T-cell based immunotherapy in experimental autoimmune encephalomyelitis and multiple sclerosis

Immunotherapy

Volumn 2, Issue 1, 2010, Pages 99-115

  O'Brien, Kate ^a   Gran, Bruno ^a,b   Rostami, Abdolmohamad ^b  

^a UNIVERSITY OF NOTTINGHAM   (United Kingdom)

^b THOMAS JEFFERSON UNIVERSITY   (United States)

Author keywords

Disease modifying treatment; Encephalomyelitis; Experimental autoimmune; Immune system; Immunotherapy; Multiple sclerosis; T cell

Indexed keywords

ALEMTUZUMAB; AZATHIOPRINE; BETA INTERFERON; BETA1A INTERFERON; CLADRIBINE; DACLIZUMAB; FINGOLIMOD; GLATIRAMER; INTERFERON BETA SERINE; INTERLEUKIN 12; INTERLEUKIN 17; INTERLEUKIN 21; INTERLEUKIN 22; INTERLEUKIN 23; MITOXANTRONE; MYELIN; MYELIN BASIC PROTEIN; NATALIZUMAB; PROTEOLIPID PROTEIN; RETINOIC ACID; TERIFLUNOMIDE;

ADD ON THERAPY; ALLERGIC ENCEPHALOMYELITIS; BONE MARROW SUPPRESSION; CARDIOTOXICITY; CELL DIFFERENTIATION; CELL THERAPY; CELL TYPE; CLINICAL TRIAL; CROHN DISEASE; HUMAN; IMMUNIZATION; IMMUNOSUPPRESSIVE TREATMENT; IMMUNOTHERAPY; MULTIPLE SCLEROSIS; NONHUMAN; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; RHEUMATOID ARTHRITIS; T LYMPHOCYTE; TH1 CELL; TH17 CELL; TH2 CELL;

ANIMALS; ENCEPHALOMYELITIS, AUTOIMMUNE, EXPERIMENTAL; HUMANS; IMMUNE TOLERANCE; IMMUNOLOGIC MEMORY; IMMUNOTHERAPY; MULTIPLE SCLEROSIS; T-LYMPHOCYTES; T-LYMPHOCYTES, HELPER-INDUCER; T-LYMPHOCYTES, REGULATORY;

EID: 77953427672     PISSN: 1750743X     EISSN: None     Source Type: Journal    
DOI: 10.2217/imt.09.61     Document Type: Review

References (155)

1. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG: Multiple sclerosis. N. Engl. J Med. 343(13), 938-952 (2000).
2. Sospedra M, Martin R: Immunology of multiple sclerosis. Annu. Rev. Immunol. 23, 683-747 (2005).
3. Grigoriadis N, Hadjigeorgiou GM: Virus-mediated autoimmunity in multiple Sclerosis. J. Autoimmune Dis. 3, 1 (2006).
4. Trapp BD, Peterson J, Ransohoff RM et al.: Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med. 338(5), 278-285 (1998).
5. Peterson JW, Bo L, Mork S, Chang A, Trapp BD: Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann. Neurol. 50(3), 389-400 (2001).
6. Becher B, Durell BG, Noelle RJ: Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J. Clin. Invest. 110(4), 493-497 (2002).
7. Chen Y, Langrish CL, McKenzie B et al.: Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J. Clin. Invest. 116(5), 1317-1326 (2006).
8. Gran B, Zhang G-X, Yu S et al.: IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. J. Immunol. 169(12), 7104-7110 (2002).
9. Komiyama Y, Nakae S, Matsuki T et al.: IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 177(1), 566-573 (2006).
10. Langrish CL, Chen Y, Blumenschein WM et al.: IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201(2), 233-240 (2005).
11. Mosmann TR, Coffman RL: Th1 and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145-173 (1989).
12. Romagnani S, Parronchi P, D'Elios MM et al.: An update on human Th1 and Th2 cells. Int. Arch. Allergy Immunol. 113(1-3), 153-156 (1997).
