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Clinical and Developmental Immunology
Volume 2012, Article ID 970789, 16 pages
http://dx.doi.org/10.1155/2012/970789
Review Article

Current Status of the Immunomodulation and Immunomediated Therapeutic Strategies for Multiple Sclerosis

1Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
2Department of Microbiology and Immunology, National Defense Medical Center, Taipei 114, Taiwan
3Center for Composite Tissue Allotransplantation, Chang Gung Memorial Hospital, Linkou, New Taipei City 333, Taiwan
4Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan
5Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan

Received 5 July 2011; Accepted 12 September 2011

Academic Editor: Philip Alex

Copyright © 2012 Shyi-Jou Chen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. V. Siffrin, A. U. Brandt, J. Herz, and F. Zipp, “New insights into adaptive immunity in chronic neuroinflammation,” Advances in Immunology, vol. 96, pp. 1–40, 2007. View at Publisher · View at Google Scholar · View at Scopus
  2. C. Beeton, A. Garcia, and K. G. Chandy, “Induction and clinical scoring of chronic-relapsing experimental autoimmune encephalomyelitis,” Journal of Visualized Experiments, no. 5, p. 224, 2007. View at Google Scholar · View at Scopus
  3. B. Schreiner, F. L. Heppner, and B. Becher, “Modeling multiple sclerosis in laboratory animals,” Seminars in Immunopathology, vol. 31, no. 4, pp. 479–495, 2009. View at Publisher · View at Google Scholar · View at Scopus
  4. T. M. Rivers, D. H. Sprunt, and G. P. Berry, “Observations on attempts to produce acute disseminated encephalomyelitis in monkeys,” The Journal of Experimental Medicine, vol. 58, no. 1, pp. 39–53, 1933. View at Google Scholar
  5. L. Steinman and S. S. Zamvil, “How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis,” Annals of Neurology, vol. 60, no. 1, pp. 12–21, 2006. View at Publisher · View at Google Scholar · View at Scopus
  6. M. Pette, K. Fujita, B. Kitze et al., “Myelin basic protein-specific T lymphocyte lines from MS patients and healthy individuals,” Neurology, vol. 40, no. 11, pp. 1770–1776, 1990. View at Google Scholar · View at Scopus
  7. H. J. Schluesener and H. Wekerle, “Autoaggressive T lymphocyte lines recognizing the encephalitogenic region of myelin basic protein: in vitro selection from unprimed rat T lymphocyte populations,” Journal of Immunology, vol. 135, no. 5, pp. 3128–3133, 1985. View at Google Scholar · View at Scopus
  8. C. P. Genain, D. Lee-Parritz, M. H. Nguyen et al., “In healthy primates, circulating autoreactive T cells mediate autoimmune disease,” Journal of Clinical Investigation, vol. 94, no. 3, pp. 1339–1345, 1994. View at Google Scholar · View at Scopus
  9. A. Ben-Nun, H. Wekerle, and I. R. Cohen, “The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis,” European Journal of Immunology, vol. 11, no. 3, pp. 195–199, 1981. View at Google Scholar · View at Scopus
  10. M. M. Fort, J. Cheung, D. Yen et al., “IL-25 Induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo,” Immunity, vol. 15, no. 6, pp. 985–995, 2001. View at Publisher · View at Google Scholar · View at Scopus
  11. V. K. Kuchroo, A. C. Anderson, H. Waldner, M. Munder, E. Bettelli, and L. B. Nicholson, “T cell response in experimental autoimmune encephalomyelitis (EAE): role of self and cross-reactive antigens in shaping, tuning, and regulating the autopathogenic T cell repertoire,” Annual Review of Immunology, vol. 20, pp. 101–123, 2002. View at Publisher · View at Google Scholar · View at Scopus
  12. A. C. Anderson, L. B. Nicholson, K. L. Legge, V. Turchin, H. Zaghouani, and V. K. Kuchroo, “High frequency of autoreactive myelin proteolipid protein-specific T cells in the periphery of naive mice: mechanisms of selection of the self-reactive repertoire,” Journal of Experimental Medicine, vol. 191, no. 5, pp. 761–770, 2000. View at Publisher · View at Google Scholar · View at Scopus
  13. S. A. Imam, M. K. Guyton, A. Haque et al., “Increased calpain correlates with Th1 cytokine profile in PBMCs from MS patients,” Journal of Neuroimmunology, vol. 190, no. 1-2, pp. 139–145, 2007. View at Publisher · View at Google Scholar · View at Scopus
  14. H. S. Panitch, R. L. Hirsch, J. Schindler, and K. P. Johnson, “Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system,” Neurology, vol. 37, no. 7, pp. 1097–1102, 1987. View at Google Scholar · View at Scopus
  15. F. Neukirch, O. Lyon-Caen, M. Clanet, J. Bousquet, J. Feingold, and P. Druet, “Asthma, nasal allergies, and multiple sclerosis,” Journal of Allergy and Clinical Immunology, vol. 99, no. 2, pp. 270–271, 1997. View at Google Scholar · View at Scopus
  16. D. G. Ando, J. Clayton, D. Kono, J. L. Urban, and E. E. Sercarz, “Encephalitogenic T cells in the B10.PL model of experimental allergic encephalomyelitis (EAE) are of the Th-1 lymphokine subtype,” Cellular Immunology, vol. 124, no. 1, pp. 132–143, 1989. View at Publisher · View at Google Scholar · View at Scopus
  17. S. S. Zamvil and L. Steinman, “The T lymphocyte in experimental allergic encephalomyelitis,” Annual Review of Immunology, vol. 8, pp. 579–621, 1990. View at Google Scholar · View at Scopus
  18. M. Yura, I. Takahashi, M. Serada et al., “Role of MOG-stimulated th1 type “light up” (GFP+) CD4+ T cells for the development of experimental autoimmune encephalomyelitis (EAE),” Journal of Autoimmunity, vol. 17, no. 1, pp. 17–25, 2001. View at Publisher · View at Google Scholar · View at Scopus
  19. T. R. Mosmann and R. L. Coffman, “TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties,” Annual Review of Immunology, vol. 7, pp. 145–173, 1989. View at Google Scholar · View at Scopus
  20. L. Adorini, J. C. Guéry, and S. Trembleau, “Manipulation of the Th1/Th2 cell balance: an approach to treat human autoimmune diseases?” Autoimmunity, vol. 23, no. 1, pp. 53–68, 1996. View at Google Scholar · View at Scopus
