Immunopathogenesis and immunotherapeutic approaches in multiple sclerosis

Expert Review of Neurotherapeutics

Volumn 5, Issue 3, 2005, Pages 379-390

  Lim, Ee Tuan ^a   Giovannoni, Gavin ^a  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

interferon; Corticosteroids; Glatiramer acetate; Immunology; Mitoxantrone; Therapy

Indexed keywords

AZATHIOPRINE; BETA1A INTERFERON; BIOGEN IDEC; CORTICOSTEROID; CYCLOPHOSPHAMIDE; GLATIRAMER; INTERFERON BETA SERINE; METHOTREXATE; METHYLPREDNISOLONE; MITOXANTRONE;

ANTIGEN PRESENTING CELL; APOPTOSIS; AUTOIMMUNE DISEASE; CARDIOTOXICITY; DEMYELINATION; DRUG MECHANISM; DRUG MEGADOSE; HUMAN; IMMUNOPATHOGENESIS; IMMUNOTHERAPY; INFLAMMATION; LEUKEMIA; MULTIPLE SCLEROSIS; REVIEW; STEM CELL TRANSPLANTATION; T LYMPHOCYTE;

HUMANS; IMMUNOTHERAPY; INTERFERON-BETA; MITOXANTRONE; MULTIPLE SCLEROSIS;

EID: 18944367950     PISSN: 14737175     EISSN: None     Source Type: Journal    
DOI: 10.1586/14737175.5.3.379     Document Type: Review

References (155)

