What do effective treatments for multiple sclerosis tell us about the molecular mechanisms involved in pathogenesis?

International Journal of Molecular Sciences

Volumn 13, Issue 10, 2012, Pages 12665-12709

  Buzzard, Katherine A ^a   Broadley, Simon A ^b,c   Butzkueven, Helmut ^d  

^a ROYAL MELBOURNE HOSPITAL   (Australia)

^b GRIFFITH UNIVERSITY   (Australia)

^c GOLD COAST UNIVERSITY HOSPITAL   (Australia)

^d UNIVERSITY OF MELBOURNE   (Australia)

Author keywords

Immunomodulation; Mechanism of action; Multiple sclerosis; Treatment

Indexed keywords

ALEMTUZUMAB; ATACICEPT; BETA INTERFERON; BETA1A INTERFERON; CYCLOSPORIN A; DACLIZUMAB; FINGOLIMOD; FUMARIC ACID DIMETHYL ESTER; GLATIRAMER; INTERLEUKIN 17; INTERLEUKIN 23; LAQUINIMOD; NATALIZUMAB; OCRELIZUMAB; PLACEBO; RITUXIMAB; TERIFLUNOMIDE; IMMUNOSUPPRESSIVE AGENT;

ALOPECIA; ARTHRALGIA; AUTOIMMUNE DISEASE; AUTOIMMUNITY; B CELL LYMPHOMA; B LYMPHOCYTE; BACKACHE; BRADYCARDIA; BRAIN HEMORRHAGE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CHRONIC LYMPHATIC LEUKEMIA; CLINICAL EFFECTIVENESS; CYTOKINE PRODUCTION; DEPRESSION; DRUG APPROVAL; DRUG EFFECT; DRUG EFFICACY; DRUG MECHANISM; DRUG MEGADOSE; DRUG RESPONSE; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; FLU LIKE SYNDROME; GASTROINTESTINAL SYMPTOM; GENITAL HERPES; GOODPASTURE SYNDROME; GRAFT REJECTION; HEART INFARCTION; HUMAN; INFUSION RELATED REACTION; INJECTION SITE REACTION; LIVER FUNCTION TEST; LOW DRUG DOSE; LYMPHOCYTE ACTIVATION; LYMPHOCYTE MIGRATION; LYMPHOCYTOPENIA; MACROPHAGE; MONOCYTE; MULTIPLE SCLEROSIS; MYASTHENIA GRAVIS; NATURAL KILLER T CELL; NONHODGKIN LYMPHOMA; NONHUMAN; OPPORTUNISTIC INFECTION; PARESTHESIA; PATHOGENESIS; PATIENT SAFETY; PERICARDITIS; PLEURISY; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; PROTEIN FUNCTION; REGULATORY T LYMPHOCYTE; RETINA MACULA EDEMA; REVIEW; RHEUMATOID ARTHRITIS; SIDE EFFECT; SYNDROME DELINEATION; T CELL LEUKEMIA; T CELL LYMPHOMA; TH17 CELL; THORAX PAIN; THYROID DISEASE; UVEITIS; CLINICAL TRIAL (TOPIC); IMMUNOLOGY; METABOLISM; NUCLEAR MAGNETIC RESONANCE IMAGING; PATHOLOGY; T LYMPHOCYTE;

B-LYMPHOCYTES; CLINICAL TRIALS AS TOPIC; HUMANS; IMMUNOSUPPRESSIVE AGENTS; MAGNETIC RESONANCE IMAGING; MULTIPLE SCLEROSIS; T-LYMPHOCYTES;

EID: 84867774238     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms131012665     Document Type: Review

References (255)

