central nervous system. J.Neuroimmunol. 127:69–79.

    PubMed  CAS  Google Scholar 

  148. Defazio, G., M. Gelati, E. Corsini, B. Nico, A. Dufour, G. Massa, and A. Salmaggi. 2002. In vitro modulation of adhesion molecules, adhesion phenomena, and fluid phase endocytosis on human umbilical vein endothelial cells and brain-derived microvascular endothelium by IFN-β1a. J.Interferon Cytokine Res. 21:267–272.

    Google Scholar 

  149. Lou, J., Y. Gasche, L. Zheng, C. Giroud, P. Morel, J. Clements, A. Ythier, and G.E. Grau. 1999. Interferon-β inhibits activated leukocyte migration through human brain microvascular endothelial cell monolayer. Lab.Invest. 79:1015–1025.

    PubMed  CAS  Google Scholar 

  150. Calabresi, P.A., C.M. Pelfrey, L.R. Tranquill, H. Maloni, and H.F. McFarland. 1997. VLA-4 expression on peripheral blood lymphocytes is downregulated after treatment of multiple sclerosis with interferon β. Neurology 49:1111–1116.

    PubMed  CAS  Google Scholar 

  151. Muraro, P.A., T. Leist, B. Bielekova, and H.F. McFarland. 2000. VLA-4/CD49d downregulated on primed T lymphocytes during interferon-β therapy in multiple sclerosis. J.Neuroimmunol. 111:186–194.

    PubMed  CAS  Google Scholar 

  152. Yong, V.W., C.A. Krekoski, P.A. Forsyth, R. Bell, and D.R. Edwards. 1998. Matrix metalloproteinases and diseases of the CNS. Trends Neurosci. 21:75–80.

    PubMed  CAS  Google Scholar 

  153. Leppert, D., R.L.P. Lindberg, L. Kappos, and S.L. Leib. 2001. Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis. Brain Res.Rev. 36:249–257.

    PubMed  CAS  Google Scholar 

  154. Stuve, O., N.P. Dooley, J.H. Uhm, J.P. Antel, G.S. Francis, G. Williams, and V.W. Yong. 1996. Interferon β-1b decreases the migration of T lymphocytes in vitro: effects on matrix metalloproteinase-9. Ann.Neurol. 40:853–863.

    PubMed  CAS  Google Scholar 

  155. Leppert, D., E. Waubant, M.R. Burk, J.R. Oksenberg, and S.L. Hauser. 1996. Interferon β-1b inhibits gelatinase secretion and in vitro migration of human T cells: a possible mechanism for treatment efficacy in multiple sclerosis. Ann.Neurol. 40:846–852.

    PubMed  CAS  Google Scholar 

  156. Ozenci, V., M. Kouwenhoven, N. Teleshova, M. Pashenkov, S. Fredrikson, and H. Link. 2000. Multiple sclerosis: pro-and anti-inflammatory cytokines and metalloproteinases are affected differentially by treatment with IFN-β. J.Neuroimmunol. 108:236–243.

    PubMed  CAS  Google Scholar 

  157. Galboiz, Y., S. Shapiro, N. Lahat, H. Rawashdeh, and A. Miller. 2001. Matrix metalloproteinases and their tissue inhibitors as markers of disease subtype and response to interferon-β therapy in relapsing and secondary-progressive multiple sclerosis patients. Ann.Neurol. 50:443–451.

    PubMed  CAS  Google Scholar 

  158. Uhm, J.H., N.P. Dooley, O. Stuve, G.S. Francis, P. Duquette, J.P. Antel, and V.W. Yong, 1999. Migratory behavior of lymphocytes isolated from multiple sclerosis patients: effects of interferon β-1b therapy. Ann.Neurol. 46:319–324.

    PubMed  CAS  Google Scholar 

  159. Comabella, M., J. Imitola, H.L. Weiner, and S.J. Khoury. 2002. Interferon-β treatment alters peripheral blood monocytes chemokine production in MS patients. J.Neuroimmunol. 127:205–212.

    Google Scholar 

  160. Zang, Y.C.Q., J.B. Haider, A.K. Samanta, J. Hong, V.M. Rivera, and I.Z. Zhang. 2001. Regulation of chemokine receptor CCR5 and production of RANTES and MIP-lα by interferon-β. J.Neuroimmunol. 112:174–180.

    PubMed  CAS  Google Scholar 

  161. Iarlori, C., M. Reale, A. Lugaresi, G. De Luca, L. Bonanni, A. Di-Iorio, C. Feliciani, P. Conti, and D. Gambi. 2000. RANTES production and expression is reduced in relapsing-remitting multiple sclerosis patients treated with interferon-β1b. J.Neuroimmunol. 107:100–107.

    PubMed  CAS  Google Scholar 

  162. Teleshova, N., M. Pashenkov, Y.M. Huang, M. Soderstrom, P. Kivisakk, V. Kostulas, M. Haglund, and H. Link. 2002. Multiple sclerosis and optic neuritis: CCR5 and CXCR3 expressing T cells are augmented in blood and cerebrospinal fluid. J.Neurology 249:723–729.