1. Martin R, McFarland HF. Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis. Crit. Rev. Clin. Lab. Sci. 32, 121-182 (1995).
2. Sibley WA, Aimard G, Devic M. Clinical viral infections and multiple sclerosis. Lancet 1, 1313-1315 (1985).
3. Panitch H. Influence of infection on exacerbations of multiple sclerosis. Ann. Neurol. 36, S25-S28 (1994).
4. Svenningsson A, Hansson GK, Andersen O et al. Adhesion molecule expression on cerebrospinal fluid T-lymphocytes: evidence for common recruitment mechanisms in multiple sclerosis, aseptic meningitis, and normal controls. Ann. Neurol. 34, 155-161 (1993).
5. Albert LJ, Inman RD. Molecular mimicry and autoimmunity. N. Engl. J. Med. 341, 2068-2074 (1999).
6. Kappos L, Comi G, Panitch H et al. Induction of a non-encephalitogenic Type 2 T-helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized Phase II trial. The Altered Peptide Ligand in Relapsing MS Study Group. Nature Med. 6, 1176-1182 (2000).
7. Erratum: Nature Med. 7, 129 (2001).
8. 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. Nature Med. 6, 1167-1175 (2000).
9. Erratum: Nature Med. 6, 1412 (2000).
10. Aharoni R, Teitelbaum D, Arnon R, Sela M. Copolymer 1 acts against the immunodominant epitope 82-100 of myelin basic protein by T-cell receptor antagonism in addition to major histocompatibility complex blocking. Proc. Natl Acad. Sci. USA 96, 634-639 (1999).
11. Salomon B, Bluestone JA. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Ann. Rev. Immunol. 19, 225-252 (2001).
12. Grewal IS, Flavell RA. CD40 and CD154 in cell-mediated immunity. Ann. Rev. Immunol. 16, 111-135 (1998).
13. Matthews JB, Ramos E, Bluestone JA. Clinical trials of transplant tolerance: slow but steady progress. Am. J. Transplant. 3, 794-803 (2003).
14. Hohlfeld R, Meinl E, Weber F et al. The role of autoimmune T-lymphocytes in the pathogenesis of multiple sclerosis. Neurology 45(Suppl. 6), S33-S38 (1995).
15. Archelos JJ, Storch MK, Hartung HP. The role of B-cells and autoantibodies in multiple sclerosis. Ann. Neurol. 47, 694-706 (2000). Surveys recent advances in the field of pathogenetic multiple sclerosis (MS) autoantibodies, focusing on the potential modes of action of these antibodies and discussing the mechanisms of their long-term persistence. The therapeutic relevance of these new findings is presented.
16. + T-cells are correlated to MRI features of tissue destruction in MS. J. Neuroimmunol. 142, 141-148 (2003).
17. Reindl M, Linington C, Brehm U et al. Antibodies against the myelin oligodendrocyte glycoprotein and the myelin basic protein in multiple sclerosis and other neurological diseases: a comparative study. Brain 122, 2047-2056 (1999).
18. Lindert RB, Haase CG, Brehm U et al. Multiple sclerosis: B- and T-cell responses to the extracellular domain of the myelin oligodendrocyte glycoprotein. Brain 122, 2089-2100 (1999).
19. Berger T, Rubner P, Schautzer F et al. Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N. Engl. J. Med. 349, 139-145 (2003).
20. Van Noort JM, van Sechel AC, Bajramovic JJ et al. The small heat-shock protein αB-crystallin as candidate autoantigen in multiple sclerosis. Nature 375, 798-801 (1995).
21. Steinman L. Presenting an odd autoantigen. Nature 375, 739-740 (1995).
22. Beck J, Rondot P, Catinot L, Falcoff E, Kirchner H, Wietzerbin J. Increased production of interferon γ and tumour necrosis factor precedes clinical manifestation in multiple sclerosis: do cytokines trigger off exacerbations. Acta Neurol. Scand. 78, 318-323 (1988).
23. Rose JW, Watt HE, White AT, Carlson NG. Treatment of multiple sclerosis with an anti-interleukin-2 receptor monoclonal antibody. Ann. Neurol. 56, 864-867 (2004).
24. van Oosten BW, Barkhof F, Truyen L et al. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal antitumor necrosis factor antibody cA2. Neurology 47, 1531-1534 (1996).
25. Lenercept Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Neurology 53, 457-465 (1999).
26. Navikas V, Link H. Cytokines and the pathogenesis of multiple sclerosis. J. Neurosci. Res. 45, 322-333 (1996).
27. De Simone R, Giampaolo A, Gallo P et al. The costimulatory molecule B7 is expressed on human microglia in culture and in multiple sclerosis acute lesions. J. Neuropathol. Exp. Neurol. 50, 175-187 (1995).
28. Windhagen A, Newcombe J, Cuzner ML et al. Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86), and interleukin-12 cytokine in multiple sclerosis lesions. Neurology 46, 2069 (1996).