13. Oppmann B, Lesley R, Blom B 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 13(5), 715-725 (2000).
14. Segal BM, Shevach EM: IL-12 unmasks latent autoimmune disease in resistant mice. J. Exp. Med. 184(2), 771-775 (1996).
15. Segal BM, Dwyer BK, Shevach EM: An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J. Exp. Med. 187(4), 537-546 (1998).
16. CuaDJ, Sherlock J, Chen Yet al.: Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421(6924), 744-748 (2003).
17. Gran B, Chu N, Zhang GX et al.: Early administration of IL-12 suppresses EAE through induction of interferon-γ. J. Neuroimmunol. 156(1-2), 123-131 (2004).
18. Aggarwal S, Ghilardi N, Xie M-H, de Sauvage FJ, Gurney AL: Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J. Biol. Chem. 278(3), 1910-1914 (2003).
19. Bettelli E, Carrier Y, Gao W et al.: Reciprocal developmental pathways for the generation of pathogenic effector Th17 and regulatory T cells. Nature (2006).
20. Gutcher I, Urich E, Wolter K, Prinz M, Becher B: Interleukin 18-independent engagement of interleukin 18 receptor-α is required for autoimmune inflammation. Nat. Immunol. 7(9), 946-953 (2006).
21. Liang SC, Tan XY, Luxenberg DP et al.: Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203(10), 2271-2279 (2006).
22. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B: TGF-β in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24(2), 179-189 (2006). ■■ The first report to show that TGF-β in the presence of IL-6 induces T-helper (Th) 17 differentiation.
23. Korn T, Bettelli E, Gao W et al.: IL-21 initiates an alternative pathway to induce proinflammatory T(H) 17 cells. Nature 448(7152), 484-487 (2007). ■ [23] and [24] show that IL-21 cooperates with TGF-β to induce Th17 differentiation.
24. Nurieva R, Yang XO, Martinez G et al.: Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448(7152), 480-483 (2007). ■ [23] and [24] show that IL-21 cooperates with TGF-β to induce Th17 differentiation.
25. Batten M, Li J, Yi S et al.: Interleukin-27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat. Immunol. 7(9), 929-936 (2006).
26. Stumhofer JS, Laurence A, Wilson EH et al.: Interleukin-27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat. Immunol. 7(9), 937-945 (2006).
27. Laurence A, Tato CM, Davidson TS et al.: Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26(3), 371-381 (2007).
28. + regulatory T cells for immunologic self-tolerance and negative control of immune responses. Ann. Rev. Immunol. 22(1), 531-562 (2004).
29. Traugott U, Reinherz EL, Raine CS: Multiple sclerosis. Distribution of T cells, T-cell subsets and la-positive macrophages in lesions of different ages. J. Neuroimmunol. 4(3), 201-221 (1983).
30. Brostoff SW, Mason DW: Experimental allergic encephalomyelitis: successful treatment in vivo with a monoclonal antibody that recognizes T helper cells. J. Immunol. 133(4), 1938-1942 (1984).
31. Pettinelli CB, McFarlin DE: Adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice after in vitro activation of lymph node cells by myelin basic protein: requirement for Lyt 1 + 2-T lymphocytes. J. Immunol. 127(4), 1420-1423 (1981).
32. Waldor MK, Sriram S, Hardy R et al.: Reversal of experimental allergic encephalomyelitis with monoclonal antibody to a T-cell subset marker. Science 227(4685), 415-417(1985).
33. Hemmer B, Hartung HP: Toward the development of rational therapies in multiple sclerosis: what is on the horizon? Ann. Neurol. 62(4), 314-326 (2007).
34. Compston A: The genetics of multiple sclerosis. J. Neurovirol. 6 (Suppl. 2), S5-S9 (2000).
35. Hafler DA, Compston A, Sawcer S et al.: Risk alleles for multiple sclerosis identified by a genomewide study. N. Engl. J. Med. 357(9), 851-862 (2007).