1. Clanet, M. Jean-Martin Charcot. 1825 to 1893. Int. MS J. 2008, 15, 59-61.
2. Orton, S.M.; Herrera, B.M.; Yee, I.M.; Valdar, W.; Ramagopalan, S.V.; Sadovnick, A.D.; Ebers, G.C. Sex ratio of multiple sclerosis in Canada: A longitudinal study. Lancet Neurol. 2006, 5, 932-936.
3. Olerup, O.; Hillert, J. HLA class II-associated genetic susceptibility in multiple sclerosis: A critical evaluation. Tissue Antigens 1991, 38, 1-15.
4. Hafler, D.A.; Compston, A.; Sawcer, S.; Lander, E.S.; Daly, M.J.; de Jager, P.L.; de Bakker, P.I.; Gabriel, S.B.; Mirel, D.B.; Ivinson, A.J.; et al. Risk alleles for multiple sclerosis identified by a genomewide study. N. Engl. J. Med. 2007, 357, 851-862.
5. Weber, F.; Fontaine, B.; Cournu-Rebeix, I.; Kroner, A.; Knop, M.; Lutz, S.; Muller-Sarnowski, F.; Uhr, M.; Bettecken, T.; Kohli, M.; et al. IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations. Genes Immun. 2008, 9, 259-263.
6. Stromnes, I.M.; Goverman, J.M. Active induction of experimental allergic encephalomyelitis. Nat. Protoc. 2006, 1, 1810-1819.
7. Wegner, C. Pathological differences in acute inflammatory demyelinating diseases of the central nervous system. Int. MS J. 2005, 12, 13-19.
8. Stromnes, I.M.; Goverman, J.M. Passive induction of experimental allergic encephalomyelitis. Nat. Protoc. 2006, 1, 1952-1960.
9. Steinman, L. Assessment of animal models for MS and demyelinating disease in the design of rational therapy. Neuron 1999, 24, 511-514.
10. Molyneux, P.D.; Filippi, M.; Barkhof, F.; Gasperini, C.; Yousry, T.A.; Truyen, L.; Lai, H.M.; Rocca, M.A.; Moseley, I.F.; Miller, D.H. Correlations between monthly enhanced MRI lesion rate and changes in T2 lesion volume in multiple sclerosis. Ann. Neurol. 1998, 43, 332-339.
11. Grossman, R.I.; Gonzalez-Scarano, F.; Atlas, S.W.; Galetta, S.; Silberberg, D.H. Multiple sclerosis: Gadolinium enhancement in MR imaging. Radiology 1986, 161, 721-725.
12. Moore, G.R.; Laule, C. Neuropathologic correlates of magnetic resonance imaging in multiple sclerosis. J. Neuropathol. Exp. Neurol. 2012, 71, 762-778.
13. McFarland, H.F.; Barkhof, F.; Antel, J.; Miller, D.H. The role of MRI as a surrogate outcome measure in multiple sclerosis. Mult. Scler. 2002, 8, 40-51.
14. Paty, D.W.; Li, D.K. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology 1993, 43, 662-667.
15. Frank, J.A.; Stone, L.A.; Smith, M.E.; Albert, P.S.; Maloni, H.; McFarland, H.F. Serial contrast-enhanced magnetic resonance imaging in patients with early relapsing-remitting multiple sclerosis: Implications for treatment trials. Ann. Neurol. 1994, 36, S86-S90.
16. Broderick, J.P.; Narayan, S.; Gaskill, M.; Dhawan, A.P.; Khoury, J. Volumetric measurement of multifocal brain lesions. Implications for treatment trials of vascular dementia and multiple sclerosis. J. Neuroimaging 1996, 6, 36-43.
17. Rudick, R.A.; Fisher, E.; Lee, J.C.; Duda, J.T.; Simon, J. Brain atrophy in relapsing multiple sclerosis: Relationship to relapses, EDSS, and treatment with interferon beta-1a. Mult. Scler. 2000, 6, 365-372.
18. Delves, P.J.; Roitt, I.M. The immune system. Second of two parts. N. Engl. J. Med. 2000, 343, 108-117.
19. Mosmann, T.R.; Sad, S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol. Today 1996, 17, 138-146.
20. Steinman, L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat. Med. 2007, 13, 139-145.
21. Ferber, I.A.; Brocke, S.; Taylor-Edwards, C.; Ridgway, W.; Dinisco, C.; Steinman, L.; Dalton, D.; Fathman, C.G. Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J. Immunol. 1996, 156, 5-7.
22. Lin, J.; Ziring, D.; Desai, S.; Kim, S.; Wong, M.; Korin, Y.; Braun, J.; Reed, E.; Gjertson, D.; Singh, R.R. TNFalpha blockade in human diseases: An overview of efficacy and safety. Clin. Immunol. 2008, 126, 13-30.
23. The Lenercept Multiple Sclerosis Study Group; The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: Results of a randomized, placebo-controlled multicenter study. Neurology 1999, 53, 457-465.
24. Langrish, C.L.; Chen, Y.; Blumenschein, W.M.; Mattson, J.; Basham, B.; Sedgwick, J.D.; McClanahan, T.; Kastelein, R.A.; Cua, D.J. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 2005, 201, 233-240.
25. El-Behi, M.; Ciric, B.; Dai, H.; Yan, Y.; Cullimore, M.; Safavi, F.; Zhang, G.X.; Dittel, B.N.; Rostami, A. The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat. Immunol. 2011, 12, 568-575.
26. Codarri, L.; Gyulveszi, G.; Tosevski, V.; Hesske, L.; Fontana, A.; Magnenat, L.; Suter, T.; Becher, B. RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat. Immunol. 2011, 12, 560-567.
27. Ponomarev, E.D.; Shriver, L.P.; Maresz, K.; Pedras-Vasconcelos, J.; Verthelyi, D.; Dittel, B.N. GM-CSF production by autoreactive T cells is required for the activation of microglial cells and the onset of experimental autoimmune encephalomyelitis. J. Immunol. 2007, 178, 39-48.
28. Hofstetter, H.H.; Ibrahim, S.M.; Koczan, D.; Kruse, N.; Weishaupt, A.; Toyka, K.V.; Gold, R. Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis. Cell. Immunol. 2005, 237, 123-130.
29. Komiyama, Y.; Nakae, S.; Matsuki, T.; Nambu, A.; Ishigame, H.; Kakuta, S.; Sudo, K.; Iwakura, Y. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 2006, 177, 566-573.
30. O'Connor, R.A.; Prendergast, C.T.; Sabatos, C.A.; Lau, C.W.; Leech, M.D.; Wraith, D.C.; Anderton, S.M. Cutting edge: Th1 cells facilitate the entry of Th17 cells to the central nervous system during experimental autoimmune encephalomyelitis. J. Immunol. 2008, 181, 3750-3754.
31. Kang, Z.; Altuntas, C.Z.; Gulen, M.F.; Liu, C.; Giltiay, N.; Qin, H.; Liu, L.; Qian, W.; Ransohoff, R.M.; Bergmann, C.; et al. Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity 2010, 32, 414-425.
32. Rodgers, J.M.; Zhou, L.; Miller, S.D. Act1, scene brain: Astrocytes play a lead role. Immunity 2010, 32, 302-304.
33. Burfoot, R.K.; Jensen, C.J.; Field, J.; Stankovich, J.; Varney, M.D.; Johnson, L.J.; Butzkueven, H.; Booth, D.; Bahlo, M.; Tait, B.D.; et al. SNP mapping and candidate gene sequencing in the class I region of the HLA complex: Searching for multiple sclerosis susceptibility genes in Tasmanians. Tissue Antigens 2008, 71, 42-50.
34. Friese, M.A.; Fugger, L. Pathogenic CD8(+) T cells in multiple sclerosis. Ann. Neurol. 2009, 66, 132-141.
35. Kuhlmann, T.; Lingfeld, G.; Bitsch, A.; Schuchardt, J.; Bruck, W. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 2002, 125, 2202-2212.
36. Tzartos, J.S.; Friese, M.A.; Craner, M.J.; Palace, J.; Newcombe, J.; Esiri, M.M.; Fugger, L. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am. J. Pathol. 2008, 172, 146-155.
37. Anderson, A.C.; Chandwaskar, R.; Lee, D.H.; Sullivan, J.M.; Solomon, A.; Rodriguez-Manzanet, R.; Greve, B.; Sobel, R.A.; Kuchroo, V.K. A transgenic model of central nervous system autoimmunity mediated by CD4(+) and CD8(+) T and B cells. J. Immunol. 2012, 188, 2084-2092.
38. Kohm, A.P.; Carpentier, P.A.; Anger, H.A.; Miller, S.D. Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J. Immunol. 2002, 169, 4712-4716.
39. Huan, J.; Culbertson, N.; Spencer, L.; Bartholomew, R.; Burrows, G.G.; Chou, Y.K.; Bourdette, D.; Ziegler, S.F.; Offner, H.; Vandenbark, A.A. Decreased FOXP3 levels in multiple sclerosis patients. J. Neurosci. Res. 2005, 81, 45-52.
40. Dalla Libera, D.; di Mitri, D.; Bergami, A.; Centonze, D.; Gasperini, C.; Grasso, M.G.; Galgani, S.; Martinelli, V.; Comi, G.; Avolio, C.; et al. T regulatory cells are markers of disease activity in multiple sclerosis patients. PLoS One 2011, 6, e21386.
41. Putheti, P.; Pettersson, A.; Soderstrom, M.; Link, H.; Huang, Y.M. Circulating CD4+CD25+ T regulatory cells are not altered in multiple sclerosis and unaffected by disease-modulating drugs. J. Clin. Immunol. 2004, 24, 155-161.
42. Michel, L.; Berthelot, L.; Pettre, S.; Wiertlewski, S.; Lefrere, F.; Braudeau, C.; Brouard, S.; Soulillou, J.P.; Laplaud, D.A. Patients with relapsing-remitting multiple sclerosis have normal Treg function when cells expressing IL-7 receptor alpha-chain are excluded from the analysis. J. Clin. Invest. 2008, 118, 3411-3419.