    Google Scholar 

  163. Satoh, J., D.W. Paty, and S.U. Kim. 1996. Counteracting effect of IFN-β on IFN-γ-induced proliferation of human astrocytes in culture. Multiple Sclerosis 1:279–287.

    PubMed  CAS  Google Scholar 

  164. Akbar, A.N., J.M. Lord, and M. Salmon. 2000. IFN-α and IFN-β: a link between immune memory and chronic inflammation. immunol.Today 21:337–342.

    PubMed  CAS  Google Scholar 

  165. Zipp, F., M. Beyer, H. Gelderblom, D. Wernet, R. Zschenderlein, and M. Weller. 2000. No induction of apoptosis by IFN-β in human antigen-specific T cells. Neurology 54:485–487.

    PubMed  CAS  Google Scholar 

  166. Schmidt, J., S. Stürzebecher, K.V. Toyka, and R. Gold. 2001. Interferon-β treatment of experimental autoimmune encephalomyelitis leads to rapid nonapototic termination of T cell infiltration. J.Neurosci.Res. 65:59–67.

    PubMed  CAS  Google Scholar 

  167. Ozenci, V., M. Kouwenhoven, Y.M. Huang, P. Kivisakk, and H. Link. 2000. Multiple sclerosis is associated with an imbalance between tumour necrosis factor-α (TNF-α)-and IL-10-secreting blood cells that is corrected by interferon-β (IFN-β) treatment. Clin.Exp.Immunol 120:147–153.

    PubMed  CAS  Google Scholar 

  168. Abu-khabar, K.S., J.A. Armstrong, and M. Ho. 1992. Type I interferons (IFN-α and-β) suppress cytotoxin (tumor necrosis factor-α and lymphotoxin) production by mitogen-stimulated human peripheral blood mononuclear cells. J.Leukocyte Biol. 52:165–172.

    PubMed  CAS  Google Scholar 

  169. Selmaj, K., C.S. Raine, M. Farooq, W.T. Norton, and C.F. Brosnan. 1991. Cytokine cytotoxicity against oligodendrocytes. Apoptosis induced by Lymphotoxin. J.Immunol. 147:1522–1529.

    PubMed  CAS  Google Scholar 

  170. Selmaj, K. and C.S. Raine. 1988. Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann.Neurol. 23:339–346.

    PubMed  CAS  Google Scholar 

  171. Ruddle, N.H., C.M. Bergman, K.M. McGrath, E.G. Lingenheld, M.L. Grunnet, S.J. Padula, and R.B. Clark. 1990. An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J.Exp.Med 172:1193–1200.

    PubMed  CAS  Google Scholar 

  172. Brod, S.A., M. Khan, L.D. Nelson, B. Decuir, M. Malone, and E. Henninger. 2000. Adoptive transfer from interferon-α-fed mice is associated with inhibition of active experimental autoimmune encephalomyelitis by decreasing recipient tumor necrosis factor-α secretion. J.Immunotherapy 23:235–245.

    CAS  Google Scholar 

  173. Rudick, R.A., R.M. Ransohoff, R. Peppler, S. Vanderbrug-Medendorp, P. Lehmann, and J. Alam. 1996. Interferon β induces interleukin-10 expression: relevance to multiple sclerosis. Ann.Neurol. 40:618–627.

    PubMed  CAS  Google Scholar 

  174. Yasuda, C.L., A. Al-Sabbagh, E.C. Oliveìra, B.M. Diaz-Bardales, A.A. Garcia, and L.M. Santos. 1999. Interferon β modulates experimental autoimmune encephalomyelitis by altering the pattern of cytokine secretion. Immunol.Invest. 28:126.

    Google Scholar 

  175. Soos, J.M., O. Stuve, S. Youssef, M. Bravo, H.M. Johnson, H.L. Weiner, and S.S. Zamvil. 2002. Oral type I IFN-τ promotes Th2 bias and enhances suppression of autoimmune encephalomyelitis by oral glatiramer acetate. J.Immunol. 169:2235.

    Google Scholar 

  176. Rudick, R.A., R.M. Ransohoff, J.C. Lee, R. Peppler, M. Yu, P.M. Mathisen, and V.K. Tuohy. 1998. In vivo effects of interferon β-1a on immunosuppressive cytokines in multiple sclerosis. Neurology 50:1294–1300.

    PubMed  CAS  Google Scholar 

  177. Ossege, L.M., E. Sindern, T. Patzold, and J.P. Malin. 1998. Immunomodulatory effects of interferon-β-1b in vivo: induction of the expression of transforming growth factor-β1 and its receptor type II. J.Neuroimmunol. 91:73–81.

    PubMed  CAS  Google Scholar 

  178. Liu, Z., C.M. Pelfrey, A. Cotleur, J.C. Lee, and R.A. Rudick. 2001. Immunomodulatory effects of interferon β-1a in multiple sclerosis. J.Neuroimmunol. 112:153–162.

    PubMed  CAS  Google Scholar 

  179. Segal, B.M., B.K. Dwyer, and E.M. Shevach. 1998. An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J.Exp.Med. 187:537–546.