36. Haines JL, Ter-Minassian M, Bazyk A et al.: A complete genomic screen for multiple sclerosis underscores a role for the major histocompatability complex. The Multiple Sclerosis Genetics Group. Nat. Genet. 13(4), 469-471 (1996).
37. + T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J. Exp. Med. 192(3), 393-404 (2000).
38. + T cells in cerebrospinal fluid from multiple sclerosis patients. Brain 125(3), 538-550 (2002).
39. Miller A, Hafler DA, Weiner HL: Tolerance and suppressor mechanisms in experimental autoimmune encephalomyelitis: implications for immunotherapy of human autoimmune diseases. FASEBJ. 5(11), 2560-2566 (1991).
40. Racke MK, Bonomo A, Scott DE et al.: Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. J. Exp. Med. 180(5), 1961-1966 (1994).
41. Liblau RS, Tisch R, Shokat K et al.: Intravenous injection of soluble antigen induces thymic and peripheral T-cells apoptosis. Proc. Natl Acad. Sci. USA 93(7), 3031-3036 (1996).
42. Kearney ER, Pape KA, Loh DY, Jenkins MK: Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. Immunity 1(4), 327-339 (1994).
43. Miller A, Zhang ZJ, Sobel RA, al-Sabbagh A, Weiner HL: Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein. VI. Suppression of adoptively transferred disease and differential effects of oral vs. intravenous tolerization. J. Neuroimmunol. 46(1-2), 73-82 (1993).
44. Miller SD, McRae BL, Vanderlugt CL et al.: Evolution of the T-cell repertoire during the course of experimental immune-mediated demyelinating diseases. Immunol. Rev. 144, 225-244 (1995).
45. Tan JK, O'Neill HC: Maturation requirements for dendritic cells in T-cell stimulation leading to tolerance versus immunity. J. Leukoc. Biol. 78(2), 319-324 (2005).
46. Baker D, O'Neill J K, Gschmeissner SE et al.: Induction of chronic relapsing experimental allergic encephalomyelitis in Biozzi mice. J. Neuroimmunol. 28(3), 261-270 (1990).
47. Pryce G, O'Neill JK, Croxford JL et al.: Autoimmune tolerance eliminates relapses but fails to halt progression in a model of multiple sclerosis. J. Neuroimmunol. 165(1-2), 41-52 (2005).
48. Hilliard B, Ventura ES, Rostami A: Effect of timing of intravenous administration of myelin basic protein on the induction of tolerance in experimental allergic encephalomyelitis. Mult. Scler. 5(1), 2-9 (1999).
49. Hilliard BA, Kamoun M, Ventura E, Rostami A: Mechanisms of suppression of experimental autoimmune encephalomyelitis by intravenous administration of myelin basic protein: role of regulatory spleen cells. Exp. Mol. Pathol. 68(1), 29-37 (2000).
50. Zhang GX, Yu S, Li Y et al.: A paradoxical role of APCs in the induction of intravenous tolerance in experimental autoimmune encephalomyelitis. J. Neuroimmunol. 161(1-2), 101-112 (2005).
51. Li H, Zhang GX, Chen Y et al.: CD11c+CD11b+ dendritic cells play an important role in intravenous tolerance and the suppression of experimental autoimmune encephalomyelitis. J. Immunol. 181(4), 2483-2493 (2008).
52. Jiang Z, Li H, Fitzgerald DC, Zhang GX, Rostami A: MOG (35-55) i.v suppresses experimental autoimmune encephalomyelitis partially through modulation of Th17 and JAK/STAT pathways. Eur. J. Immunol. 39(3), 789-799 (2009).
53. + T cells. J. Immunol. 164(1), 265-272 (2000).
54. Verbeek R, van der Mark K, Wawrousek EF, Plomp AC, van Noort JM: Tolerization of an established αβ-crystallin-reactive T-cell response by intravenous antigen. Immunology 121(3), 416-426 (2007).