  21. M. Krakowski and T. Owens, “Interferon-γ confers resistance to experimental allergic encephalomyelitis,” European Journal of Immunology, vol. 26, no. 7, pp. 1641–1646, 1996. View at Publisher · View at Google Scholar · View at Scopus
  22. E. H. Tran, E. N. Prince, and T. Owens, “IFN-γ shapes immune invasion of the central nervous system via regulation of chemokines,” Journal of Immunology, vol. 164, no. 5, pp. 2759–2768, 2000. View at Google Scholar · View at Scopus
  23. B. Gran, G. X. Zhang, S. Yu 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,” Journal of Immunology, vol. 169, no. 12, pp. 7104–7110, 2002. View at Google Scholar · View at Scopus
  24. G. X. Zhang, B. Gran, S. Yu et al., “Induction of experimental autoimmune encephalomyelitis in IL-12 receptor-β2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system,” Journal of Immunology, vol. 170, no. 4, pp. 2153–2160, 2003. View at Google Scholar · View at Scopus
  25. I. Gutcher, E. Urich, K. Wolter, M. Prinz, and B. Becher, “Interleukin 18-independent engagement of interleukin 18 receptor-α is required for autoimmune inflammation,” Nature Immunology, vol. 7, no. 9, pp. 946–953, 2006. View at Publisher · View at Google Scholar · View at Scopus
  26. I. A. Ferber, S. Brocke, C. Taylor-Edwards et al., “Mice with a disrupted IFN-γ gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE),” Journal of Immunology, vol. 156, no. 1, pp. 5–7, 1996. View at Google Scholar · View at Scopus
  27. B. Oppmann, R. Lesley, B. Blom et al., “Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12,” Immunity, vol. 13, no. 5, pp. 715–725, 2000. View at Google Scholar · View at Scopus
  28. D. J. Cua, J. Sherlock, Y. Chen et al., “Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain,” Nature, vol. 421, no. 6924, pp. 744–748, 2003. View at Publisher · View at Google Scholar · View at Scopus
  29. S. Aggarwal, N. Ghilardi, M. H. Xie, F. J. De Sauvage, and A. L. Gurney, “Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17,” Journal of Biological Chemistry, vol. 278, no. 3, pp. 1910–1914, 2003. View at Publisher · View at Google Scholar · View at Scopus
  30. C. L. Langrish, Y. Chen, W. M. Blumenschein et al., “IL-23 drives a pathogenic T cell population that induces autoimmune inflammation,” Journal of Experimental Medicine, vol. 201, no. 2, pp. 233–240, 2005. View at Publisher · View at Google Scholar · View at Scopus
  31. H. Park, Z. Li, X. O. Yang et al., “A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17,” Nature Immunology, vol. 6, no. 11, pp. 1133–1141, 2005. View at Publisher · View at Google Scholar · View at Scopus
  32. L. E. Harrington, R. D. Hatton, P. R. Mangan et al., “Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages,” Nature Immunology, vol. 6, no. 11, pp. 1123–1132, 2005. View at Publisher · View at Google Scholar · View at Scopus
  33. C. Dong, “Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells,” Nature Reviews Immunology, vol. 6, no. 4, pp. 329–333, 2006. View at Publisher · View at Google Scholar · View at Scopus
  34. P. Miossec, T. Korn, and V. K. Kuchroo, “Interleukin-17 and type 17 helper T cells,” The New England Journal of Medicine, vol. 361, no. 9, pp. 848–898, 2009. View at Publisher · View at Google Scholar · View at Scopus
  35. F. Annunziato, L. Cosmi, V. Santarlasci et al., “Phenotypic and functional features of human Th17 cells,” Journal of Experimental Medicine, vol. 204, no. 8, pp. 1849–1861, 2007. View at Publisher · View at Google Scholar · View at Scopus
  36. C. J. Hedegaard, M. Krakauer, K. Bendtzen, H. Lund, F. Sellebjerg, and C. H. Nielsen, “T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis,” Immunology, vol. 125, no. 2, pp. 161–169, 2008. View at Publisher · View at Google Scholar · View at Scopus
  37. C. Parham, M. Chirica, J. Timans et al., “A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R,” Journal of Immunology, vol. 168, no. 11, pp. 5699–5708, 2002. View at Google Scholar · View at Scopus
  38. P. R. Mangan, L. E. Harrington, D. B. O'Quinn et al., “Transforming growth factor-β induces development of the T H17 lineage,” Nature, vol. 441, no. 7090, pp. 231–234, 2006. View at Publisher · View at Google Scholar · View at Scopus
  39. E. Bettelli, Y. Carrier, W. Gao et al., “Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells,” Nature, vol. 441, no. 7090, pp. 235–238, 2006. View at Publisher · View at Google Scholar · View at Scopus
  40. L. Yang, D. E. Anderson, C. Baecher-Allan et al., “IL-21 and TGF-β are required for differentiation of human T H17 cells,” Nature, vol. 454, no. 7202, pp. 350–352, 2008. View at Publisher · View at Google Scholar · View at Scopus
  41. T. Korn, E. Bettelli, W. Gao et al., “IL-21 initiates an alternative pathway to induce proinflammatory T H17 cells,” Nature, vol. 448, no. 7152, pp. 484–487, 2007. View at Publisher · View at Google Scholar · View at Scopus
  42. C. Lock, G. Hermans, R. Pedotti et al., “Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis,” Nature Medicine, vol. 8, no. 5, pp. 500–508, 2002. View at Publisher · View at Google Scholar · View at Scopus
  43. T. Korn, E. Bettelli, M. Oukka, and V. K. Kuchroo, “IL-17 and Th17 cells,” Annual Review of Immunology, vol. 27, pp. 485–517, 2009. View at Publisher · View at Google Scholar · View at Scopus
  44. Z. Chen and J. J. O'Shea, “Th17 cells: a new fate for differentiating helper T cells,” Immunologic Research, vol. 41, no. 2, pp. 87–102, 2008. View at Publisher · View at Google Scholar · View at Scopus
  45. A. E. Lovett-Racke, A. E. Rocchini, J. Choy et al., “Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes,” Immunity, vol. 21, no. 5, pp. 719–731, 2004. View at Publisher · View at Google Scholar · View at Scopus