43. Viglietta, V.; Baecher-Allan, C.; Weiner, H.L.; Hafler, D.A. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J. Exp. Med. 2004, 199, 971-979.
44. Caligiuri, M.A. Human natural killer cells. Blood 2008, 112, 461-469.
45. Cooper, M.A.; Fehniger, T.A.; Turner, S.C.; Chen, K.S.; Ghaheri, B.A.; Ghayur, T.; Carson, W.E.; Caligiuri, M.A. Human natural killer cells: A unique innate immunoregulatory role for the CD56(bright) subset. Blood 2001, 97, 3146-3151.
46. Berzins, S.P.; Smyth, M.J.; Baxter, A.G. Presumed guilty: Natural killer T cell defects and human disease. Nat. Rev. Immunol. 2011, 11, 131-142.
47. Benczur, M.; Petranyl, G.G.; Palffy, G.; Varga, M.; Talas, M.; Kotsy, B.; Foldes, I.; Hollan, S.R. Dysfunction of natural killer cells in multiple sclerosis: A possible pathogenetic factor. Clin. Exp. Immunol. 1980, 39, 657-662.
48. Zhang, B.; Yamamura, T.; Kondo, T.; Fujiwara, M.; Tabira, T. Regulation of experimental autoimmune encephalomyelitis by natural killer (NK) cells. J. Exp. Med. 1997, 186, 1677-1687.
49. Kaudewitz, P.; Zander, H.; Abb, J.; Ziegler-Heitbrock, H.W.; Riethmuller, G. Genetic influence on natural cytotoxicity and interferon production in multiple sclerosis studies in monozygotic discordant twins. Hum. Immunol. 1983, 7, 51-58.
50. Lucchinetti, C.; Bruck, W.; Parisi, J.; Scheithauer, B.; Rodriguez, M.; Lassmann, H. Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination. Ann. Neurol. 2000, 47, 707-717.
51. Serafini, B.; Rosicarelli, B.; Magliozzi, R.; Stigliano, E.; Aloisi, F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 2004, 14, 164-174.
52. Magliozzi, R.; Howell, O.; Vora, A.; Serafini, B.; Nicholas, R.; Puopolo, M.; Reynolds, R.; Aloisi, F. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 2007, 130, 1089-1104.
53. Lovato, L.; Willis, S.N.; Rodig, S.J.; Caron, T.; Almendinger, S.E.; Howell, O.W.; Reynolds, R.; O'Connor, K.C.; Hafler, D.A. Related B cell clones populate the meninges and parenchyma of patients with multiple sclerosis. Brain 2011, 134, 534-541.
54. Lechner-Scott, J.; Spencer, B.; de Malmanche, T.; Attia, J.; Fitzgerald, M.; Trojano, M.; Grand'maison, F.; Gomez, J.A.; Izquierdo, G.; Duquette, P.; et al. The frequency of CSF oligoclonal banding in multiple sclerosis increases with latitude. Mult. Scler. 2012, 18, 974-982.
55. Obermeier, B.; Lovato, L.; Mentele, R.; Bruck, W.; Forne, I.; Imhof, A.; Lottspeich, F.; Turk, K.W.; Willis, S.N.; Wekerle, H.; et al. Related B cell clones that populate the CSF and CNS of patients with multiple sclerosis produce CSF immunoglobulin. J. Neuroimmunol. 2011, 233, 245-248.
56. Bernard, C.C.; de Rosbo, N.K. Immunopathological recognition of autoantigens in multiple sclerosis. Acta Neurol. (Napoli) 1991, 13, 171-178.
57. Owens, G.P.; Bennett, J.L.; Lassmann, H.; O'Connor, K.C.; Ritchie, A.M.; Shearer, A.; Lam, C.; Yu, X.; Birlea, M.; DuPree, C.; et al Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid. Ann. Neurol. 2009, 65, 639-649.
58. Genain, C.P.; Cannella, B.; Hauser, S.L.; Raine, C.S. Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat. Med. 1999, 5, 170-175.
59. Wootla, B.; Denic, A.; Keegan, B.M.; Winters, J.L.; Astapenko, D.; Warrington, A.E.; Bieber, A.J.; Rodriguez, M. Evidence for the role of B cells and immunoglobulins in the pathogenesis of multiple sclerosis. Neurol. Res. Int. 2011, 2011, 780712.
60. Disanto, G.; Morahan, J.M.; Barnett, M.H.; Giovannoni, G.; Ramagopalan, S.V. The evidence for a role of B cells in multiple sclerosis. Neurology 2012, 78, 823-832.
61. Thorley-Lawson, D.A.; Gross, A. Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N. Engl. J. Med. 2004, 350, 1328-1337.
62. Ascherio, A.; Munger, K.L. Environmental risk factors for multiple sclerosis. Part I: The role of infection. Ann. Neurol. 2007, 61, 288-299.
63. Thacker, E.L.; Mirzaei, F.; Ascherio, A. Infectious mononucleosis and risk for multiple sclerosis: A meta-analysis. Ann. Neurol. 2006, 59, 499-503.
64. Farrell, R.A.; Antony, D.; Wall, G.R.; Clark, D.A.; Fisniku, L.; Swanton, J.; Khaleeli, Z.; Schmierer, K.; Miller, D.H.; Giovannoni, G. Humoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI. Neurology 2009, 73, 32-38.
65. Pender, M.P. Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases. Trends Immunol. 2003, 24, 584-588.
66. Pender, M.P. CD8+ T-Cell deficiency, epstein-barr virus infection, vitamin D deficiency, and steps to autoimmunity: A unifying hypothesis. Autoimmune Dis. 2012, 2012, 189096.
67. Tzartos, J.S.; Khan, G.; Vossenkamper, A.; Cruz-Sadaba, M.; Lonardi, S.; Sefia, E.; Meager, A.; Elia, A.; Middeldorp, J.M.; Clemens, M.; et al. Association of innate immune activation with latent Epstein-Barr virus in active MS lesions. Neurology 2012, 78, 15-23.
68. Serafini, B.; Rosicarelli, B.; Franciotta, D.; Magliozzi, R.; Reynolds, R.; Cinque, P.; Andreoni, L.; Trivedi, P.; Salvetti, M.; Faggioni, A., et al. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J. Exp. Med. 2007, 204, 2899-2912.
69. Willis, S.N.; Stadelmann, C.; Rodig, S.J.; Caron, T.; Gattenloehner, S.; Mallozzi, S.S.; Roughan, J.E.; Almendinger, S.E.; Blewett, M.M.; Bruck, W., et al. Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain 2009, 132, 3318-3328.
70. Sargsyan, S.A.; Shearer, A.J.; Ritchie, A.M.; Burgoon, M.P.; Anderson, S.; Hemmer, B.; Stadelmann, C.; Gattenlohner, S.; Owens, G.P.; Gilden, D., et al. Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis. Neurology 2010, 74, 1127-1135.
71. Lang, H.L.; Jacobsen, H.; Ikemizu, S.; Andersson, C.; Harlos, K.; Madsen, L.; Hjorth, P.; Sondergaard, L.; Svejgaard, A.; Wucherpfennig, K., et al. A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat. Immunol. 2002, 3, 940-943.
72. Miller, G. Immortalization of human lymphocytes by Epstein-Barr virus. Yale J. Biol. Med. 1982, 55, 305-310.
73. Ray, A.; Mann, M.K.; Basu, S.; Dittel, B.N. A case for regulatory B cells in controlling the severity of autoimmune-mediated inflammation in experimental autoimmune encephalomyelitis and multiple sclerosis. J. Neuroimmunol. 2011, 230, 1-9.
74. Hauser, S.L.; Waubant, E.; Arnold, D.L.; Vollmer, T.; Antel, J.; Fox, R.J.; Bar-Or, A.; Panzara, M.; Sarkar, N.; Agarwal, S., et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 2008, 358, 676-688.
75. Bar-Or, A.; Calabresi, P.A.; Arnold, D.; Markowitz, C.; Shafer, S.; Kasper, L.H.; Waubant, E.; Gazda, S.; Fox, R.J.; Panzara, M., et al. Rituximab in relapsing-remitting multiple sclerosis: A 72-week, open-label, phase I trial. Ann. Neurol. 2008, 63, 395-400.
76. Naismith, R.T.; Piccio, L.; Lyons, J.A.; Lauber, J.; Tutlam, N.T.; Parks, B.J.; Trinkaus, K.; Song, S.K.; Cross, A.H. Rituximab add-on therapy for breakthrough relapsing multiple sclerosis: A 52-week phase II trial. Neurology 2010, 74, 1860-1867.
77. Harp, C.T.; Lovett-Racke, A.E.; Racke, M.K.; Frohman, E.M.; Monson, N.L. Impact of myelin-specific antigen presenting B cells on T cell activation in multiple sclerosis. Clin. Immunol. 2008, 128, 382-391.
78. Bar-Or, A.; Fawaz, L.; Fan, B.; Darlington, P.J.; Rieger, A.; Ghorayeb, C.; Calabresi, P.A.; Waubant, E.; Hauser, S.L.; Zhang, J., et al. Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS? Ann. Neurol. 2010, 67, 452-461.
79. Benveniste, E.N. Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J. Mol. Med. (Berl) 1997, 75, 165-173.
80. Ferguson, B.; Matyszak, M.K.; Esiri, M.M.; Perry, V.H. Axonal damage in acute multiple sclerosis lesions. Brain 1997, 120, 393-399.
81. Frischer, J.M.; Bramow, S.; Dal-Bianco, A.; Lucchinetti, C.F.; Rauschka, H.; Schmidbauer, M.; Laursen, H.; Sorensen, P.S.; Lassmann, H. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 2009, 132, 1175-1189.
82. Xiao, B.G.; Link, H. Is there a balance between microglia and astrocytes in regulating Th1/Th2-cell responses and neuropathologies? Immunol. Today 1999, 20, 477-479.