55. Bai XF, Shi FD, Xiao BG et al.: Nasal administration of myelin basic protein prevents relapsing experimental autoimmune encephalomyelitis in DA rats by activating regulatory cells expressing IL-4 and TGF-β mRNA. J. Neuroimmunol. 80(1-2), 65-75 (1997).
56. Burkhart C, Liu GY, Anderton SM, Metzler B, Wraith DC: Peptide-induced T cell regulation of experimental autoimmune encephalomyelitis: a role for IL-10. Int. Immunol. 11(10), 1625-1634 (1999)
57. Bitar DM, Whitacre CC: Suppression of experimental autoimmune encephalomyelitis by the oral administration of myelin basic protein. Cell Immunol. 112(2), 364-370 (1988).
58. Higgins PJ, Weiner HL: Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein and its fragments. J. Immunol. 140(2), 440-445 (1988).
59. Weiner HL, Mackin GA, Matsui M et al.: Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science 259(5099), 1321-1324 (1993).
60. Faria AM, Weiner HL: Oral tolerance. Immunol. Rev. 206, 232-259 (2005).
61. + population of regulatory T cells.
62. Evavold BD, Allen PM: Separation of IL-4 production from Th cell proliferation by an altered T cell receptor ligand. Science 252(5010), 1308-1310(1991).
63. Racioppi L, Ronchese F, Matis LA, Germain RN: Peptide-major histocompatibility complex class II complexes with mixed agonist/antagonist properties provide evidence for ligand-related differences in T cell receptor-dependent intracellular signaling. J. Exp. Med. 177(4), 1047-1060 (1993).
64. De Magistris MT, Alexander J, Coggeshall M et al.: Antigen analog-major histocompatibility complexes act as antagonists of the T cell receptor. Cell 68(4), 625-634 (1992).
65. Brocke S, Gijbels K, Allegretta M et al.: Treatment of experimental encephalomyelitis with a peptide analogue of myelin basic protein. Nature 379(6563), 343-346 (1996).
66. Goverman J, Woods A, Larson L et al.: Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell 72(4), 551-560 (1993).
67. Brabb T, Goldrath AW, von Dassow P et al.: Triggers of autoimmune disease in a murine TCR-transgenic model for multiple sclerosis. J. Immunol. 159(1), 497-507 (1997).
68. Lafaille JJ, Nagashima K, Katsuki M, Tonegawa S: High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice. Cell. 78(3), 399-408 (1994).
69. Offner H, Adlard K, Bebo BF Jr et al.: Vaccination with BV8S2 protein amplifies TCR-specific regulation and protection against experimental autoimmune encephalomyelitis in TCR BV8S2 transgenic mice. J. Immunol. 161(5), 2178-2186 (1998).
70. Vandenbark AA, Rich C, Mooney J et al.: Recombinant TCR ligand induces tolerance to myelin oligodendrocyte glycoprotein 35-55 peptide and reverses clinical and histological signs of chronic experimental autoimmune encephalomyelitis in HLA-DR2 transgenic mice. J. Immunol. 171(1), 127-133 (2003).
71. Moisini I, Nguyen P, Fugger L, Geiger TL: Redirecting therapeutic T cells against myelin-specificT lymphocytes using a humanized myelin basic protein-HLA-DR2-ζ chimeric receptor. J. Immunol. 180(5), 3601-3611 (2008).
72. Ito K, Bian HJ, Molina M et al.: HLA-DR4-IE chimeric class II transgenic, murine class II-deficient mice are susceptible to experimental allergic encephalomyelitis. J. Exp. Med. 183(6), 2635-2644 (1996).
73. Muraro PA, Vergelli M, Kalbus M et al.: Immunodominance of a low-affinity major histocompatibility complex-binding myelin basic protein epitope (residues 111-129) in HLA-DR4 (B1*0401) subjects is associated with a restricted T cell receptor repertoire. J. Clin. Invest. 100(2), 339-349 (1997).