  46. W. Ouyang, S. H. Ranganath, K. Weindel et al., “Inhibition of Th1 development mediated by GATA-3 through an IL-4- independent mechanism,” Immunity, vol. 9, no. 5, pp. 745–755, 1998. View at Google Scholar · View at Scopus
  47. W. Ouyang, M. Löhning, Z. Gao et al., “Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment,” Immunity, vol. 12, no. 1, pp. 27–37, 2000. View at Google Scholar · View at Scopus
  48. E. Bettelli, B. Sullivan, S. J. Szabo, R. A. Sobel, L. H. Glimcher, and V. K. Kuchroo, “Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis,” Journal of Experimental Medicine, vol. 200, no. 1, pp. 79–87, 2004. View at Publisher · View at Google Scholar · View at Scopus
  49. R. A. O'Connor, C. T. Prendergast, C. A. Sabatos et al., “Cutting edge: Th1 cells facilitate the entry of Th17 cells to the central nervous system during experimental autoimmune encephalomyelitis,” Journal of Immunology, vol. 181, no. 6, pp. 3750–3754, 2008. View at Google Scholar · View at Scopus
  50. L. J. Edwards, R. A. Robins, and C. S. Constantinescu, “Th17/Th1 phenotype in demyelinating disease,” Cytokine, vol. 50, no. 1, pp. 19–23, 2010. View at Publisher · View at Google Scholar · View at Scopus
  51. S. Y. Pai, M. L. Truitt, and I. C. Ho, “GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 7, pp. 1993–1998, 2004. View at Publisher · View at Google Scholar · View at Scopus
  52. I. I. Ivanov, B. S. McKenzie, L. Zhou et al., “The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells,” Cell, vol. 126, no. 6, pp. 1121–1133, 2006. View at Publisher · View at Google Scholar · View at Scopus
  53. J. D. Fontenot, M. A. Gavin, and A. Y. Rudensky, “Foxp3 programs the development and function of CD4+CD25+ regulatory T cells,” Nature Immunology, vol. 4, no. 4, pp. 330–336, 2003. View at Publisher · View at Google Scholar · View at Scopus
  54. K. Hirota, B. Martin, and M. Veldhoen, “Development, regulation and functional capacities of Th17 cells,” Seminars in Immunopathology, vol. 32, no. 1, pp. 3–16, 2010. View at Publisher · View at Google Scholar · View at Scopus
  55. R. S. Lopez-Diego and H. L. Weiner, “Novel therapeutic strategies for multiple sclerosis—a multifaceted adversary,” Nature Reviews Drug Discovery, vol. 7, no. 11, pp. 909–925, 2008. View at Publisher · View at Google Scholar · View at Scopus
  56. D. Matusevicius, P. Kivisäkk, B. He et al., “Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis,” Multiple Sclerosis, vol. 5, no. 2, pp. 101–104, 1999. View at Google Scholar
  57. R. M. Ransohoff, P. Kivisäkk, and G. Kidd, “Three or more routes for leukocyte migration into the central nervous system,” Nature Reviews Immunology, vol. 3, no. 7, pp. 569–581, 2003. View at Publisher · View at Google Scholar · View at Scopus
  58. B. G. Xiao, A. Diab, J. Zhu, P. Van Der Meide, and H. Link, “Astrocytes induce hyporesponses of myelin basic protein-reactive T and B cell function,” Journal of Neuroimmunology, vol. 89, no. 1-2, pp. 113–121, 1998. View at Publisher · View at Google Scholar · View at Scopus
  59. C. D. Dijkstra, C. J. A. De Groot, and I. Huitinga, “The role of macrophages in demyelination,” Journal of Neuroimmunology, vol. 40, no. 2-3, pp. 183–188, 1992. View at Publisher · View at Google Scholar · View at Scopus
  60. L. H. Kasper and J. Shoemaker, “Multiple sclerosis immunology: the healthy immune system vs the MS immune system,” Neurology, vol. 74, pp. S2–S8, 2010. View at Publisher · View at Google Scholar · View at Scopus
  61. P. Deshpande, I. L. King, and B. M. Segal, “Cutting edge: CNS CD11c+ cells, from mice with encephalomyelitis polarize Th17 cells, and support CD25+CD4+ T cell-mediated immunosuppression, suggesting dual roles in the disease process,” Journal of Immunology, vol. 178, no. 11, pp. 6695–6699, 2007. View at Google Scholar · View at Scopus
  62. H. F. Cserr and P. M. Knopf, “Cervical lymphatics, the blood-brain barrier and the immunoreactivity of the brain: a new view,” Immunology Today, vol. 13, no. 12, pp. 507–512, 1992. View at Google Scholar · View at Scopus
  63. B. Hemmer, S. Nessler, D. Zhou, B. Kieseier, and H. P. Hartung, “Immunopathogenesis and immunotherapy of multiple sclerosis,” Nature Clinical Practice Neurology, vol. 2, no. 4, pp. 201–211, 2006. View at Publisher · View at Google Scholar · View at Scopus
  64. H. Neumann, A. Cavalie, D. E. Jenne, and H. Wekerle, “Induction of MHC class I genes in neurons,” Science, vol. 269, no. 5223, pp. 549–552, 1995. View at Google Scholar · View at Scopus
  65. A. A. Dandekar, G. F. Wu, L. Pewe, and S. Perlman, “Axonal damage is T cell mediated and occurs concomitantly with demyelination in mice infected with a neurotropic coronavirus,” Journal of Virology, vol. 75, no. 13, pp. 6115–6120, 2001. View at Publisher · View at Google Scholar · View at Scopus
  66. L. Probert, H. P. Eugster, K. Akassoglu et al., “TNFR1 signalling is critical for the development of demyelination and the limitation of T-cell responses during immune-mediated CNS disease,” Brain, vol. 123, no. 10, pp. 2005–2019, 2000. View at Google Scholar · View at Scopus
  67. J. S. Tzartos, M. A. Friese, M. J. Craner et al., “Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis,” American Journal of Pathology, vol. 172, no. 1, pp. 146–155, 2008. View at Publisher · View at Google Scholar · View at Scopus
  68. S. Q. Crome, A. Y. Wang, C. Y. Kang, and M. K. Levings, “The role of retinoic acid-related orphan receptor variant 2 and IL-17 in the development and function of human CD4+ T cells,” European Journal of Immunology, vol. 39, no. 6, pp. 1480–1493, 2009. View at Publisher · View at Google Scholar · View at Scopus
  69. Y. Li, N. Chu, A. Hu, B. Gran, A. Rostami, and G. X. Zhang, “Increased IL-23p19 expression in multiple sclerosis lesions and its induction in microglia,” Brain, vol. 130, no. 2, pp. 490–501, 2007. View at Publisher · View at Google Scholar · View at Scopus