83. De Simone, R.; Giampaolo, A.; Giometto, B.; Gallo, P.; Levi, G.; Peschle, C.; Aloisi, F. The costimulatory molecule B7 is expressed on human microglia in culture and in multiple sclerosis acute lesions. J. Neuropathol. Exp. Neurol. 1995, 54, 175-187.
84. Cannella, B.; Raine, C.S. The adhesion molecule and cytokine profile of multiple sclerosis lesions. Ann. Neurol. 1995, 37, 424-435.
85. Chao, C.C.; Hu, S.; Sheng, W.S.; Peterson, P.K. Tumor necrosis factor-alpha production by human fetal microglial cells: Regulation by other cytokines. Dev. Neurosci. 1995, 17, 97-105.
86. Merrill, J.E.; Ignarro, L.J.; Sherman, M.P.; Melinek, J.; Lane, T.E. Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. J. Immunol. 1993, 151, 2132-2141.
87. Prineas, J.W.; Wright, R.G. Macrophages, lymphocytes, and plasma cells in the perivascular compartment in chronic multiple sclerosis. Lab. Invest. 1978, 38, 409-421.
88. Dalakas, M.; Wright, R.G.; Prineas, J.W. Nature of the reversible white matter lesion in multiple sclerosis. Effects of acute inflammation on myelinated tissue studied in the rabbit eye. Brain 1980, 103, 515-524.
89. Walsh, M.J.; Murray, J.M. Dual implication of 2',3'-cyclic nucleotide 3' phosphodiesterase as major autoantigen and C3 complement-binding protein in the pathogenesis of multiple sclerosis. J. Clin. Invest. 1998, 101, 1923-1931.
90. Langer-Gould, A.; Atlas, S.W.; Green, A.J.; Bollen, A.W.; Pelletier, D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N. Engl. J. Med. 2005, 353, 375-381.
91. Jacobs, L.D.; Cookfair, D.L.; Rudick, R.A.; Herndon, R.M.; Richert, J.R.; Salazar, A.M.; Fischer, J.S.; Goodkin, D.E.; Granger, C.V.; Simon, J.H., et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann. Neurol. 1996, 39, 285-294.
92. Ebers, G.C.; PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 1998, 352, 1498-1504.
93. The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993, 43, 655-661.
94. Rudick, R.A.; Goodkin, D.E.; Jacobs, L.D.; Cookfair, D.L.; Herndon, R.M.; Richert, J.R.; Salazar, A.M.; Fischer, J.S.; Granger, C.V.; Simon, J.H., et al. Impact of interferon beta-1a on neurologic disability in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Neurology 1997, 49, 358-363.
95. Johnson, K.P.; Brooks, B.R.; Cohen, J.A.; Ford, C.C.; Goldstein, J.; Lisak, R.P.; Myers, L.W.; Panitch, H.S.; Rose, J.W.; Schiffer, R.B., et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: Results of a phase III multicenter, double-blind placebo-controlled trial. Neurology 1995, 45, 1268-1276.
96. Polman, C.H.; O'Connor, P.W.; Havrdova, E.; Hutchinson, M.; Kappos, L.; Miller, D.H.; Phillips, J.T.; Lublin, F.D.; Giovannoni, G.; Wajgt, A., et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 2006, 354, 899-910.
97. Kappos, L.; Radue, E.W.; O'Connor, P.; Polman, C.; Hohlfeld, R.; Calabresi, P.; Selmaj, K.; Agoropoulou, C.; Leyk, M.; Zhang-Auberson, L., et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 2010, 362, 387-401.
98. Khatri, B.; Barkhof, F.; Comi, G.; Hartung, H.P.; Kappos, L.; Montalban, X.; Pelletier, J.; Stites, T.; Wu, S.; Holdbrook, F., et al. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: A randomised extension of the TRANSFORMS study. Lancet Neurol. 2011, 10, 520-529.
99. Fox, R. Clinical Efficacy of BG-12 in Relapsing-Remitting Multiple Sclerosis (RRMS): Data from the Phase 3 CONFIRM Study. Available online: http://www.abstracts2view.com/aan/view.php?nu=AAN12L_S01_003 (accessed on 18 September 2012).
100. Gold, R. Clinical Efficacy of BG-12, An Oral Therapy, in Relapsing-Remitting Multiple Sclerosis: Data from the Phase 3 DEFINE Trial. Available online: http://registration.akm.ch/einsicht.php?XNABSTRACT_ID=137258&XNSPRACHE_ID=2&XNKONGRESS_ID=150&XNMASKEN_ID=900 (accessed on 18 September 2012).
101. Phillips, J.T.; Fox, L.M.; Miller, D.C.; Kita, M.; Hutchinson, M.; Havrdova, E.; Raghupathi, K.; Yuan, H.; Novas, M.; Viglietta, V., et al. Safety and Tolerability of BG-12 in Patients with Relapsing-Remitting Multiple Sclerosis (RRMS): Analyses from the CONFIRM Study. In Proceedings of American Academy of Neurology, New Orleans, LA, USA, 21-28 April 2012.
102. O'Connor, P.; Wolinsky, J.S.; Confavreux, C.; Comi, G.; Kappos, L.; Olsson, T.P.; Benzerdjeb, H.; Truffinet, P.; Wang, L.; Miller, A.; et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N. Engl. J. Med. 2011, 365, 1293-1303.
103. Comi, G.; Jeffery, D.; Kappos, L.; Montalban, X.; Boyko, A.; Rocca, M.A.; Filippi, M. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N. Engl. J. Med. 2012, 366, 1000-1009.
104. Cohen, J.A. Efficacy and Safety Results from Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis II (CARE-MS II): A Phase 3 Study in Relapsing-Remitting Multiple Sclerosis Patients Who Relapsed on Prior Therapy. In Proceedings of American Academy of Neurology (AAN), New Orleans, LA, USA, 21-28 April,2012; Vol. S01.004.
105. Coles, A.J. Efficacy and Safety Results from Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis I (CARE-MS I): A Phase 3 Study in Relapsing-Remitting Treatment-Naïve Patients. In Proceedings of American Academy of Neurology, New Orleans, LA, USA, 21-28 April,2012; Volume S01.006.
106. Goodin, D.S.; Jones, J.; Li, D.; Traboulsee, A.; Reder, A.T.; Beckmann, K.; Konieczny, A.; Knappertz, V. Establishing long-term efficacy in chronic disease: Use of recursive partitioning and propensity score adjustment to estimate outcome in MS. PLoS One 2011, 6, e22444.
107. Shirani, A.; Zhao, Y.; Karim, M.E.; Evans, C.; Kingwell, E.; van der Kop, M.L.; Oger, J.; Gustafson, P.; Petkau, J.; Tremlett, H. Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA 2012, 308, 247-256.
108. McCoy, L.; Tsunoda, I.; Fujinami, R.S. Multiple sclerosis and virus induced immune responses: Autoimmunity can be primed by molecular mimicry and augmented by bystander activation. Autoimmunity 2006, 39, 9-19.
109. Chadha, K.C.; Ambrus, J.L., Jr.; Dembinski, W.; Ambrus, J.L., Sr. Interferons and interferon inhibitory activity in disease and therapy. Exp. Biol. Med. (Maywood) 2004, 229, 285-290.
110. Kozovska, M.E.; Hong, J.; Zang, Y.C.; Li, S.; Rivera, V.M.; Killian, J.M.; Zhang, J.Z. Interferon beta induces T-helper 2 immune deviation in MS. Neurology 1999, 53, 1692-1697.
111. Liu, Z.; Pelfrey, C.M.; Cotleur, A.; Lee, J.C.; Rudick, R.A. Immunomodulatory effects of interferon beta-1a in multiple sclerosis. J. Neuroimmunol. 2001, 112, 153-162.
112. Ozenci, V.; Kouwenhoven, M.; Huang, Y.M.; Xiao, B.; Kivisakk, P.; Fredrikson, S.; Link, H. Multiple sclerosis: Levels of interleukin-10-secreting blood mononuclear cells are low in untreated patients but augmented during interferon-beta-1b treatment. Scand. J. Immunol. 1999, 49, 554-561.
113. Chen, M.; Chen, G.; Nie, H.; Zhang, X.; Niu, X.; Zang, Y.C.; Skinner, S.M.; Zhang, J.Z.; Killian, J.M.; Hong, J. Regulatory effects of IFN-beta on production of osteopontin and IL-17 by CD4+ T Cells in MS. Eur. J. Immunol. 2009, 39, 2525-2536.
114. Zhang, L.; Yuan, S.; Cheng, G.; Guo, B. Type I IFN promotes IL-10 production from T cells to suppress Th17 cells and Th17-associated autoimmune inflammation. PLoS One 2011, 6, e28432.
115. Guo, B.; Chang, E.Y.; Cheng, G. The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice. J. Clin. Invest. 2008, 118, 1680-1690.
116. Shinohara, M.L.; Kim, J.H.; Garcia, V.A.; Cantor, H. Engagement of the type I interferon receptor on dendritic cells inhibits T helper 17 cell development: Role of intracellular osteopontin. Immunity 2008, 29, 68-78.
117. Ramgolam, V.S.; Sha, Y.; Jin, J.; Zhang, X.; Markovic-Plese, S. IFN-beta inhibits human Th17 cell differentiation. J. Immunol. 2009, 183, 5418-5427.
118. Kieseier, B.C. The mechanism of action of interferon-beta in relapsing multiple sclerosis. CNS Drugs 2011, 25, 491-502.
119. Saraste, M.; Irjala, H.; Airas, L. Expansion of CD56Bright natural killer cells in the peripheral blood of multiple sclerosis patients treated with interferon-beta. Neurol. Sci. 2007, 28, 121-126.