74. Huh J, Yao K, Quigley L et al.: Limited repertoire of H LA-DRB 1*0401-restricted MBP111-129-specific T cells in HLA-DRB1*0401 Tg mice and their pathogenic potential. J. Neuroimmunol. 151(1-2), 94-102 (2004).
75. Fridkis-Hareli M, Teitelbaum D, Gurevich E et al.: Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen-presenting cells - specificity and promiscuity. Proc. Natl Acad. Sci. USA 91(11), 4872-4876 (1994).
76. Vandenbark AA, Chou YK, Whitham R et al.: Treatment of multiple sclerosis with T-cell receptor peptides: results of a double-blind pilot trial. Nat. Med. 2(10), 1109-1115 (1996).
77. Vandenbark AA, Morgan E, Bartholomew R et al.: TCR peptide therapy in human autoimmune diseases. Neurochem. Res. 26(6), 713-730 (2001).
78. Bielekova B, Goodwin B, Richert N et al.: Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a Phase II clinical trial with an altered peptide ligand. Nat. Med. 6(10), 1167-1175 (2000).
79. Leonard JP, Waldburger KE, Goldman SJ: Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin-12. J. Exp. Med. 181(1), 381-386 (1995).
80. Constantinescu CS, Wysocka M, Hilliard B et al.: Antibodies against IL-12 prevent superantigen-induced andspontaneous relapses of experimental autoimmune encephalomyelitis. J. Immunol. 161(9), 5097-5104 (1998).
81. Ichikawa M, Koh CS, Inoue K et al.: Anti-IL-12 antibody prevents the development and progression of multiple sclerosis-like relapsing-remitting demyelinating disease in NOD mice induced with myelin oligodendrocyte glycoprotein peptide. J. Neuroimmunol. 102(1), 56-66 (2000).
82. Segal BM, Constantinescu CS, Raychaudhuri A et al.: Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a Phase II, double-blind, placebocontrolled, randomised, dose-ranging study. Lancet Neurol. 7(9), 796-804 (2008). ■ Neutralization of IL-12 and IL-23 was tested. The negative result may have been due to the inclusion of patients with advanced disease.
83. Hofstetter HH, Ibrahim SM, Koczan D et al.: Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis. Cell Immunol. 237(2), 123-130 (2005).
84. Suntharalingam G, Perry MR, Ward S et al.: Cytokine storm in a Phase 1 trial of the anti-CD 28 monoclonal antibody TGN1412. N. Engl. J. Med. 355(10), 1018-1028 (2006). ■■ Highlights the need for extreme caution in the translation of therapies that are considered safe and effective in animal models to use in human subjects.
85. Jiang H, Milo R, Swoveland P et al.: Interferon β-1b reduces interferon γ-induced antigen-presenting capacity of human glial and B cells. J. Neuroimmunol. 61(1), 17-25 (1995).
86. Panitch HS, Hirsch RL, Schindler J, Johnson KP: Treatment of multiple sclerosis with γ-interferon: exacerbations associated with activation of the immune system. Neurology 37(7), 1097-1102 (1987).
87. Teleshova N, Bao W, Kivisakk P et al.: Elevated CD40 ligand expressing blood T-cell levels in multiple sclerosis are reversed by interferon-β treatment. Scand. J. Immunol. 51(3), 312-320 (2000).
88. + B cells in active multiple sclerosis and reversal by interferon β-lb therapy. J. Clin. Invest. 99(11), 2664-2671 (1997).
89. Dhib-Jalbut S: Mechanisms of interferon-β action in multiple sclerosis. Mult. Scler. 3(6), 397-401 (1997).
90. Rep MH, Schrijver HM, van Lopik T et al.: Interferon (IFN)-β treatment enhances CD95 and interleukin 10 expression but reduces interferon-γ producing T cells in MS patients. J. Neuroimmunol. 96(1), 92-100 (1999).