    PubMed  CAS  Google Scholar 

  180. McRae, B.L., R.T. Semnani, M.P. Hayes, and G.A. van Seventer. 1998. Type I IFNs inhibit human dendritic cell IL-12 production and Th1 cell development. J.Immunol 160:4298–4304.

    PubMed  CAS  Google Scholar 

  181. McRae, B.L., B.A. Beilfuss, and G.A. van Seventer. 2000. IFN-β differentially regulates CD40-induced cytokine secretion by human dendritic cells. J.Immunol. 164:23–28.

    PubMed  CAS  Google Scholar 

  182. Tuohy, V.K., M. Yu, L. Yin, P.M. Mathisen, J.M. Johnson, and J.A. Kawczak. 2000. Modulation of the IL-10/IL-12 cytokine circuit by interferon-β inhibits the development of epitope spreading and disease progression in murine autoimmune encephalomyelitis. J.Neuroimmunol. 111:55–63.

    PubMed  CAS  Google Scholar 

  183. Noronha, A., A. Toscas, and M.A. Jensen. 1992. Contrasting effects of α, β and γ interferons on nonspecific suppressor function in multiple sclerosis. Ann.Neurol. 31:103–106.

    PubMed  CAS  Google Scholar 

  184. Noronha, A., A. Toscas, and M.A. Jensen. 1990. Interferon β augments suppressor cell function in multiple sclerosis. Ann.Neurol 27:207–210.

    PubMed  CAS  Google Scholar 

  185. Martal, J.L, N.M. Chene, L.P. Huynh, R.M. L’Haridon, P.B. Reinaud, M.W. Guillomot, M.A. Charlier, and S.Y. Charpigny. 1998. IFN-τ: a novel subtype I IFN1. Structural characteristics, non-ubiquitous expression, structure-function relationships, a pregnancy hormonal embryonic signal and cross-species therapeutic potentialities. Biochimie 80:755–777.

    PubMed  CAS  Google Scholar 

  186. Soos, J.M. and H.M. Johnson. 1999. Interferon-τ. Prospects for clinical use in autoimmune disease. Biodrugs 11:125–135.

    PubMed  CAS  Google Scholar 

  187. Soos, J.M., P.S. Subramaniam, A.C. Hobeika, J. Schiffenbauer, and H.M. Johnson. 1995. The IFN pregnancy recognition hormone IFN-τ blocks both development and superantigen reactivation of experimental allergic encephalomyelitis without associated toxicity. J.Immunol. 155:2747–2753.

    PubMed  CAS  Google Scholar 

  188. Subramaniam, P.S., S.A. Khan, C.H. Pontzer, and H.M. Johnson. 1995. Differential recognition of the type 1 interferon receptor by interferons T and a is responsible for their disparate cytotoxicities. Proc.Natl.Acad.Sci. USA 92:12270–12274.

    PubMed  CAS  Google Scholar 

  189. Soos, J.M., M.G. Mujtaba, P.S. Subramaniam, W.J. Streit, and H.M. Johnson. 1997. Oral feeding of interferon τ can prevent the acute and chronic relapsing forms of experimental allergic encephalomyelitis. J.Neuroimmunol. 75:43–50.

    PubMed  CAS  Google Scholar 

  190. Mujtaba, M.G., W.J. Streit, and H.M. Johnson. 1998. IFN-τ suppresses both the autoreactive humoral and cellular immune responses and induces stable remission in mice with chronic experimental allergic encephalomyelitis. Cell.Immunol. 186:94–102.

    PubMed  CAS  Google Scholar 

  191. Mujtaba. M.G., J.M. Soos, and H.M. Johnson. 1997. CD4 T suppressor cells mediate interferon tau protection against experimental allergic encephalomyelitis. J.Neuroimmunol. 75:35–42.

    PubMed  CAS  Google Scholar 

  192. Powell, H.S., D. Mitchell, J. Lederman, J. Bucklmeier, S.S. Zamvil, M. Graham, N.H. Ruddle, and L. Steinman. 1990. Lympotoxin and tumor necrosis factor a production by myelin basic protein specific T cells clones correlates with encephalogenicity. Int.Immunol. 2:539.

    PubMed  CAS  Google Scholar 

  193. Tennakoon, D.K., R. Smith, M.D. Stewart, T.E. Spencer, M. Nayak, and C.J.R. Welsh. 2001. Ovine IFN-τ modulates the xpression of MHC antigens on murine cerebrovascular endothelial cells and inhibits replication of Theiler’s virus. J.Interferon Cytokine Res. 21:785–792.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2005 Springer Science+Business Media, Inc.

About this chapter

Cite this chapter

Heremans, H., Billiau, A. (2005). The Role of Interferons in Experimental Autoimmune Encephalomyelitis. In: Lavi, E., Constantinescu, C.S. (eds) Experimental Models of Multiple Sclerosis. Springer, Boston, MA. https://doi.org/10.1007/0-387-25518-4_15

Download citation

Publish with us

Policies and ethics