120. Vandenbark, A.A.; Huan, J.; Agotsch, M.; La Tocha, D.; Goelz, S.; Offner, H.; Lanker, S.; Bourdette, D. Interferon-beta-1a treatment increases CD56bright natural killer cells and CD4+CD25+ Foxp3 expression in subjects with multiple sclerosis. J. Neuroimmunol. 2009, 215, 125-128.
121. Sanvito, L.; Tomita, A.; Chihara, N.; Okamoto, T.; Lin, Y.; Ogawa, M.; Gran, B.; Aranami, T.; Yamamura, T. Increase of Ki-67+ natural killer cells in multiple sclerosis patients treated with interferon-beta and interferon-beta combined with low-dose oral steroids. J. Neuroimmunol. 2011, 236, 111-117.
122. Martinez-Rodriguez, J.E.; Lopez-Botet, M.; Munteis, E.; Rio, J.; Roquer, J.; Montalban, X.; Comabella, M. Natural killer cell phenotype and clinical response to interferon-beta therapy in multiple sclerosis. Clin. Immunol. 2011, 141, 348-356.
123. De Andres, C.; Aristimuno, C.; de Las Heras, V.; Martinez-Gines, M.L.; Bartolome, M.; Arroyo, R.; Navarro, J.; Gimenez-Roldan, S.; Fernandez-Cruz, E.; Sanchez-Ramon, S. Interferon beta-1a therapy enhances CD4+ regulatory T-cell function: An ex vivo and in vitro longitudinal study in relapsing-remitting multiple sclerosis. J. Neuroimmunol. 2007, 182, 204-211.
124. Korporal, M.; Haas, J.; Balint, B.; Fritzsching, B.; Schwarz, A.; Moeller, S.; Fritz, B.; Suri-Payer, E.; Wildemann, B. Interferon beta-induced restoration of regulatory T-cell function in multiple sclerosis is prompted by an increase in newly generated naive regulatory T cells. Arch. Neurol. 2008, 65, 1434-1439.
125. Chen, M.; Chen, G.; Deng, S.; Liu, X.; Hutton, G.J.; Hong, J. IFN-beta induces the proliferation of CD4+CD25+Foxp3+ regulatory T cells through upregulation of GITRL on dendritic cells in the treatment of multiple sclerosis. J. Neuroimmunol. 2012, 242, 39-46.
126. Caggiula, M.; Batocchi, A.P.; Frisullo, G.; Angelucci, F.; Patanella, A.K.; Sancricca, C.; Nociti, V.; Tonali, P.A.; Mirabella, M. Neurotrophic factors in relapsing remitting and secondary progressive multiple sclerosis patients during interferon beta therapy. Clin. Immunol. 2006, 118, 77-82.
127. Boutros, T.; Croze, E.; Yong, V.W. Interferon-beta is a potent promoter of nerve growth factor production by astrocytes. J. Neurochem. 1997, 69, 939-946.
128. Biernacki, K.; Antel, J.P.; Blain, M.; Narayanan, S.; Arnold, D.L.; Prat, A. Interferon beta promotes nerve growth factor secretion early in the course of multiple sclerosis. Arch. Neurol. 2005, 62, 563-568.
129. Ramgolam, V.S.; Sha, Y.; Marcus, K.L.; Choudhary, N.; Troiani, L.; Chopra, M.; Markovic-Plese, S. B cells as a therapeutic target for IFN-beta in relapsing-remitting multiple sclerosis. J. Immunol. 2011, 186, 4518-4526.
130. Ebers, G.C.; Reder, A.T.; Traboulsee, A.; Li, D.; Langdon, D.; Goodin, D.S.; Wolf, C.; Beckmann, K.; Konieczny, A. Long-term follow-up of the original interferon-beta1b trial in multiple sclerosis: Design and lessons from a 16-year observational study. Clin. Ther. 2009, 31, 1724-1736.
131. Kim, S.H.; Kim, W.; Li, X.F.; Jung, I.J.; Kim, H.J. Does interferon beta treatment exacerbate neuromyelitis optica spectrum disorder? Mult. Scler. 2012, doi:10.1177/1352458512439439.
132. Axtell, R.C.; de Jong, B.A.; Boniface, K.; van der Voort, L.F.; Bhat, R.; de Sarno, P.; Naves, R.; Han, M.; Zhong, F.; Castellanos, J.G., et al. T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat. Med. 2010, 16, 406-412.
133. Bushnell, S.E.; Zhao, Z.; Stebbins, C.C.; Cadavid, D.; Buko, A.M.; Whalley, E.T.; Davis, J.A.; Versage, E.M.; Richert, J.R.; Axtell, R.C., et al. Serum IL-17F does not predict poor response to IM IFNbeta-1a in relapsing-remitting MS. Neurology 2012, 79, 531-537.
134. Sela, M.; Teitelbaum, D. Glatiramer acetate in the treatment of multiple sclerosis. Expert Opin. Pharmacother. 2001, 2, 1149-1165.
135. Bornstein, M.B.; Miller, A.; Slagle, S.; Weitzman, M.; Crystal, H.; Drexler, E.; Keilson, M.; Merriam, A.; Wassertheil-Smoller, S.; Spada, V., et al. A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N. Engl. J. Med. 1987, 317, 408-414.
136. Comi, G.; Filippi, M.; Wolinsky, J.S. European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis. Ann. Neurol. 2001, 49, 290-297.
137. Mikol, D.D.; Barkhof, F.; Chang, P.; Coyle, P.K.; Jeffery, D.R.; Schwid, S.R.; Stubinski, B.; Uitdehaag, B.M. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): A multicentre, randomised, parallel, open-label trial. Lancet Neurol. 2008, 7, 903-914.
138. O'Connor, P.; Filippi, M.; Arnason, B.; Comi, G.; Cook, S.; Goodin, D.; Hartung, H.P.; Jeffery, D.; Kappos, L.; Boateng, F., et al. 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: A prospective, randomised, multicentre study. Lancet Neurol. 2009, 8, 889-897.
139. Kala, M.; Miravalle, A.; Vollmer, T. Recent insights into the mechanism of action of glatiramer acetate. J. Neuroimmunol. 2011, 235, 9-17.
140. Vieira, P.L.; Heystek, H.C.; Wormmeester, J.; Wierenga, E.A.; Kapsenberg, M.L. Glatiramer acetate (copolymer-1, copaxone) promotes Th2 cell development and increased IL-10 production through modulation of dendritic cells. J. Immunol. 2003, 170, 4483-4488.
141. Aharoni, R.; Eilam, R.; Stock, A.; Vainshtein, A.; Shezen, E.; Gal, H.; Friedman, N.; Arnon, R. Glatiramer acetate reduces Th-17 inflammation and induces regulatory T-cells in the CNS of mice with relapsing-remitting or chronic EAE. J. Neuroimmunol. 2010, 225, 100-111.
142. Jee, Y.; Liu, R.; Bai, X.F.; Campagnolo, D.I.; Shi, F.D.; Vollmer, T.L. Do Th2 cells mediate the effects of glatiramer acetate in experimental autoimmune encephalomyelitis? Int. Immunol. 2006, 18, 537-544.
143. Tennakoon, D.K.; Mehta, R.S.; Ortega, S.B.; Bhoj, V.; Racke, M.K.; Karandikar, N.J. Therapeutic induction of regulatory, cytotoxic CD8+ T cells in multiple sclerosis. J. Immunol. 2006, 176, 7119-7129.
144. Karandikar, N.J.; Crawford, M.P.; Yan, X.; Ratts, R.B.; Brenchley, J.M.; Ambrozak, D.R.; Lovett-Racke, A.E.; Frohman, E.M.; Stastny, P.; Douek, D.C., et al. Glatiramer acetate (Copaxone) therapy induces CD8(+) T cell responses in patients with multiple sclerosis. J. Clin. Invest. 2002, 109, 641-649.
145. Kala, M.; Rhodes, S.N.; Piao, W.H.; Shi, F.D.; Campagnolo, D.I.; Vollmer, T.L. B cells from glatiramer acetate-treated mice suppress experimental autoimmune encephalomyelitis. Exp. Neurol. 2010, 221, 136-145.
146. Begum-Haque, S.; Sharma, A.; Christy, M.; Lentini, T.; Ochoa-Reparaz, J.; Fayed, I.F.; Mielcarz, D.; Haque, A.; Kasper, L.H. Increased expression of B cell-associated regulatory cytokines by glatiramer acetate in mice with experimental autoimmune encephalomyelitis. J. Neuroimmunol. 2010, 219, 47-53.
147. Begum-Haque, S.; Christy, M.; Ochoa-Reparaz, J.; Nowak, E.C.; Mielcarz, D.; Haque, A.; Kasper, L.H. Augmentation of regulatory B cell activity in experimental allergic encephalomyelitis by glatiramer acetate. J. Neuroimmunol. 2011, 232, 136-144.
148. Lalive, P.H.; Neuhaus, O.; Benkhoucha, M.; Burger, D.; Hohlfeld, R.; Zamvil, S.S.; Weber, M.S. Glatiramer acetate in the treatment of multiple sclerosis: Emerging concepts regarding its mechanism of action. CNS Drugs 2011, 25, 401-414.
149. Weber, M.S.; Prod'homme, T.; Youssef, S.; Dunn, S.E.; Rundle, C.D.; Lee, L.; Patarroyo, J.C.; Stuve, O.; Sobel, R.A.; Steinman, L., et al. Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat. Med. 2007, 13, 935-943.
150. Toker, A.; Slaney, C.Y.; Backstrom, B.T.; Harper, J.L. Glatiramer acetate treatment directly targets CD11b(+)Ly6G(-) monocytes and enhances the suppression of autoreactive T cells in experimental autoimmune encephalomyelitis. Scand. J. Immunol. 2011, 74, 235-243.
151. Sarchielli, P.; Zaffaroni, M.; Floridi, A.; Greco, L.; Candeliere, A.; Mattioni, A.; Tenaglia, S.; di Filippo, M.; Calabresi, P. Production of brain-derived neurotrophic factor by mononuclear cells of patients with multiple sclerosis treated with glatiramer acetate, interferon-beta 1a, and high doses of immunoglobulins. Mult. Scler. 2007, 13, 313-331.