  70. H. Kebir, K. Kreymborg, I. Ifergan et al., “Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation,” Nature Medicine, vol. 13, no. 10, pp. 1173–1175, 2007. View at Publisher · View at Google Scholar · View at Scopus
  71. R. A. Linker, F. Lühder, K. J. Kallen et al., “IL-6 transsignalling modulates the early effector phase of EAE and targets the blood-brain barrier,” Journal of Neuroimmunology, vol. 205, no. 1-2, pp. 64–72, 2008. View at Publisher · View at Google Scholar · View at Scopus
  72. I. Ifergan, H. Kébir, M. Bernard et al., “The blood-brain barrier induces differentiation of migrating monocytes into Th17-polarizing dendritic cells,” Brain, vol. 131, no. 3, pp. 785–799, 2008. View at Publisher · View at Google Scholar · View at Scopus
  73. D. Miljkovic, M. Momcilovic, I. Stojanovic, S. Stosic-Grujicic, Z. Ramic, and M. Mostarica-Stojkovic, “Astrocytes stimulate interleukin-17 and interferon-γ production in vitro,” Journal of Neuroscience Research, vol. 85, no. 16, pp. 3598–3606, 2007. View at Publisher · View at Google Scholar · View at Scopus
  74. J. Das Sarma, B. Ciric, R. Marek et al., “Functional interleukin-17 receptor A is expressed in central nervous system glia and upregulated in experimental autoimmune encephalomyelitis,” Journal of Neuroinflammation, vol. 6, article 14, 2009. View at Publisher · View at Google Scholar · View at Scopus
  75. X. Ma, S. L. Reynolds, B. J. Baker, X. Li, E. N. Benveniste, and H. Qin, “IL-17 enhancement of the IL-6 signaling cascade in astrocytes,” Journal of Immunology, vol. 184, no. 9, pp. 4898–4906, 2010. View at Publisher · View at Google Scholar · View at Scopus
  76. Z. Kang, C. Z. Altuntas, M. F. Gulen et al., “Astrocyte-restricted ablation of interleukin-17-induced act1-mediated signaling ameliorates autoimmune encephalomyelitis,” Immunity, vol. 32, no. 3, pp. 414–425, 2010. View at Publisher · View at Google Scholar · View at Scopus
  77. D. Merkler, R. Böscke, B. Schmelting et al., “Differential macrophage/microglia activation in neocortical EAE lesions in the marmoset monkey,” Brain Pathology, vol. 16, no. 2, pp. 117–123, 2006. View at Publisher · View at Google Scholar
  78. J. R. Lees, Y. Iwakura, and J. H. Russell, “Host T cells are the main producers of IL-17 within the central nervous system during initiation of experimental autoimmune encephalomyelitis induced by adoptive transfer of Th1 cell lines,” Journal of Immunology, vol. 180, no. 12, pp. 8066–8072, 2008. View at Google Scholar · View at Scopus
  79. C. Sutton, C. Brereton, B. Keogh, K. H. G. Mills, and E. C. Lavelle, “A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis,” Journal of Experimental Medicine, vol. 203, no. 7, pp. 1685–1691, 2006. View at Publisher · View at Google Scholar · View at Scopus
  80. B. A. De Jong, T. W. J. Huizinga, E. L. E. M. Bollen et al., “Production of IL-1β and IL-1Ra as risk factors for susceptibility and progression of relapse-onset multiple sclerosis,” Journal of Neuroimmunology, vol. 126, no. 1-2, pp. 172–179, 2002. View at Publisher · View at Google Scholar · View at Scopus
  81. E. K. Broberg, A. A. Salmi, and V. Hukkanen, “IL-4 is the key regulator in herpes simplex virus-based gene therapy of BALB/c experimental autoimmune encephalomyelitis,” Neuroscience Letters, vol. 364, no. 3, pp. 173–178, 2004. View at Publisher · View at Google Scholar · View at Scopus
  82. J. Haas, A. Hug, A. Viehöver et al., “Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis,” European Journal of Immunology, vol. 35, no. 11, pp. 3343–3352, 2005. View at Publisher · View at Google Scholar · View at Scopus
  83. S. P. Singh, H. H. Zhang, J. F. Foley, M. N. Hedrick, and J. M. Farber, “Human T cells that are able to produce IL-17 express the chemokine receptor CCR6,” Journal of Immunology, vol. 180, no. 1, pp. 214–221, 2008. View at Google Scholar · View at Scopus
  84. S. Haak, A. L. Croxford, K. Kreymborg et al., “IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice,” Journal of Clinical Investigation, vol. 119, no. 1, pp. 61–69, 2009. View at Publisher · View at Google Scholar · View at Scopus
  85. X. Liu, S. L. Yun, C. R. Yu, and C. E. Egwuagu, “Loss of STAT3 in CD4+ T cells prevents development of experimental autoimmune diseases,” Journal of Immunology, vol. 180, no. 9, pp. 6070–6076, 2008. View at Google Scholar · View at Scopus
  86. I. M. Stromnes, L. M. Cerretti, D. Liggitt, R. A. Harris, and J. M. Goverman, “Differential regulation of central nervous system autoimmunity by T H1 and TH17 cells,” Nature Medicine, vol. 14, no. 3, pp. 337–342, 2008. View at Publisher · View at Google Scholar · View at Scopus
  87. L. Zhou, I. I. Ivanov, R. Spolski et al., “IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways,” Nature Immunology, vol. 8, no. 9, pp. 967–974, 2007. View at Publisher · View at Google Scholar · View at Scopus
  88. Z. Zhang, J. T. Rosenbaum, W. Zhong, C. Lim, and D. J. Hinrichs, “Costimulation of Th17 cells: adding fuel or putting out the fire in the inflamed gut?” Seminars in Immunopathology, vol. 32, no. 1, pp. 55–70, 2010. View at Publisher · View at Google Scholar · View at Scopus
  89. T. L. Vollmer, R. Liu, M. Price, S. Rhodes, A. La Cava, and F. D. Shi, “Differential effects of IL-21 during initiation and progression of autoimmunity against neuroantigen,” Journal of Immunology, vol. 174, no. 5, pp. 2696–2701, 2005. View at Google Scholar · View at Scopus
  90. C. Pot, H. Jin, A. Awasthi et al., “Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells,” Journal of Immunology, vol. 183, no. 2, pp. 797–801, 2009. View at Publisher · View at Google Scholar · View at Scopus