91. Calabresi PA, Tranquill LR, Dambrosia JM et al.: Increases in soluble VCAM-1 correlate with a decrease in MRI lesions in multiple sclerosis treated with interferon β-1b. Ann. Neurol. 41(5), 669-674 (1997).
92. Dhib-Jalbut S, Jiang H, Williams GJ: The effect of interferon β-1b on lymphocyte-endothelial cell adhesion. J. Neuroimmunol. 71(1-2), 215-222(1996).
93. Schreiner B, Mitsdoerffer M, Kieseier BC et al.: Interferon-β enhances monocyte and dendritic cell expression of B7-H1 (PD-L1), a strong inhibitor of autologous T-cell activation: relevance for the immune modulatory effect in multiple sclerosis. J. Neuroimmunol. 155(1-2), 172-182 (2004).
94. Shapiro S, Galboiz Y, Lahat N, Kinarty A, Miller A: The 'immunological-synapse' at its APC side in relapsing and secondary-progressive multiple sclerosis: modulation by interferon-β J. Neuroimmunol. 144(1-2), 116-124 (2003).
95. Gran B, Tranquill LR, Chen M et al.: Mechanisms of immunomodulation by glatiramer acetate. Neurology 55(11), 1704-1714 (2000).
96. Neuhaus O, Farina C, Wekerle H, Hohlfeld R: Mechanisms of action of glatiramer acetate in multiple sclerosis. Neurology 56(6), 702-708 (2001).
97. Duda PW, Schmied MC, Cook SL, Krieger JI, Hafler DA: Glatiramer acetate (Copaxone®) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J. Clin. Invest. 105(7), 967-976 (2000).
98. Weber MS, Starck M, Wagenpfeil S et al.: Multiple sclerosis: glatiramer acetate inhibits monocyte reactivity in vitro and in vivo. Brain 127(Pt 6), 1370-1378 (2004).
99. Weber MS, Prod'homme T, Youssef S et al.: Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat. Med. 13(8), 935-943 (2007).
100. Maier K, Kuhnert AV, Taheri N et al.: Effects of glatiramer acetate and interferon-β on neurodegeneration in a model of multiple sclerosis:a comparative study. Am. J. Pathol. 169(4), 1353-1364 (2006).
101. Yednock TA, Cannon C, Fritz LC et al.: Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin. Nature 356(6364), 63-66 (1992).
102. Stuve O, Marra CM, Jerome KR et al.: Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann. Neurol. 59(5), 743-747 (2006).
103. Stuve O: The effects of natalizumab on the innate and adaptive immune system in the central nervous system. J. Neurol. Sci. 274(1-2), 39-41 (2008).
104. Massacesi L, Parigi A, Barilaro A et al.: Efficacy of azathioprine on multiple sclerosis new brain lesions evaluated using magnetic resonance imaging. Arch. Neurol. 62(12), 1843-1847 (2005).
105. Amato MP, Pracucci G, Ponziani G et al.: Long-term safety of azathioprine therapy in multiple sclerosis. Neurology 43(4), 831-833 (1993).
106. Casetta I, Iuliano G, Filippini G: Azathioprine for multiple sclerosis. Cochrane Database Syst. Rev. (4), CD003982 (2007).
107. Fox EJ: Mechanism of action of mitoxantrone. Neurology 63(12 Suppl. 6), S15-S18 (2004).
108. Martinelli Boneschi F, Rovaris M, Capra R, Comi G: Mitoxantrone for multiple sclerosis. Cochrane Database Syst. Rev. (4), CD002127 (2005).
109. Fox EJ: Management of worsening multiple sclerosis with mitoxantrone: a review. Clin. Ther. 28(4), 461-474 (2006).
110. Sipe JC, Romine JS, Koziol JA et al.: Cladribine in treatment of chronic progressive multiple sclerosis. Lancet 344(8914), 9-13 (1994).