152. Blanco, Y.; Moral, E.A.; Costa, M.; Gomez-Choco, M.; Torres-Peraza, J.F.; Alonso-Magdalena, L.; Alberch, J.; Jaraquemada, D.; Arbizu, T.; Graus, F., et al. Effect of glatiramer acetate (Copaxone) on the immunophenotypic and cytokine profile and BDNF production in multiple sclerosis: A longitudinal study. Neurosci. Lett. 2006, 406, 270-275.
153. Aharoni, R.; Eilam, R.; Domev, H.; Labunskay, G.; Sela, M.; Arnon, R. The immunomodulator glatiramer acetate augments the expression of neurotrophic factors in brains of experimental autoimmune encephalomyelitis mice. Proc. Natl. Acad. Sci. USA 2005, 102, 19045-19050.
154. Azoulay, D.; Vachapova, V.; Shihman, B.; Miler, A.; Karni, A. Lower brain-derived neurotrophic factor in serum of relapsing remitting MS: Reversal by glatiramer acetate. J. Neuroimmunol. 2005, 167, 215-218.
155. Ziemssen, T.; Kumpfel, T.; Schneider, H.; Klinkert, W.E.; Neuhaus, O.; Hohlfeld, R. Secretion of brain-derived neurotrophic factor by glatiramer acetate-reactive T-helper cell lines: Implications for multiple sclerosis therapy. J. Neurol. Sci. 2005, 233, 109-112.
156. Pucci, E.; Giuliani, G.; Solari, A.; Simi, S.; Minozzi, S.; di Pietrantonj, C.; Galea, I. Natalizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst. Rev. 2011, CD007621.
157. Bloomgren, G.; Richman, S.; Hotermans, C.; Subramanyam, M.; Goelz, S.; Natarajan, A.; Lee, S.; Plavina, T.; Scanlon, J.V.; Sandrock, A., et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N. Engl. J. Med. 2012, 366, 1870-1880.
158. Biogen Idec Tysabri Safety Update. Available online: http://www.tapp.com.au/members/Tysabri_Safety_Update_160812.pdf (accessed on 23 August 2012).
159. Weiner, L.P.; Herndon, R.M.; Narayan, O.; Johnson, R.T.; Shah, K.; Rubinstein, L.J.; Preziosi, T.J.; Conley, F.K. Isolation of virus related to SV40 from patients with progressive multifocal leukoencephalopathy. N. Engl. J. Med. 1972, 286, 385-390.
160. Major, E.O.; Ault, G.S. Progressive multifocal leukoencephalopathy: Clinical and laboratory observations on a viral induced demyelinating disease in the immunodeficient patient. Curr. Opin. Neurol. 1995, 8, 184-190.
161. Kappos, L.; Bates, D.; Edan, G.; Eraksoy, M.; Garcia-Merino, A.; Grigoriadis, N.; Hartung, H.P.; Havrdova, E.; Hillert, J.; Hohlfeld, R., et al. Natalizumab treatment for multiple sclerosis: Updated recommendations for patient selection and monitoring. Lancet Neurol. 2011, 10, 745-758.
162. Vellinga, M.M.; Castelijns, J.A.; Barkhof, F.; Uitdehaag, B.M.; Polman, C.H. Postwithdrawal rebound increase in T2 lesional activity in natalizumab-treated MS patients. Neurology 2008, 70, 1150-1151.
163. Stuve, O.; Cravens, P.D.; Frohman, E.M.; Phillips, J.T.; Remington, G.M.; von Geldern, G.; Cepok, S.; Singh, M.P.; Tervaert, J.W.; de Baets, M., et al. Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology 2009, 72, 396-401.
164. Rice, G.P.; Hartung, H.P.; Calabresi, P.A. Anti-alpha4 integrin therapy for multiple sclerosis: Mechanisms and rationale. Neurology 2005, 64, 1336-1342.
165. Sato, T.; Tachibana, K.; Nojima, Y.; D'Avirro, N.; Morimoto, C. Role of the VLA-4 molecule in T cell costimulation. Identification of the tyrosine phosphorylation pattern induced by the ligation of VLA-4. J. Immunol. 1995, 155, 2938-2947.
166. Ramos-Cejudo, J.; Oreja-Guevara, C.; Stark Aroeira, L.; Rodriguez de Antonio, L.; Chamorro, B.; Diez-Tejedor, E. Treatment with natalizumab in relapsing-remitting multiple sclerosis patients induces changes in inflammatory mechanism. J. Clin. Immunol. 2011, 31, 623-631.
167. Skarica, M.; Eckstein, C.; Whartenby, K.A.; Calabresi, P.A. Novel mechanisms of immune modulation of natalizumab in multiple sclerosis patients. J. Neuroimmunol. 2011, 235, 70-76.
168. Kivisakk, P.; Healy, B.C.; Viglietta, V.; Quintana, F.J.; Hootstein, M.A.; Weiner, H.L.; Khoury, S.J. Natalizumab treatment is associated with peripheral sequestration of proinflammatory T cells. Neurology 2009, 72, 1922-1930.
169. Bar-Or, A.; Nuttall, R.K.; Duddy, M.; Alter, A.; Kim, H.J.; Ifergan, I.; Pennington, C.J.; Bourgoin, P.; Edwards, D.R.; Yong, V.W. Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis. Brain 2003, 126, 2738-2749.
170. Chun, J.; Brinkmann, V. A mechanistically novel, first oral therapy for multiple sclerosis: The development of fingolimod (FTY720, Gilenya). Discov. Med. 2011, 12, 213-228.
171. Fujino, M.; Funeshima, N.; Kitazawa, Y.; Kimura, H.; Amemiya, H.; Suzuki, S.; Li, X.K. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J. Pharmacol. Exp. Ther. 2003, 305, 70-77.
172. Kataoka, H.; Sugahara, K.; Shimano, K.; Teshima, K.; Koyama, M.; Fukunari, A.; Chiba, K. FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. Cell. Mol. Immunol. 2005, 2, 439-448.
173. Webb, M.; Tham, C.S.; Lin, F.F.; Lariosa-Willingham, K.; Yu, N.; Hale, J.; Mandala, S.; Chun, J.; Rao, T.S. Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J. Neuroimmunol. 2004, 153, 108-121.
174. Cohen, J.A.; Chun, J. Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis. Ann. Neurol. 2011, 69, 759-777.
175. Mehling, M.; Lindberg, R.; Raulf, F.; Kuhle, J.; Hess, C.; Kappos, L.; Brinkmann, V. Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. Neurology 2010, 75, 403-410.
176. Kivisakk, P.; Mahad, D.J.; Callahan, M.K.; Sikora, K.; Trebst, C.; Tucky, B.; Wujek, J.; Ravid, R.; Staugaitis, S.M.; Lassmann, H., et al. Expression of CCR7 in multiple sclerosis: Implications for CNS immunity. Ann. Neurol. 2004, 55, 627-638.
177. Choi, J.W.; Gardell, S.E.; Herr, D.R.; Rivera, R.; Lee, C.W.; Noguchi, K.; Teo, S.T.; Yung, Y.C.; Lu, M.; Kennedy, G., et al. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc. Natl. Acad. Sci. USA 2011, 108, 751-756.
178. Altmeyer, P.J.; Matthes, U.; Pawlak, F.; Hoffmann, K.; Frosch, P.J.; Ruppert, P.; Wassilew, S.W.; Horn, T.; Kreysel, H.W.; Lutz, G., et al. Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients. J. Am. Acad. Dermarol. 1994, 30, 977-981.
179. Moharregh-Khiabani, D.; Linker, R.A.; Gold, R.; Stangel, M. Fumaric Acid and its esters: An emerging treatment for multiple sclerosis. Curr. Neuropharmacol. 2009, 7, 60-64.
180. Hayden, M.S.; Ghosh, S. NF-kappaB, the first quarter-century: Remarkable progress and outstanding questions. Genes Dev. 2012, 26, 203-234.
181. Schon, M.P.; Boehncke, W.H. Psoriasis. N. Engl. J. Med. 2005, 352, 1899-1912.
182. de Jong, R.; Bezemer, A.C.; Zomerdijk, T.P.; van de Pouw-Kraan, T.; Ottenhoff, T.H.; Nibbering, P.H. Selective stimulation of T helper 2 cytokine responses by the anti-psoriasis agent monomethylfumarate. Eur. J. Immunol. 1996, 26, 2067-2074.
183. Treumer, F.; Zhu, K.; Glaser, R.; Mrowietz, U. Dimethylfumarate is a potent inducer of apoptosis in human T cells. J. Invest. Dermatol. 2003, 121, 1383-1388.
184. Schilling, S.; Goelz, S.; Linker, R.; Luehder, F.; Gold, R. Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration. Clin. Exp. Immunol. 2006, 145, 101-107.
185. Linker, R.A.; Lee, D.H.; Ryan, S.; van Dam, A.M.; Conrad, R.; Bista, P.; Zeng, W.; Hronowsky, X.; Buko, A.; Chollate, S., et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 2011, 134, 678-692.
186. Scannevin, R.H.; Chollate, S.; Jung, M.Y.; Shackett, M.; Patel, H.; Bista, P.; Zeng, W.; Ryan, S.; Yamamoto, M.; Lukashev, M., et al. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J. Pharmacol. Exp. Ther. 2012, 341, 274-284.
187. Lin, S.X.; Lisi, L.; Dello Russo, C.; Polak, P.E.; Sharp, A.; Weinberg, G.; Kalinin, S.; Feinstein, D.L. The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1. ASN Neuro 2011, 3, doi:10.1042/AN20100033.
188. Schweckendiek, W. Treatment of psoriasis vulgaris. Med. Monatsschr. 1959, 13, 103-104.
189. Claussen, M.C.; Korn, T. Immune mechanisms of new therapeutic strategies in MS: Teriflunomide. Clin. Immunol. 2012, 142, 49-56.
190. Dimitrova, P.; Skapenko, A.; Herrmann, M.L.; Schleyerbach, R.; Kalden, J.R.; Schulze-Koops, H. Restriction of de novo pyrimidine biosynthesis inhibits Th1 cell activation and promotes Th2 cell differentiation. J. Immunol. 2002, 169, 3392-3399.
191. Xu, X.; Williams, J.W.; Bremer, E.G.; Finnegan, A.; Chong, A.S. Inhibition of protein tyrosine phosphorylation in T cells by a novel immunosuppressive agent, leflunomide. J. Biol. Chem. 1995, 270, 12398-12403.