  91. D. C. Fitzgerald, B. Ciric, T. Touil et al., “Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis,” Journal of Immunology, vol. 179, no. 5, pp. 3268–3275, 2007. View at Google Scholar · View at Scopus
  92. A. Jäger, V. Dardalhon, R. A. Sobel, E. Bettelli, and V. K. Kuchroo, “Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes,” Journal of Immunology, vol. 183, no. 11, pp. 7169–7177, 2009. View at Publisher · View at Google Scholar · View at Scopus
  93. A. M. Mueller, X. Pedré, S. Killian, M. David, and A. Steinbrecher, “The Decoy Receptor 3 (DcR3, TNFRSF6B) suppresses Th17 immune responses and is abundant in human cerebrospinal fluid,” Journal of Neuroimmunology, vol. 209, no. 1-2, pp. 57–64, 2009. View at Publisher · View at Google Scholar · View at Scopus
  94. E. C. Nowak, C. T. Weaver, H. Turner et al., “IL-9 as a mediator of Th17-driven inflammatory disease,” Journal of Experimental Medicine, vol. 206, no. 8, pp. 1653–1660, 2009. View at Publisher · View at Google Scholar · View at Scopus
  95. H. Wiendl, K. V. Toyka, P. Rieckmann et al., “Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations,” Journal of Neurology, vol. 255, no. 10, pp. 1449–1463, 2008. View at Publisher · View at Google Scholar · View at Scopus
  96. D. S. Goodin, E. M. Frohman, G. P. Garmany et al., “Disease modifying therapies in multiple sclerosis: report of the therapeutics and technology assessment subcommittee of the American academy of neurology and the MS council for clinical practice guidelines,” Neurology, vol. 58, no. 2, pp. 169–178, 2002. View at Google Scholar · View at Scopus
  97. T. Henze, P. Rieckmann, and K. V. Toyka, “Symptomatic treatment of multiple sclerosis: multiple Sclerosis Therapy Consensus Group (MSTCG) of the German Multiple Sclerosis Society,” European Neurology, vol. 56, no. 2, pp. 78–105, 2006. View at Publisher · View at Google Scholar · View at Scopus
  98. B. Hemmer and H. P. Hartung, “Toward the development of rational therapies in multiple sclerosis: what is on the horizon?” Annals of Neurology, vol. 62, no. 4, pp. 314–326, 2007. View at Publisher · View at Google Scholar · View at Scopus
  99. B. Bielekova and B. L. Becker, “Monoclonal antibodies in MS: mechanisms of action,” Neurology, vol. 74, pp. S31–S40, 2010. View at Publisher · View at Google Scholar · View at Scopus
  100. D. Bates, “Alemtuzumab,” International MS journal/MS Forum, vol. 16, no. 3, pp. 75–76, 2009. View at Google Scholar · View at Scopus
  101. K. Hawker, P. O'Connor, M. S. Freedman et al., “Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial,” Annals of Neurology, vol. 66, no. 4, pp. 460–471, 2009. View at Publisher · View at Google Scholar · View at Scopus
  102. B. Bielekova, T. Howard, A. N. Packer et al., “Effect of anti-CD25 antibody daclizumab in the inhibition of inflammation and stabilization of disease progression in multiple sclerosis,” Archives of Neurology, vol. 66, no. 4, pp. 483–489, 2009. View at Publisher · View at Google Scholar · View at Scopus
  103. S. Dhib-Jalbut, “Mechanisms of action of interferons and glatiramer acetate in multiple sclerosis,” Neurology, vol. 58, no. 8, pp. S3–S9, 2002. View at Google Scholar · View at Scopus
  104. M. Krakauer, P. Sorensen, M. Khademi, T. Olsson, and F. Sellebjerg, “Increased IL-10 mRNA and IL-23 mRNA expression in multiple sclerosis: interferon-β treatment increases IL-10 mRNA expression while reducing IL-23 mRNA expression,” Multiple Sclerosis, vol. 14, no. 5, pp. 622–630, 2008. View at Publisher · View at Google Scholar
  105. V. S. Ramgolam, Y. Sha, J. Jin, X. Zhang, and S. Markovic-Plese, “IFN-β inhibits human Th17 cell differentiation,” Journal of Immunology, vol. 183, no. 8, pp. 5418–5427, 2009. View at Publisher · View at Google Scholar · View at Scopus
  106. B. Guo, E. Y. Chang, and G. Cheng, “The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice,” Journal of Clinical Investigation, vol. 118, no. 5, pp. 1680–1690, 2008. View at Publisher · View at Google Scholar · View at Scopus
  107. C. M. Sweeney, R. Lonergan, S. A. Basdeo et al., “IL-27 mediates the response to IFN-β therapy in multiple sclerosis patients by inhibiting Th17 cells,” Brain, Behavior and Immunity, vol. 25, no. 6, pp. 1170–1181, 2011. View at Publisher · View at Google Scholar
  108. C. L. Galligan, L. M. Pennell, T. T. Murooka et al., “Interferon-β is a key regulator of proinflammatory events in experimental autoimmune encephalomyelitis,” Multiple Sclerosis, vol. 16, no. 12, pp. 1458–1473, 2010. View at Publisher · View at Google Scholar
  109. R. C. Axtell, B. A. De Jong, K. Boniface et al., “T helper type 1 and 17 cells determine efficacy of interferon-β in multiple sclerosis and experimental encephalomyelitis,” Nature Medicine, vol. 16, no. 4, pp. 406–412, 2010. View at Publisher · View at Google Scholar · View at Scopus
  110. R. C. Axtell, C. Raman, and L. Steinman, “Interferon-β exacerbates Th17-mediated inflammatory disease,” Trends in Immunology, vol. 32, no. 6, pp. 272–277, 2011. View at Publisher · View at Google Scholar
  111. J. Antel and A. Bar-Or, “Roles of immunoglobulins and B cells in multiple sclerosis: from pathogenesis to treatment,” Journal of Neuroimmunology, vol. 180, no. 1-2, pp. 3–8, 2006. View at Publisher · View at Google Scholar · View at Scopus
  112. S. Fillatreau, D. Gray, and S. M. Anderton, “Not always the bad guys: B cells as regulators of autoimmune pathology,” Nature Reviews Immunology, vol. 8, no. 5, pp. 391–397, 2008. View at Publisher · View at Google Scholar · View at Scopus
  113. V. S. Ramgolam, Y. Sha, K. L. Marcus et al., “B cells as a therapeutic target for IFN-β in relapsing-remitting multiple sclerosis,” Journal of Immunology, vol. 186, no. 7, pp. 4518–4526, 2011. View at Publisher · View at Google Scholar