111. Sipe JC, Romine JS, Koziol JA et al.: Development of dadribine treatment in multiple sclerosis. Mult. Scler. 1(6), 343-347 (1996).
112. Rice GP, Filippi M, Comi G: Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI Study Group. Neurology 54(5), 1145-1155 (2000).
113. Brousil JA, Roberts RJ, Schlein AL: Cladribine: an investigational immunomodulatory agent for multiple sclerosis. Ann. Pharmacother. 40(10), 1814-1821 (2006).
114. Stelmasiak Z, Solski J, Nowicki J et al: Effect of parenteral cladribine on relapse rates in patients with relapsing forms of multiple sclerosis: results of a 2-year, double-blind, placebo-controlled, crossover study. Mult. Scler. 15(6), 767-770 (2009).
115. Budde K, Schmouder RL, Brunkhorst R et al.: First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients. J. Am. Soc. Nephrol. 13(4), 1073-1083 (2002).
116. Fujino M, Funeshima N, Kitazawa Y et al.: Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J. Pharmacol. Exp. Ther. 305(1), 70-77 (2003).
117. Mehling M, Brinkmann V, Antel J et al.: FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology 71(16), 1261-1267 (2008).
118. Brinkmann V, Cyster JG, Hla T: FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am. J. Transplant. 4(7), 1019-1025 (2004).
119. Mandala S, Hajdu R, Bergstrom J et al.: Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296(5566), 346-349 (2002).
120. Matloubian M, Lo CG, Cinamon G et al.: Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on SlP receptor 1. Nature 427(6972), 355-360 (2004).
121. O'Connor P, Comi G, Montalban X et al.: Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a Phase II extension study. Neurology 72(1), 73-79 (2009).
122. Waldmann TA: Anti-Tac (daclizumab, Zenapax®) in the treatment of leukemia, autoimmune diseases, and in the prevention of allograft rejection: a 25-year personal odyssey. J. Clin. Immunol. 27(1), 1-18 (2007).
123. Bielekova B, Richert N, Howard T et al.: Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon β. Proc. Natl Acad. ScL USA 101(23), 8705-8708 (2004).
124. Rose JW, Watt HE, White AT, Carlson NG: Treatment of multiple sclerosis with an anti-interleukin-2 receptor monoclonal antibody. Ann. Neurol. 56(6), 864-867 (2004).
125. bright natural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (dadizumab) in multiple sclerosis. Proc. Natl Acad. Sci. USA 103(15), 5941-5946 (2006).
126. Coles AJ, Compston DA, Selmaj KW et al.: Alemtuzumab vs. interferon β-1a in early multiple sclerosis. N. Engl. J. Med. 359(17), 1786-1801 (2008). ■■ Alemtuzumab is a monoclonal antibody against CD52. It is considered the most effective experimental therapy for patients with early relapsing-remitting multiple sclerosis. Careful monitoring is required for potential immune-mediated side effects.
127. Cox AL, Thompson SA, Jones JL et al.: Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur. J. Immunol. 35(11), 3332-3342 (2005).
128. Coles AJ, Wing M, Smith S et al.: Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 354(9191), 1691-1695 (1999).
129. Jones JL, Phuah CL, Cox AL et al.: IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J. Clin. Invest. (2009).
130. Herrmann ML, Schleyerbach R, Kirschbaum BJ: Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology 47(2-3), 273-289 (2000).
131. Korn T, Magnus T, Toyka K, Jung S: Modulation of effector cell functions in experimental autoimmune encephalomyelitis by leflunomide - mechanisms independent of pyrimidine depletion. J. Leukoc. Biol. 76(5), 950-960 (2004).
132. Massacesi L, Abbamondi AL, Sarlo F, Amaducci L: The control of experimental allergic encephalomyelitis with retinoic acid. Further studies. Riv. Neurol. 57(3), 166-169 (1987).
133. Roberts AB, Sporn MB: Mechanistic interrelationships between two superfamilies: the steroid/retinoid receptors and transforming growth factor-β. Cancer Surv. 14, 205-220 (1992).