29. Drulovic J, Mostarica-Stojkovic M, Levic Z et al. Interleukin-12 and tumor necrosis factor-α levels in cerebrospinal fluid of multiple sclerosis patients. J. Neurol. Sci. 147, 145-150 (1997).
30. Nicoletti F, Patti F, Cocuzza C et al. Elevated serum levels of interleukin-12 in chronic progressive multiple sclerosis. J. Neuroimmunol. 70, 87-90 (1996).
31. Balashov KE, Smith DR, Khoury SJ et al. Increased interleukin-12 production in progressive multiple sclerosis: induction by activated CD4(+) T-cells via CD40 ligand. Proc. Natl Acad. Sci. USA 94, 599-603 (1997).
32. Kennedy MK, Torrance DS, Picha KS, Mohler KM. Analysis of cytokine mRNA expression in the central nervous system of mice with experimental autoimmune encephalomyelitis reveals that IL-10 mRNA expression correlates with recovery. J. Immunol. 149, 2496-2505 (1992).
33. Khoury SJ, Hancock WW, Weiner HL. Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor beta, interleukin-4, and prostaglandin E expression in the brain. J. Exp. Med. 176, 1355-1364 (1992).
34. Rieckmann P, Albrecht M, Kitze B et al. Tumor necrosis factor-α messenger RNA expression in patients with multiple sclerosis is associated with disease activity. Ann. Neurol. 37, 82-88 (1995).
35. Link J, Söderström M, Olsson T, Höjeberg B, Ljungdahl Å, Link H. Increased transforming growth factor-α, interleukin-4, and interferon-α in multiple sclerosis. Ann. Neurol. 36, 379-386 (1994).
36. Söderström M, Hillert J, Link J, Navikas V, Fredrikson S, Link H. Expression of IFN-β and TGF-α in multiple sclerosis in relation to HLA-Dw2 phenotype and stage of disease. Multiple Sclerosis 1, 173-180 (1995).
37. Furlan R, Poliani PL, Marconi PC et al. Central nervous system gene therapy with interleukin-4 inhibits progression of ongoing relapsing-remitting autoimmune encephalomyelitis in Biozzi AB/H mice. Gene Ther. 8, 13-19 (2001).
38. Poliani PL, Brok H, Furlan R et al. Delivery to the central nervous system of a nonreplicative herpes simplex Type 1 vector engineered with the interleukin-4 gene protects rhesus monkeys from hyperacute autoimmune encephalomyelitis. Hum. Gene Ther. 12, 905-920 (2001).
39. Nabel GJ. Genetic, cellular and immune approaches to disease therapy: past and future. Nature Med. 10, 135-141 (2004).
40. Miyagishi R, Kikuchi S, Fukazawa T, Tashiro K. Macrophage inflammatory protein-1α in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological diseases. J. Neurol. Sci. 129, 223-227 (1995).
41. McManus C, Berman JW, Brett FM et al. MCP-1, MCP-2 and MCP-3 expression in multiple sclerosis lesions: an immunohistochemical and in situ hybridization study. J. Neuroimmunol. 86, 20-29 (1998).
42. Sorensen TL, Tani M, Jensen J et al. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J. Clin. Invest. 103, 807-815 (1999).
43. Van Der Voorn P, Tekstra J, Beelen RH et al. Expression of MCP-1 by reactive astrocytes in demyelinating multiple sclerosis lesions. Am. J. Pathol. 154, 45-51 (1999).
44. Cannella B, Raine CS. The adhesion molecule and cytokine profile of multiple sclerosis lesions. Ann. Neurol. 37, 424-435 (1995).
45. Archelos JJ, Hartung HP. The role of adhesion molecules in multiple sclerosis: biology, pathogenesis and therapeutic implications. Mol. Med. Today 3, 310-321 (1997).
46. Gearing JH, Newman W. Circulating adhesion molecules in disease. Immunol. Today 14, 506-507 (1993).
47. Tubridy N, Behan PO, Capildeo R et al. The effect of anti-α4 integrin antibody on brain lesion activity in MS. The UK Antegren Study Group. Neurology 53, 466-472 (1999).
48. Miller DH, Khan OA, Sheremata WA et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 348, 15-23 (2003).
49. US Food and Drug Administration. First monoclonal antibody treatment for multiple sclerosis approved. FDA News P04-P107 (2004).
50. Rosenberg GA, Dencoff JE, Correa N et al. Effect of steroids on CSF matrix metalloproteinases in multiple sclerosis: relation to blood-brain barrier injury. Neurology 46, 1262-1632 (1996).
51. Lee MA, Palace J, Stabler G, Ford J, Gearing A, Miller K. Serum gelatinase B, TIMP-1 and TIMP-2 levels in multiple sclerosis. A longitudinal clinical and MRI study. Brain 122, 191-197 (1999).
52. Waubant E, Goodkin DE, Gee L et al. Serum MMP-9 and TIMP-1 levels are related to MRI activity in relapsing multiple sclerosis. Neurology 53, 1397-1401 (1999).