  114. R. M. Valenzuela, K. Costello, M. Chen, A. Said, K. P. Johnson, and S. Dhib-Jalbut, “Clinical response to glatiramer acetate correlates with modulation of IFN-γ and IL-4 expression in multiple sclerosis,” Multiple Sclerosis, vol. 13, no. 6, pp. 754–762, 2007. View at Publisher · View at Google Scholar
  115. M. Saresella, I. Marventano, R. Longhi et al., “CD4+CD25+FoxP3+PD1- Regulatory T cells in acute and stable relapsing-remitting multiple sclerosis and their modulation by therapy,” FASEB Journal, vol. 22, no. 10, pp. 3500–3508, 2008. View at Publisher · View at Google Scholar · View at Scopus
  116. J. Hong, N. Li, X. Zhang, B. Zheng, and J. Z. Zhang, “Induction of CD4+CD25+ regulatory T cells by copolymer-I through activation of transcription factor Foxp3,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 18, pp. 6449–6454, 2005. View at Publisher · View at Google Scholar · View at Scopus
  117. P. L. Vieira, H. C. Heystek, J. Wormmeester, E. A. Wierenga, and M. L. Kapsenberg, “Glatiramer acetate (copolymer-1, copaxone) promotes Th2 cell development and increased IL-10 production through modulation of dendritic cells,” Journal of Immunology, vol. 170, no. 9, pp. 4483–4488, 2003. View at Google Scholar · View at Scopus
  118. S. Jung, I. Siglienti, O. Grauer, T. Magnus, G. Scarlato, and K. Toyka, “Induction of IL-10 in rat peritoneal macrophages and dendritic cells by glatiramer acetate,” Journal of Neuroimmunology, vol. 148, no. 1-2, pp. 63–73, 2004. View at Publisher · View at Google Scholar · View at Scopus
  119. I. Elovaara, M. Ukkonen, M. Leppäkynnäs et al., “Adhesion molecules in multiple sclerosis: relation to subtypes of disease and methylprednisolone therapy,” Archives of Neurology, vol. 57, no. 4, pp. 546–551, 2000. View at Google Scholar
  120. I. Elovaara, M. Lällä, E. Spare, T. Lehtimäki, and P. Dastidar, “Methylprednisolone reduces adhesion molecules in blood and cerebrospinal fluid in patients with MS,” Neurology, vol. 51, no. 6, pp. 1703–1708, 1998. View at Google Scholar
  121. B. E. Theien, C. L. Vanderlugt, T. N. Eagar et al., “Discordant effects of anti-VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis,” Journal of Clinical Investigation, vol. 107, no. 8, pp. 995–1006, 2001. View at Google Scholar · View at Scopus
  122. O. Stüve, C. M. Marra, K. R. Jerome et al., “Immune surveillance in multiple sclerosis patients treated with natalizumab,” Annals of Neurology, vol. 59, no. 5, pp. 743–747, 2006. View at Publisher · View at Google Scholar · View at Scopus
  123. A. Langer-Gould, S. W. Atlas, A. J. Green, A. W. Bollen, and D. Pelletier, “Progressive multifocal leukoencephalopathy in a patient treated with natalizumab,” The New England Journal of Medicine, vol. 353, no. 4, pp. 375–381, 2005. View at Publisher · View at Google Scholar · View at Scopus
  124. B. K. Kleinschmidt-DeMasters and K. L. Tyler, “Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon β-1a for multiple sclerosis,” The New England Journal of Medicine, vol. 353, no. 4, pp. 369–374, 2005. View at Publisher · View at Google Scholar · View at Scopus
  125. K. Hellwig and R. Gold, “Progressive multifocal leukoencephalopathy and natalizumab,” Journal of Neurology, vol. 258, no. 11, pp. 1920–1928, 2011. View at Google Scholar
  126. L. Gorelik, M. Lerner, S. Bixler et al., “Anti-JC virus antibodies: implications for PML risk stratification,” Annals of Neurology, vol. 68, no. 3, pp. 295–303, 2010. View at Publisher · View at Google Scholar · View at Scopus
  127. R. Richard, “New risk data on PML puts hard numbers on antibody status, immunosuppressants, and treatment duration,” Neurology Today, vol. 11, no. 14, p. 8, 2011. View at Google Scholar
  128. C. Warnke, T. Menge, H. P. Hartung et al., “Natalizumab and progressive multifocal leukoencephalopathy: what are the causal factors and can it be avoided?” Archives of Neurology, vol. 67, no. 8, pp. 923–930, 2010. View at Publisher · View at Google Scholar · View at Scopus
  129. H. P. Hartung, R. Gonsette, N. König et al., “Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial,” The Lancet, vol. 360, no. 9350, pp. 2018–2025, 2002. View at Publisher · View at Google Scholar · View at Scopus
  130. A. Vogelgesang, S. Rosenberg, S. Skrzipek, B. M. Bröker, and A. Dressel, “Mitoxantrone treatment in multiple sclerosis induces TH2-type cytokines,” Acta Neurologica Scandinavica, vol. 122, no. 4, pp. 237–243, 2010. View at Publisher · View at Google Scholar
  131. R. Hohlfeld, “Multiple sclerosis: cladribine-a contentious therapeutic contender for MS,” Nature Reviews Neurology, vol. 7, no. 8, pp. 425–427, 2011. View at Publisher · View at Google Scholar
  132. M. Matloubian, C. G. Lo, G. Cinamon et al., “Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1,” Nature, vol. 427, no. 6972, pp. 355–360, 2004. View at Publisher · View at Google Scholar · View at Scopus
  133. R. Ehling, T. Berger, and M. Reindl, “Multiple sclerosis—established and novel therapeutic approaches,” Central Nervous System Agents in Medicinal Chemistry, vol. 10, no. 1, pp. 3–15, 2010. View at Google Scholar · View at Scopus
  134. C. R. Strader, C. J. Pearce, and N. H. Oberlies, “Fingolimod (FTY720): a recently approved multiple sclerosis drug based on a fungal secondary metabolite,” Journal of Natural Products, vol. 74, no. 4, pp. 900–907, 2011. View at Publisher · View at Google Scholar
  135. S. Y. Lim and C. S. Constantinescu, “Current and future disease-modifying therapies in multiple sclerosis,” International Journal of Clinical Practice, vol. 64, no. 5, pp. 637–650, 2010. View at Publisher · View at Google Scholar · View at Scopus
  136. J. Harada, M. Foley, M. A. Moskowitz, and C. Waeber, “Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells,” Journal of Neurochemistry, vol. 88, no. 4, pp. 1026–1039, 2004. View at Google Scholar · View at Scopus