192. Zeyda, M.; Poglitsch, M.; Geyeregger, R.; Smolen, J.S.; Zlabinger, G.J.; Horl, W.H.; Waldhausl, W.; Stulnig, T.M.; Saemann, M.D. Disruption of the interaction of T cells with antigen-presenting cells by the active leflunomide metabolite teriflunomide: Involvement of impaired integrin activation and immunologic synapse formation. Arthritis Rheum. 2005, 52, 2730-2739.
193. 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. 2004, 76, 950-960.
194. Merrill, J.E.; Hanak, S.; Pu, S.F.; Liang, J.; Dang, C.; Iglesias-Bregna, D.; Harvey, B.; Zhu, B.; McMonagle-Strucko, K. Teriflunomide reduces behavioral, electrophysiological, and histopathological deficits in the Dark Agouti rat model of experimental autoimmune encephalomyelitis. J. Neurol. 2009, 256, 89-103.
195. Wolinsky, J.S.; Narayana, P.A.; Noseworthy, J.H.; Lublin, F.D.; Whitaker, J.N.; Linde, A.; Gjorstrup, P.; Sullivan, H.C.; North American Linomide Investigators. Linomide in relapsing and secondary progressive MS: Part II: MRI results. MRI Analysis Center of the University of Texas-Houston, Health Science Center, and the. Neurology 2000, 54, 1734-1741.
196. Noseworthy, J.H.; Wolinsky, J.S.; Lublin, F.D.; Whitaker, J.N.; Linde, A.; Gjorstrup, P.; Sullivan, H.C. North American Linomide Investigators. Linomide in relapsing and secondary progressive MS: Part I: Trial design and clinical results. Neurology 2000, 54, 1726-1733.
197. Tan, I.L.; Nijeholt, G.J.L.; Polman, C.H.; Ader, H.J.; Barkhof, F. Linomide in the treatment of multiple sclerosis: MRI results from prematurely terminated phase-III trials. Mult. Scler. 2000, 6, 99-104.
198. Wegner, C.; Stadelmann, C.; Pfortner, R.; Raymond, E.; Feigelson, S.; Alon, R.; Timan, B.; Hayardeny, L.; Bruck, W. Laquinimod interferes with migratory capacity of T cells and reduces IL-17 levels, inflammatory demyelination and acute axonal damage in mice with experimental autoimmune encephalomyelitis. J. Neuroimmunol. 2010, 227, 133-143.
199. Brunmark, C.; Runstrom, A.; Ohlsson, L.; Sparre, B.; Brodin, T.; Astrom, M.; Hedlund, G. The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 2002, 130, 163-172.
200. Yang, J.S.; Xu, L.Y.; Xiao, B.G.; Hedlund, G.; Link, H. Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-beta in Lewis rats. J. Neuroimmunol. 2004, 156, 3-9.
201. Bruck, W.; Wegner, C. Insight into the mechanism of laquinimod action. J. Neurol. Sci. 2011, 306, 173-179.
202. Zou, L.P.; Abbas, N.; Volkmann, I.; Nennesmo, I.; Levi, M.; Wahren, B.; Winblad, B.; Hedlund, G.; Zhu, J. Suppression of experimental autoimmune neuritis by ABR-215062 is associated with altered Th1/Th2 balance and inhibited migration of inflammatory cells into the peripheral nerve tissue. Neuropharmacology 2002, 42, 731-739.
203. Gurevich, M.; Gritzman, T.; Orbach, R.; Tuller, T.; Feldman, A.; Achiron, A. Laquinimod suppress antigen presentation in relapsing-remitting multiple sclerosis: In-vitro high-throughput gene expression study. J. Neuroimmunol. 2010, 221, 87-94.
204. Thone, J.; Ellrichmann, G.; Seubert, S.; Peruga, I.; Lee, D.H.; Conrad, R.; Hayardeny, L.; Comi, G.; Wiese, S.; Linker, R.A., et al. Modulation of autoimmune demyelination by laquinimod via induction of brain-derived neurotrophic factor. Am. J. Pathol. 2012, 180, 267-274.
205. Linker, R.A.; Lee, D.H.; Demir, S.; Wiese, S.; Kruse, N.; Siglienti, I.; Gerhardt, E.; Neumann, H.; Sendtner, M.; Luhder, F., et al. Functional role of brain-derived neurotrophic factor in neuroprotective autoimmunity: Therapeutic implications in a model of multiple sclerosis. Brain 2010, 133, 2248-2263.
206. Lee, D.H.; Geyer, E.; Flach, A.C.; Jung, K.; Gold, R.; Flugel, A.; Linker, R.A.; Luhder, F. Central nervous system rather than immune cell-derived BDNF mediates axonal protective effects early in autoimmune demyelination. Acta Neuropathol. 2012, 123, 247-258.
207. Gilleece, M.H.; Dexter, T.M. Effect of Campath-1H antibody on human hematopoietic progenitors in vitro. Blood 1993, 82, 807-812.
208. Coles, A.J.; Fox, E.; Vladic, A.; Gazda, S.K.; Brinar, V.; Selmaj, K.W.; Skoromets, A.; Stolyarov, I.; Bass, A.; Sullivan, H., et al. Alemtuzumab more effective than interferon beta-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology 2012, 78, 1069-1078.
209. Coles, A.J.; Cox, A.; Le Page, E.; Jones, J.; Trip, S.A.; Deans, J.; Seaman, S.; Miller, D.H.; Hale, G.; Waldmann, H., et al. The window of therapeutic opportunity in multiple sclerosis: Evidence from monoclonal antibody therapy. J. Neurol. 2006, 253, 98-108.
210. Thompson, S.A.; Jones, J.L.; Cox, A.L.; Compston, D.A.; Coles, A.J. B-cell reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis. J. Clin. Immunol. 2010, 30, 99-105.
211. Cox, A.L.; Thompson, S.A.; Jones, J.L.; Robertson, V.H.; Hale, G.; Waldmann, H.; Compston, D.A.; Coles, A.J. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur. J. Immunol. 2005, 35, 3332-3342.
212. Coles, A.J.; Compston, D.A.; Selmaj, K.W.; Lake, S.L.; Moran, S.; Margolin, D.H.; Norris, K.; Tandon, P.K. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N. Engl. J. Med. 2008, 359, 1786-1801.
213. Jones, J.L.; Phuah, C.L.; Cox, A.L.; Thompson, S.A.; Ban, M.; Shawcross, J.; Walton, A.; Sawcer, S.J.; Compston, A.; Coles, A.J. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J. Clin. Invest. 2009, 119, 2052-2061.
214. Lutterotti, A.; Martin, R. Getting specific: Monoclonal antibodies in multiple sclerosis. Lancet Neurol. 2008, 7, 538-547.
215. Kim, H.P.; Imbert, J.; Leonard, W.J. Both integrated and differential regulation of components of the IL-2/IL-2 receptor system. Cytokine Growth Factor Rev. 2006, 17, 349-366.
216. Sen, H.N.; Levy-Clarke, G.; Faia, L.J.; Li, Z.; Yeh, S.; Barron, K.S.; Ryan, J.G.; Hammel, K.; Nussenblatt, R.B. High-dose daclizumab for the treatment of juvenile idiopathic arthritis-associated active anterior uveitis. Am. J. Ophthalmol.2009, 148, 696-703 e691.
217. Yeh, S.; Wroblewski, K.; Buggage, R.; Li, Z.; Kurup, S.K.; Sen, H.N.; Dahr, S.; Sran, P.; Reed, G.F.; Robinson, R., et al. High-dose humanized anti-IL-2 receptor alpha antibody (daclizumab) for the treatment of active, non-infectious uveitis. J. Autoimmun. 2008, 31, 91-97.
218. Buggage, R.R.; Levy-Clarke, G.; Sen, H.N.; Ursea, R.; Srivastava, S.K.; Suhler, E.B.; Altemare, C.; Velez, G.; Ragheb, J.; Chan, C.C., et al. A double-masked, randomized study to investigate the safety and efficacy of daclizumab to treat the ocular complications related to Behcet's disease. Ocul. Immunol. Inflamm. 2007, 15, 63-70.
219. Nussenblatt, R.B.; Fortin, E.; Schiffman, R.; Rizzo, L.; Smith, J.; van Veldhuisen, P.; Sran, P.; Yaffe, A.; Goldman, C.K.; Waldmann, T.A., et al. Treatment of noninfectious intermediate and posterior uveitis with the humanized anti-Tac mAb: A phase I/II clinical trial. Proc. Natl. Acad. Sci. USA 1999, 96, 7462-7466.
220. Webster, A.C.; Ruster, L.P.; McGee, R.; Matheson, S.L.; Higgins, G.Y.; Willis, N.S.; Chapman, J.R.; Craig, J.C. Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database Syst. Rev. 2010, CD003897.
221. Wynn, D.; Kaufman, M.; Montalban, X.; Vollmer, T.; Simon, J.; Elkins, J.; O'Neill, G.; Neyer, L.; Sheridan, J.; Wang, C., et al. Daclizumab in active relapsing multiple sclerosis (CHOICE study): A phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol. 2010, 9, 381-390.
222. Giovannoni, G.; Gold, R.; Selmaj, K.; Havrdova, E.; Montalban, X.; Radue, E.W.; Stefoski, D.; Robinson, R.; Riester, K.; Elkins, J., et al. A randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of daclizumab HYP monotherapy in relasping-remitting multiple sclerosis: Primary results of the SELECT trial. In Proceedings of European and Americas Committees on Treatment and Research in Multiple Sclerosis (ECTRIMS), Amsterdam, The Netherlands, 19-22 October 2011.
223. Martin, J.F.; Perry, J.S.; Jakhete, N.R.; Wang, X.; Bielekova, B. An IL-2 paradox: Blocking CD25 on T cells induces IL-2-driven activation of CD56(bright) NK cells. J. Immunol. 2010, 185, 1311-1320.