53. Popovic N, Schubart A, Goetz BD, Zhang SC, Linington C, Duncan ID. Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann. Neurol. 51, 215-223 (2002).
54. Youssef S, Stuve O, Patarroyo JC et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420, 78-84 (2002).
55. Greenwood J, Walters CE, Pryce G et al. Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. Fed. Am. Soc. Exp. Biol. J. 17, 905-907 (2003).
56. Vollmer T, Key L, Durkalski V et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 363, 1607-1608 (2004).
57. Feinstein DL, Galea E, Gavrilyuk V et al. Peroxisome proliferator- activated receptor-gamma agonists prevent experimental autoimmune encephalomyelitis. Ann. Neurol. 51, 694-702 (2002).
58. Linington C, Bradl M, Lassmann H, Brunner C, Vass K. Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein. Am. J. Pathol. 130, 443-454 (1988).
59. Genain CP, Cannella B, Hauser SL, Raine CS. Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nature Med. 5, 170-175 (1999).
60. Raine CS, Cannella B, Hauser SL, Genain CP. Demyelination in primate autoimmune encephalomyelitis and acute multiple sclerosis lesions: a case for antigen-specific antibody mediation. Ann. Neurol. 46, 144-160 (1999).
61. Cross AH, Lyons JA, Naismith RT, Lauber JM. Preliminary results of B-cell depletion in relapsing MS. J. Neuroimmunol. 154, 95 (2004).
62. 2+.
63. Brand-Schieber E, Werner P. Calcium channel blockers ameliorate disease in a mouse model of multiple sclerosis. Exp. Neurol. 189, 5-9 (2004).
64. Kapoor R, Davies M, Blaker PA, Hall SM, Smith KJ. Blockers of sodium and calcium entry protect axons from nitric oxide-mediated degeneration. Ann. Neurol. 53, 174-180 (2003).
65. Lo AC, Saab CY, Black JA, Waxman SG. Phenytoin protects spinal cord axons and preserves axonal conduction and neurological function in a model of neuroinflammation in vivo. J. Neurophysiol. 90, 3566-3571 (2003).
66. Groom AJ, Smith T, Turski L. Multiple sclerosis and glutamate. Ann. NY Acad. Sci. 993, 229-275 (2003).
67. Howlert AC, Barth F, Bonner TI et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol. Rev. 54, 161-202 (2002).
68. Pryce G, Ahmed Z, Hankey DJ et al. Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain 126, 2191-2202 (2003).
69. van Oosten BW, Killestein J, Mathus-Vliegen EM, Polman CH. Multiple sclerosis following treatment with a cannabinoid receptor-1 antagonist. Multiple Sclerosis 10, 330-331 (2004).
70. Zajicek J, Fox P, Sanders H et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 362, 1517-1526 (2003).
71. Zajicek J, Fox P, Sanders H et al. The Cannabinoids in MS study-final results from 12 months follow-up. Multiple Sclerosis 10(Suppl. 2), S115 (2004).
72. Gold R, Hartung HP, Lassmann H. T-cell apoptosis in autoimmune diseases: termination of inflammation in the nervous system and other sites with specialized immune-defense mechanisms. Trends Neurosci. 20, 399-404 (1997).
73. Ford AL, Foulcher E, Lemckert FA, Sedgwick JD. Microglia induce CD4 T-lymphocyte final effector function and death. J. Exp. Med. 184, 1737-1745 (1996).
74. Bauer J, Wekerle H, Lassmann H. Apoptosis in brain-specific autoimmune disease. Curr. Opin. Immunol. 7, 839-843 (1995).
75. Dowling P, Shang GF, Raval S et al. Involvement of the CD95 (apo-1/fas) receptor/ligand system in multiple-sclerosis brain. J. Exp. Med. 184, 1513-1518 (1996).
76. Ichikawa H, Ota K, Iwata M. Increased Fas antigen on T-cells in multiple sclerosis. J. Neuroimmunol. 71, 125-129 (1996).
77. Racke MK, Critchfield JM, Quigley L et al. Intravenous antigen administration as a therapy for autoimmune demyelinating disease. Ann. Neurol. 39, 46-56 (1996).
78. Coles AJ, Wing M, Smith S et al. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 354, 1691-1695 (1999).
79. Coles AJ, Wing MG, Molyneux P et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann. Neurol. 46, 296-304 (1999).
80. Zhang J, Medaer R, Stinissen P, Hafler D, Raus J. MHC-restricted depletion of human myelin basic protein-reactive T-cells by T-cell vaccination. Science 261, 1451-1454 (1993).
81. Medaer R, Stinissen P, Truyen L, Raus J, Zhang J. Depletion of myelin-basic-protein autoreactive T-cells by T-cell vaccination: pilot trial in multiple sclerosis. Lancet 346, 807-808 (1995).
82. Kraus J, Ling AK, Hamm S, Voigt K, Oschmann P, Engelhardt B. Interferon-β stabilizes barrier characteristics of brain endothelial cells in vitro. Ann. Neurol. 56, 192-205 (2004).