  137. M. L. Allende and R. L. Proia, “Sphingosine-1-phosphate receptors and the development of the vascular system,” Biochimica et Biophysica Acta, vol. 1582, no. 1–3, pp. 222–227, 2002. View at Publisher · View at Google Scholar · View at Scopus
  138. P. S. Jolly, M. Bektas, A. Olivera et al., “Transactivation of sphingosine-1-phosphate receptors by FcεRI triggering is required for normal mast cell degranulation and chemotaxis,” Journal of Experimental Medicine, vol. 199, no. 7, pp. 959–970, 2004. View at Publisher · View at Google Scholar · View at Scopus
  139. C. Donati, E. Meacci, F. Nuti, L. Becciolini, M. Farnararo, and P. Bruni, “Sphingosine 1-phosphate regulates myogenic differentiation: a major role for S1P2 receptor,” FASEB Journal, vol. 19, no. 3, pp. 449–451, 2005. View at Publisher · View at Google Scholar · View at Scopus
  140. V. Krump-Konvalinkova, S. Yasuda, T. Rubic et al., “Stable knock-down of the sphingosine 1-phosphate receptor S1P1 influences multiple functions of human endothelial cells,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 3, pp. 546–552, 2005. View at Publisher · View at Google Scholar · View at Scopus
  141. C. Halin, M. L. Scimone, R. Bonasio et al., “The S1P-analog FTY720 differentially modulates T-cell homing via HEV: T-cell-expressed S1P1 amplifies integrin activation in peripheral lymph nodes but not in Peyer patches,” Blood, vol. 106, no. 4, pp. 1314–1322, 2005. View at Publisher · View at Google Scholar · View at Scopus
  142. R. Tao, H. E. Hoover, J. Zhang, N. Honbo, C. C. Alano, and J. S. Karliner, “Cardiomyocyte S1P1 receptor-mediated extracellular signal-related kinase signaling and desensitization,” Journal of Cardiovascular Pharmacology, vol. 53, no. 6, pp. 486–494, 2009. View at Publisher · View at Google Scholar · View at Scopus
  143. V. Brinkmann, M. D. Davis, C. E. Heise et al., “The immune modulator FTY720 targets sphingosine 1-phosphate receptors,” Journal of Biological Chemistry, vol. 277, no. 24, pp. 21453–21457, 2002. View at Publisher · View at Google Scholar · View at Scopus
  144. H. Kataoka, K. Sugahara, K. Shimano et al., “FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration,” Cellular & Molecular Immunology, vol. 2, no. 6, pp. 439–448, 2005. View at Google Scholar · View at Scopus
  145. V. Brinkmann, “FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system,” British Journal of Pharmacology, vol. 158, no. 5, pp. 1173–1182, 2009. View at Publisher · View at Google Scholar · View at Scopus
  146. M. Mehling, R. Lindberg, F. Raulf et al., “Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis,” Neurology, vol. 75, no. 5, pp. 403–410, 2010. View at Publisher · View at Google Scholar · View at Scopus
  147. M. Webb, C. S. Tham, F. F. Lin et al., “Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice,” Journal of Neuroimmunology, vol. 153, no. 1-2, pp. 108–121, 2004. View at Publisher · View at Google Scholar · View at Scopus
  148. R. Van Doorn, J. Van Horssen, D. Verzijl et al., “Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions,” GLIA, vol. 58, no. 12, pp. 1465–1476, 2010. View at Publisher · View at Google Scholar · View at Scopus
  149. N. Rouach, A. Pébay, W. Même et al., “S1P inhibits gap junctions in astrocytes: involvement of G and Rho GTPase/ROCK,” European Journal of Neuroscience, vol. 23, no. 6, pp. 1453–1464, 2006. View at Publisher · View at Google Scholar
  150. E. Beutler, “Cladribine (2-chlorodeoxyadenosine),” The Lancet, vol. 340, no. 8825, pp. 952–956, 1992. View at Publisher · View at Google Scholar · View at Scopus
  151. D. A. Carson, D. B. Wasson, R. Taetle, and A. Yu, “Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes,” Blood, vol. 62, no. 4, pp. 737–743, 1983. View at Google Scholar · View at Scopus
  152. D. Yates, “Multiple sclerosis: orally administered cladribine displays efficacy in multiple sclerosis trial,” Nature Reviews Neurology, vol. 6, no. 4, p. 182, 2010. View at Publisher · View at Google Scholar · View at Scopus
  153. G. Giovannoni, S. Cook, K. Rammohan et al., “Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis,” The Lancet Neurology, vol. 10, no. 4, pp. 329–337, 2011. View at Publisher · View at Google Scholar
  154. G. Giovannoni, G. Comi, S. Cook et al., “A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis,” The New England Journal of Medicine, vol. 362, no. 5, pp. 416–426, 2010. View at Publisher · View at Google Scholar · View at Scopus
  155. L. J. Barten, D. R. Allington, K. A. Procacci, and M. P. Rivey, “New approaches in the management of multiple sclerosis,” Drug Design, Development and Therapy, vol. 4, pp. 343–366, 2010. View at Publisher · View at Google Scholar
  156. A. Minagar, J. S. Alexander, M. A. Sahraian, and R. Zivadinov, “Alemtuzumab and multiple sclerosis: therapeutic application,” Expert Opinion on Biological Therapy, vol. 10, no. 3, pp. 421–429, 2010. View at Publisher · View at Google Scholar · View at Scopus
  157. H. Offner, “Neuroimmunoprotective effects of estrogen and derivatives in experimental autoimmune encephalomyelitis: therapeutic implications for multiple sclerosis,” Journal of Neuroscience Research, vol. 78, no. 5, pp. 603–624, 2004. View at Publisher · View at Google Scholar · View at Scopus
  158. T. L. Papenfuss, N. D. Powell, M. A. McClain et al., “Estriol generates tolerogenic dendritic cells in vivo that protect against autoimmunity,” Journal of Immunology, vol. 186, no. 6, pp. 3346–3355, 2011. View at Publisher · View at Google Scholar
  159. C. A. Dinarello, “Anti-inflammatory agents: present and future,” Cell, vol. 140, no. 6, pp. 935–950, 2010. View at Publisher · View at Google Scholar · View at Scopus
  160. C. Natarajan and J. J. Bright, “Peroxisome proliferator-activated receptor-gamma agonist inhibit experimental allergic encephalomyelitis by blocking IL-12 production, IL-12 signaling and Th1 differentiation,” Genes and Immunity, vol. 3, no. 2, pp. 59–70, 2002. View at Publisher · View at Google Scholar · View at Scopus