134. Mucida D, Park Y, Kim G et al.: Reciprocal Th17 and regulatory T cell differentiation mediated by retinoic acid. Science 317(5835), 256-260 (2007).
135. Bettelli E, Oukka M, Kuchroo VK: Th-17 cells in the circle of immunity and autoimmunity. Nat. Immunol. 8(4), 345-350 (2007).
136. Korn T, Reddy J, Gao W et al.: Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat. Med. 13(4), 423-431 (2007).
137. + regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J. Immunol. 169(9), 4712-4716 (2002).
138. + regulatory T cells in patients with multiple sclerosis. J. Exp. Med. 199(7), 971-979 (2004).
139. Beriou G, Costantino CM, Ashley CW et al.: IL-17 producing human peripheral regulatory T cells retain suppressive function. Blood 113(18), 4240-4249 (2009).
140. Zhou L, Ivanov, II, Spolski R et al.: IL-6 programs Th-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 8(9), 967-974 (2007).
141. Wei L, Laurence A, Elias KM, O'Shea JJ: IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J. Biol. Chem. 282(48), 34605-34610 (2007).
142. Huber M, Brustle A, Reinhard K et al.: IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype. Proc. Natl Acad. Sci. USA 105(52), 20846-20851 (2008).
143. Wolk K, Sabat R: Interleukin-22: a novel T- and NK-cell derived cytokine that regulates the biology of tissue cells. Cytokine Growth Factor Rev. 17(5), 367-380 (2006).
144. + T lymphocytes. Cell Res. 16(11), 902-907 (2006).
145. Zheng Y, Valdez PA, Danilenko DM et al.: Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 14(3), 282-289 (2008).
146. Kreymborg K, Etzensperger R, Dumoutier L et al.: IL-22 is expressed by Th17 cells in an IL-23-dependent fashion, but not required for the development of autoimmune encephalomyelitis. J. Immunol. 179(12), 8098-8104 (2007).
147. Fitzgerald DC, Ciric B, Touil T et al.: Suppressive effect of 1L-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis. J. Immunol. 179(5), 3268-3275 (2007).
148. Awasthi A, Carrier Y, Peron JP et al.: A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat. Immunol. 8(12), 1380-1389 (2007).
149. Fitzgerald DC, Zhang GX, El-Behi M et al.: Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. Nat. Immunol. 8(12), 1372-1379 (2007). ■ IL-27 is a negative regulator of Th17. It suppresses autoimmune inflammation by secreting IL-10.
150. - effector T cells. Nat. Immunol. 9(12), 1347-1355 (2008). ■ [150] and [151] introduced a new lineage of T helper cells designated as Th9. These effector cells can inhibit the generation of regulatory T cells by suppressing Foxp3.
151. Veldhoen M, Uyttenhove C, van Snick J et al.: Transforming growth factor-β 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat. Immunol. 9(12), 1341-1346 (2008). ■ [150] and [151] introduced a new lineage of T helper cells designated as Th9. These effector cells can inhibit the generation of Treg cells by suppressing Foxp3.
152. Weinshenker BG, Bass B, Karlik S, Ebers GC, Rice GP: An open trial of OKT3 in patients with multiple sclerosis. Neurology 41(7), 1047-1052 (1991).
153. Lindsey JW, Hodgkinson S, Mehta R et al.: Repeated treatment with chimeric anti-CD4 antibody in multiple sclerosis. Ann. Neurol. 36(2), 183-189 (1994).
154. Lindsey JW, Hodgkinson S, Mehta R et al.: Phase 1 clinical trial of chimeric monoclonal anti-CD4 antibody in multiple sclerosis. Neurology 44(3 Pt 1), 413-419 (1994).
155. van Oosten BW, Lai M, Barkhof F et al.: A phase II trial of anti-CD4 antibodies in the treatment of multiple sclerosis. Mult. Scler. 1(6), 339-342 (1996).