83. Jacobs LD, Cookfair DL, Rudick RA et al. Intramuscular interferon β-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG) Ann. Neurol. 39, 285-294 (1996).
84. Erratum: Ann. Neurol. 40, 480 (1996).
85. 1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet 352, 1498-1504 (1998).
86. Erratum: Lancet 353, 678 (1999).
87. Anon. Interferon β-1b is effective in relapsing remitting multiple sclerosis. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFN-β Multiple Sclerosis Study Group. Neurology 43, 655-661 (1993).
88. Neuhaus O, Farina C, Wekerle H, Hohlfeld R. Mechanisms of action of glatiramer acetate in multiple sclerosis. Neurology 56, 702-708 (2001).
89. Arnon R, Aharoni R. Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications. Proc. Natl. Acad. Sci. USA 101(Suppl. 2), 14593-14598 (2004).
90. Johnson KP, Brooks BR, Cohen JA et al. Co-polymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a Phase III multicenter, double-blind placebo-controlled trial. The co-polymer 1 Multiple Sclerosis Study Group. Neurology 45, 1268-1276 (1995).
91. Edan G, Miller D, Clanet M et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria. J. Neurol. Neurosurg. Psychiat. 62, 112-118 (1997).
92. Millefiorini E, Gasperini C, Pozzilli C et al. Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome. J. Neurol. 244, 153-159 (1997).
93. Hartung HP, Gonsette R, Konig N et al. Mitoxantrone in Multiple Sclerosis Study Group (MIMS). Lancet 360, 2018-2025 (2002).
94. Mauch E, Kornhuber HH, Krapf H, Fetzer U, Laufen H. Treatment of multiple sclerosis with mitoxantrone. Eur. Arch. Psychiat. Clin. Neurosci. 242, 96-102 (1992).
95. Ridge SC, Sloboda AE, McReynolds RA, Levine S, Oronsky AL, Kerwar SS. Suppression of experimental allergic encephalomyelitis by mitoxantrone. Clin. Immunol. Immunopathol. 35, 35-42 (1985).
96. Bellosillo B, Colomer D, Pons G, Gil J. Mitoxantrone, a topoisomerase II inhibitor, induces apoptosis of B-chronic lymphocytic leukaemia cells. Br. J. Haematol. 100, 142-146 (1998).
97. Neuhaus O, Wiendl H, Kieseier BC et al. Multiple scelrosis: immunological effects of mitoxantrone in vitro reveal antigen-presenting cells as major targets. Eur. J. Neurol. 9(Suppl. 2), 130 (2002).
98. Khoury SJ, Bharanidharan P, Bourcier K, Cook SL, Stazzaone L, Weiner HL. Immunologic effects of mitoxantrone therapy in patients with multiple sclerosis. Neurology 58(Suppl. 3), 245-246 (2002).
99. Levine S, Saltzman A. Regional suppression therapy after onset and prevention of relapses in experimental allergic encephalomyelitis by mitoxantrone. J. Neuroimmunol. 13, 175-181 (1986).
100. Lublin FD, Lavasa M, Viti C, Knobler RL. Suppression of acute and relapsing experimental allergic encephalomyelitis with mitoxantrone. Clin. Immunol. Immunopathol. 45, 122-128 (1987).
101. Weilbach FX, Chan A, Toyka KV, Gold R. Mitoxantrone-induced immunological changes in MS patients - ex vivo studies on proliferation and cell death of peripheral blood leucocytes. J. Neurol. 249(Suppl. 1), 1-113 (2002).
102. Weiner HL. Multiple sclerosis is an inflammatory T-cell-mediated autoimmune disease. Arch. Neurol. 61, 1613-1615 (2004). Succinct review of immunopathogenesis, currently available immunomodulatory therapies, the correlation of clinical features and biomarkers and the relationship of MS to experimental allergic encephalomyelitis.
103. Lamers KJ, Uitdehaag BM, Hommes OR, Doesburg W, Wevers RA, von Geel WJ. The short-term effect of an immunosuppressive treatment on CSF myelin basic protein in chronic progressive multiple sclerosis. J. Neurol. Neurosurg. Psychiat. 51, 1334-1337 (1988).
104. Moody DJ, Kagan J, Liao D, Ellison GW, Myers LW. Administration of monthly-pulse cyclophosphamide in multiple sclerosis patients. Effects of long-term treatment on immunologic parameters. J. Neuroimmunol. 14, 161-173 (1987).
105. Comabella M, Balashov K, Issazadeh S, Smith D, Weiner HL, Khoury SJ. Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy. J. Clin. Invest. 102, 671-678 (1998).
106. The Canadian Co-operative Multiple Sclerosis Study Group. The Canadian cooperative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. Lancet 337, 441-446 (1991).
107. Likosky WH, Fireman B, Elmore R et al. Intense immunosuppression in chronic progressive multiple sclerosis: the Kaiser study. J. Neurol. Neurosurg. Psychiat. 54, 1055-1060 (1991).
108. Patti F, Reggio E, Palermo F et al. Stabilization of rapidly worsening multiple sclerosis for 36 months in patients treated with Interferon β plus cyclophosphamide followed by interferon β. J. Neurol. 251, 1502-1506 (2004).