  161. S. Kanakasabai, W. Chearwae, C. C. Walline, W. Iams, S. M. Adams, and J. J. Bright, “Peroxisome proliferator-activated receptor δ agonists inhibit T helper type 1 (Th1) and Th17 responses in experimental allergic encephalomyelitis,” Immunology, vol. 130, no. 4, pp. 572–588, 2010. View at Publisher · View at Google Scholar · View at Scopus
  162. M. Nikodemova, J. Lee, Z. Fabry, and I. D. Duncan, “Minocycline attenuates experimental autoimmune encephalomyelitis in rats by reducing T cell infiltration into the spinal cord,” Journal of Neuroimmunology, vol. 219, no. 1-2, pp. 33–37, 2010. View at Publisher · View at Google Scholar · View at Scopus
  163. R. K. Zabad, L. M. Metz, T. R. Todoruk et al., “The clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes: a pilot study,” Multiple Sclerosis, vol. 13, no. 4, pp. 517–526, 2007. View at Publisher · View at Google Scholar
  164. M. L. Brines, P. Ghezzi, S. Keenan et al., “Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 19, pp. 10526–10531, 2000. View at Google Scholar · View at Scopus
  165. D. Agnello, P. Bigini, P. Villa et al., “Erythropoietin exerts an anti-inflammatory effect on the CNS in a model of experimental autoimmune encephalomyelitis,” Brain Research, vol. 952, no. 1, pp. 128–134, 2002. View at Publisher · View at Google Scholar · View at Scopus
  166. R. Yuan, Y. Maeda, W. Li, W. Lu, S. Cook, and P. Dowling, “Erythropoietin: a potent inducer of peripheral immuno/inflammatory modulation in autoimmune EAE,” PLoS ONE, vol. 3, no. 4, e1924, 2008. View at Publisher · View at Google Scholar · View at Scopus
  167. S. J. Chen, Y. L. Wang, W. T. Lo et al., “Erythropoietin enhances endogenous haem oxygenase-1 and represses immune responses to ameliorate experimental autoimmune encephalomyelitis,” Clinical and Experimental Immunology, vol. 162, no. 2, pp. 210–223, 2010. View at Publisher · View at Google Scholar · View at Scopus
  168. D. Demjen, S. Klussmann, S. Kleber et al., “Neutralization of CD95 ligand promotes regeneration and functional recovery after spinal cord injury,” Nature Medicine, vol. 10, no. 4, pp. 389–395, 2004. View at Publisher · View at Google Scholar · View at Scopus
  169. R. M. Pitti, S. A. Marsters, D. A. Lawrence et al., “Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer,” Nature, vol. 396, no. 6712, pp. 699–703, 1998. View at Publisher · View at Google Scholar · View at Scopus
  170. S. Hayashi, Y. Miura, T. Nishiyama et al., “Decoy receptor 3 expressed in rheumatoid synovial fibroblasts protects the cells against fas-induced apoptosis,” Arthritis and Rheumatism, vol. 56, no. 4, pp. 1067–1075, 2007. View at Publisher · View at Google Scholar · View at Scopus
  171. J. Zhang, T. W. Salcedo, X. Wan et al., “Modulation of T-cell responses to alloantigens by TR6/DcR3,” Journal of Clinical Investigation, vol. 107, no. 11, pp. 1459–1468, 2001. View at Google Scholar · View at Scopus
  172. K. Y. Yu, B. Kwon, J. Ni, Y. Zhai, R. Ebner, and B. S. Kwon, “A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis,” Journal of Biological Chemistry, vol. 274, no. 20, pp. 13733–13736, 1999. View at Publisher · View at Google Scholar · View at Scopus
  173. K. A. Sabelko-Downes, A. H. Cross, and J. H. Russell, “Dual role for Fas ligand in the initiation of and recovery from experimental allergic encephalomyelitis,” Journal of Experimental Medicine, vol. 189, no. 8, pp. 1195–1205, 1999. View at Publisher · View at Google Scholar · View at Scopus
  174. S. J. Chen, Y. L. Wang, J. H. Kao et al., “Decoy receptor 3 ameliorates experimental autoimmune encephalomyelitis by directly counteracting local inflammation and downregulating Th17 cells,” Molecular Immunology, vol. 47, no. 2-3, pp. 567–574, 2009. View at Publisher · View at Google Scholar · View at Scopus
  175. T. Korn, “Pathophysiology of multiple sclerosis,” Journal of Neurology, vol. 255, no. 6, pp. 2–6, 2008. View at Publisher · View at Google Scholar · View at Scopus
  176. Y. Komiyama, S. Nakae, T. Matsuki et al., “IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis,” Journal of Immunology, vol. 177, no. 1, pp. 566–573, 2006. View at Google Scholar · View at Scopus
  177. L. Steinman, “Mixed results with modulation of T H-17 cells in human autoimmune diseases,” Nature Immunology, vol. 11, no. 1, pp. 41–44, 2010. View at Publisher · View at Google Scholar · View at Scopus
  178. A. C. Murphy, S. J. Lalor, M. A. Lynch, and K. H. G. Mills, “Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis,” Brain, Behavior, and Immunity, vol. 24, no. 4, pp. 641–651, 2010. View at Publisher · View at Google Scholar · View at Scopus
  179. J. M. Fletcher, S. J. Lalor, C. M. Sweeney, N. Tubridy, and K. H. G. Mills, “T cells in multiple sclerosis and experimental autoimmune encephalomyelitis,” Clinical and Experimental Immunology, vol. 162, no. 1, pp. 1–11, 2010. View at Publisher · View at Google Scholar · View at Scopus
  180. A. E. Lovett-Racke, Y. Yang, and M. K. Racke, “Th1 versus Th17: are T cell cytokines relevant in multiple sclerosis?” Biochimica et Biophysica Acta, vol. 1812, no. 2, pp. 246–251, 2011. View at Publisher · View at Google Scholar · View at Scopus
  181. Y. L. Wang, F. C. Chou, H. H. Sung et al., “Decoy receptor 3 protects non-obese diabetic mice from autoimmune diabetes by regulating dendritic cell maturation and function,” Molecular Immunology, vol. 47, no. 16, pp. 2552–2562, 2010. View at Publisher · View at Google Scholar · View at Scopus
  182. R. T. Naismith, L. Piccio, J. A. Lyons et al., “Rituximab add-on therapy for breakthrough relapsing multiple sclerosis: a 52-week phase II trial,” Neurology, vol. 74, no. 23, pp. 1860–1867, 2010. View at Publisher · View at Google Scholar · View at Scopus