224. Hao, J.; Campagnolo, D.; Liu, R.; Piao, W.; Shi, S.; Hu, B.; Xiang, R.; Zhou, Q.; Vollmer, T.; van Kaer, L.; et al. Interleukin-2/interleukin-2 antibody therapy induces target organ natural killer cells that inhibit central nervous system inflammation. Ann. Neurol. 2011, 69, 721-734.
225. Bielekova, B.; Howard, T.; Packer, A.N.; Richert, N.; Blevins, G.; Ohayon, J.; Waldmann, T.A.; McFarland, H.F.; Martin, R. Effect of anti-CD25 antibody daclizumab in the inhibition of inflammation and stabilization of disease progression in multiple sclerosis. Arch. Neurol. 2009, 66, 483-489.
226. Fehniger, T.A.; Bluman, E.M.; Porter, M.M.; Mrozek, E.; Cooper, M.A.; VanDeusen, J.B.; Frankel, S.R.; Stock, W.; Caligiuri, M.A. Potential mechanisms of human natural killer cell expansion in vivo during low-dose IL-2 therapy. J. Clin. Invest. 2000, 106, 117-124.
227. Hao, J.; Liu, R.; Piao, W.; Zhou, Q.; Vollmer, T.L.; Campagnolo, D.I.; Xiang, R.; La Cava, A.; van Kaer, L.; Shi, F.D. Central nervous system (CNS)-resident natural killer cells suppress Th17 responses and CNS autoimmune pathology. J. Exp. Med. 2010, 207, 1907-1921.
228. Bielekova, B.; Catalfamo, M.; Reichert-Scrivner, S.; Packer, A.; Cerna, M.; Waldmann, T.A.; McFarland, H.; Henkart, P.A.; Martin, R. Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. Proc. Natl. Acad. Sci. USA 2006, 103, 5941-5946.
229. Wuest, S.C.; Edwan, J.H.; Martin, J.F.; Han, S.; Perry, J.S.; Cartagena, C.M.; Matsuura, E.; Maric, D.; Waldmann, T.A.; Bielekova, B. A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy. Nat. Med. 2011, 17, 604-609.
230. Snyder, J.T.; Shen, J.; Azmi, H.; Hou, J.; Fowler, D.H.; Ragheb, J.A. Direct inhibition of CD40L expression can contribute to the clinical efficacy of daclizumab independently of its effects on cell division and Th1/Th2 cytokine production. Blood 2007, 109, 5399-5406.
231. Barun, B.; Bar-Or, A. Treatment of multiple sclerosis with anti-CD20 antibodies. Clin. Immunol. 2012, 142, 31-37.
232. Edwards, J.C.; Cambridge, G. B-cell targeting in rheumatoid arthritis and other autoimmune diseases. Nat. Rev. Immunol. 2006, 6, 394-403.
233. Clifford, D.B.; Ances, B.; Costello, C.; Rosen-Schmidt, S.; Andersson, M.; Parks, D.; Perry, A.; Yerra, R.; Schmidt, R.; Alvarez, E., et al. Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis. Arch. Neurol. 2011, 68, 1156-1164.
234. Molloy, E.S.; Calabrese, L.H. Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: Evolving role of biologic therapies. Arthritis Rheum. 2012, 64, 3043-3051.
235. Tuccori, M.; Focosi, D.; Maggi, F.; Cosottini, M.; Meini, B.; Lena, F.; Blandizzi, C.; del Tacca, M.; Petrini, M. Progressive multifocal leukoencephalopathy: A report of three cases in HIV-negative patients with non-Hodgkin's lymphomas treated with rituximab. Ann. Hematol. 2010, 89, 519-522.
236. Hawker, K.; O'Connor, P.; Freedman, M.S.; Calabresi, P.A.; Antel, J.; Simon, J.; Hauser, S.; Waubant, E.; Vollmer, T.; Panitch, H., et al. Rituximab in patients with primary progressive multiple sclerosis: Results of a randomized double-blind placebo-controlled multicenter trial. Ann. Neurol. 2009, 66, 460-471.
237. He, D.; Zhou, H.; Han, W.; Zhang, S. Rituximab for relapsing-remitting multiple sclerosis. Cochrane Database Syst. Rev. 2011, doi:10.1002/14651858.CD009130.pub2.
238. Piccio, L.; Naismith, R.T.; Trinkaus, K.; Klein, R.S.; Parks, B.J.; Lyons, J.A.; Cross, A.H. Changes in B- and T-lymphocyte and chemokine levels with rituximab treatment in multiple sclerosis. Arch. Neurol. 2010, 67, 707-714.
239. Barr, T.A.; Shen, P.; Brown, S.; Lampropoulou, V.; Roch, T.; Lawrie, S.; Fan, B.; O'Connor, R.A.; Anderton, S.M.; Bar-Or, A. et al. B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells. J. Exp. Med. 2012, 209, 1001-1010.
240. Genovese, M.C.; Kaine, J.L.; Lowenstein, M.B.; Del Giudice, J.; Baldassare, A.; Schechtman, J.; Fudman, E.; Kohen, M.; Gujrathi, S.; Trapp, R.G., et al. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A phase I/II randomized, blinded, placebo-controlled, dose-ranging study. Arthritis Rheum. 2008, 58, 2652-2661.
241. Kappos, L.; Li, D.; Calabresi, P.A.; O'Connor, P.; Bar-Or, A.; Barkhof, F.; Yin, M.; Leppert, D.; Glanzman, R.; Tinbergen, J.; Hauser, S.L. Ocrelizumab in relapsing-remitting multiple sclerosis: A phase 2, randomised, placebo-controlled, multicentre trial. Lancet 2011, 378, 1779-1787.
242. Stohl, W.; Gomez-Reino, J.; Olech, E.; Dudler, J.; Fleischmann, R.M.; Zerbini, C.A.; Ashrafzadeh, A.; Grzeschik, S.; Bieraugel, R.; Green, J.; et al. Safety and efficacy of ocrelizumab in combination with methotrexate in MTX-naive subjects with rheumatoid arthritis: The phase III FILM trial. Ann. Rheum. Dis. 2012, doi:10.1136/annrheumdis-2011-200706.
243. Harigai, M.; Tanaka, Y.; Maisawa, S. Safety and efficacy of various dosages of ocrelizumab in Japanese patients with rheumatoid arthritis with an inadequate response to methotrexate therapy: A placebo-controlled double-blind parallel-group study. J. Rheumatol. 2012, 39, 486-495.
244. Hartung, H.P.; Kieseier, B.C. Atacicept: Targeting B cells in multiple sclerosis. Ther. Adv. Neurol. Disord. 2010, 3, 205-216.
245. Dillon, S.R.; Gross, J.A.; Ansell, S.M.; Novak, A.J. An APRIL to remember: Novel TNF ligands as therapeutic targets. Nat. Rev. Drug Discov. 2006, 5, 235-246.
246. Thangarajh, M.; Gomes, A.; Masterman, T.; Hillert, J.; Hjelmstrom, P. Expression of B-cell-activating factor of the TNF family (BAFF) and its receptors in multiple sclerosis. J. Neuroimmunol. 2004, 152, 183-190.
247. Thangarajh, M.; Masterman, T.; Hillert, J.; Moerk, S.; Jonsson, R. A proliferation-inducing ligand (APRIL) is expressed by astrocytes and is increased in multiple sclerosis. Scand. J. Immunol. 2007, 65, 92-98.
248. Thangarajh, M.; Masterman, T.; Rot, U.; Duvefelt, K.; Brynedal, B.; Karrenbauer, V.D.; Hillert, J. Increased levels of APRIL (a proliferation-inducing ligand) mRNA in multiple sclerosis. J. Neuroimmunol. 2005, 167, 210-214.
249. Mackay, F.; Woodcock, S.A.; Lawton, P.; Ambrose, C.; Baetscher, M.; Schneider, P.; Tschopp, J.; Browning, J.L. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J. Exp. Med. 1999, 190, 1697-1710.
250. Gross, J.A.; Dillon, S.R.; Mudri, S.; Johnston, J.; Littau, A.; Roque, R.; Rixon, M.; Schou, O.; Foley, K.P.; Haugen, H. et al. TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease. Impaired B cell maturation in mice lacking BLyS. Immunity 2001, 15, 289-302.
251. Carbonatto, M.; Yu, P.; Bertolino, M.; Vigna, E.; Steidler, S.; Fava, L.; Daghero, C.; Roattino, B.; Onidi, M.; Ardizzone, M. et al. Nonclinical safety, pharmacokinetics, and pharmacodynamics of atacicept. Toxicol. Sci. 2008, 105, 200-210.
252. Ginzler, E.M.; Wax, S.; Rajeswaran, A.; Copt, S.; Hillson, J.; Ramos, E.; Singer, N.G. Atacicept in combination with MMF and corticosteroids in lupus nephritis: Results of a prematurely terminated trial. Arthritis Res. Ther. 2012, 14, R33.
253. Van Vollenhoven, R.F.; Kinnman, N.; Vincent, E.; Wax, S.; Bathon, J. Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate: Results of a phase II, randomized, placebo-controlled trial. Arthritis Rheum. 2011, 63, 1782-1792.
254. Tak, P.P.; Thurlings, R.M.; Rossier, C.; Nestorov, I.; Dimic, A.; Mircetic, V.; Rischmueller, M.; Nasonov, E.; Shmidt, E.; Emery, P.; Munafo, A. Atacicept in patients with rheumatoid arthritis: Results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating, single- and repeated-dose study. Arthritis Rheum. 2008, 58, 61-72.
255. Harp, C.T.; Ireland, S.; Davis, L.S.; Remington, G.; Cassidy, B.; Cravens, P.D.; Stuve, O.; Lovett-Racke, A.E.; Eagar, T.N.; Greenberg, B.M., et al. Memory B cells from a subset of treatment-naive relapsing-remitting multiple sclerosis patients elicit CD4(+) T-cell proliferation and IFN-gamma production in response to myelin basic protein and myelin oligodendrocyte glycoprotein. Eur. J. Immunol. 2010, 40, 2942-2956.