109. Patti F, Amato MP, Filippi M, Gallo P, Trojano M, Comi GC. A double-blind, placebo-controlled, Phase II, add-on study of cyclophosphamide (CTX) for 24 months in patients affected by multiple sclerosis on a background therapy with interferon-β study denomination: CYCLIN. J. Neurol. Sci. 223, 69-71 (2004).
110. Syed A, Rizvi MD, Khurram B. Other therapy options and future strategies for treating patients with multiple sclerosis. Neurology 63, S47-S54 (2004).
111. Goodkin DE, Rudick RA, VanderBrug Medendorp S et al. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann. Neurol. 37, 30-40 (1995).
112. 1a and oral methotrexate in MS. Neurology 58, 314-317 (2002).
113. Yudkin PL, Ellison GW, Ghezzi A et al. Overview of azathioprine treatment in multiple sclerosis. Lancet 338, 1051-1055 (1991).
114. Palace J, Rothwell P. New treatments and azathioprine in multiple sclerosis. Lancet 350, 261 (1997).
115. Fernandez O, Fernandez V, De Ramon E. Azathioprine and methotrexate in multiple sclerosis. J. Neurol Sci. 223, 29-34 (2004).
116. 1b and azathioprine combination therapy in multiple sclerosis. Neurology 62(Suppl. 5), A491 (2004).
117. Mach F. Toward a role for statins in immunomodulation. Mol. Interv. 24, 478-480 (2002).
118. Polman CH, Uitdehaag BM. New and emerging treatment options for multiple sclerosis. Lancet Neurol. 2, 563-536 (2003). Comprehensive review discussing a number of emerging MS therapies including natalizumab, alemtuzumab, statins and estrogens.
119. Vollmer T, Key L, Durkalski V et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 15(363), 1607-1608 (2004).
120. + selected autologous peripheral blood stem cell transplantation for multiple sclerosis: report of toxicity and treatment results at one year of follow-up in 15 patients. Haematologica 88, 306-314 (2003).
121. Burt RK, Traynor AE, Pope R et al. Treatment of autoimmune disease by intense immunosuppressive conditioning and autologous hematopoietic stem cell transplantation. Blood 92, 3505-3514 (1998).
122. Nash RA, Bowen JD, McSweeney PA et al. High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis. Blood 102, 2364-2372 (2003).
123. Openshaw H, Lund BT, Kashyap A et al. Peripheral blood stem cell transplantation in multiple sclerosis with busulfan and cyclophosphamide conditioning: report of toxicity and immunological monitoring. Biol. Blood Marrow Transplant. 6, 563-575 (2000).
124. Saiz A, Carreras E, Berenguer J et al. MRI and CSF oligoclonal bands after autologous hematopoietic stem cell transplantation in MS. Neurology 56, 1084-1089 (2001).
125. Milligan NM, Newcombe R, Compston DA. A double-blind controlled trial of high dose methylprednisolone in patients with multiple sclerosis: 1 clinical effects. J. Neurol. Neurosurg. Psychiat. 50, 511-516 (1987).
126. Trotter JL, Garvey WF. Prolonged effects of large-dose methylprednisolone infusion in multiple sclerosis. Neurology 30, 702-708 (1980).
127. Durelli L, Cocito D, Riccio A et al. High-dose intravenous methylprednisolone in the treatment of multiple sclerosis: clinical-immunologic correlations. Neurology 36, 238-243 (1986).
128. Wajgt A, Gorny MK, Jenek R. The influence of high-dose prednisone medication on autoantibody specific activity and on circulating immune complex level in cerebrospinal fluid of multiple sclerosis patients. Acta Neurol. Scand. 68, 378-385 (1983).
129. Warren KG, Catz I, Jeffrey VM, Carroll DJ. Effect of methylprednisolone on CSF IgG parameters, myelin basic protein and antimyelin basic protein in multiple sclerosis exacerbations. Can. J. Neurol. Sci. 13, 25-30 (1986).
130. Compston A, Coles A. Multiple sclerosis. Lancet 359, 1221-1231 (2002).
131. Erratum: Lancet 360, 648 (2002).
132. Gallo P, Chiusole M, Sanzari M et al. Effect of high-dose steroid therapy on T-cell subpopulations. A longitudinal study in MS patients. Acta Neurol. Scand. 89, 95-101 (1994).
133. Liu J, Marino MW, Wong G et al. TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination. Nature Med. 4, 78-83 (1998).
134. Dal Canto RA, Shaw MK, Nolan GP, Steinman L, Fathman CG. Local delivery of TNF by retrovirus-transduced T-lymphocytes exacerbates experimental autoimmune encephalomyelitis. Clin. Immunol. 90, 10-14 (1999).
135. Fenyk-Melody JE, Garrison AE, Brunnert SR et al. Experimental autoimmune encephalomyelitis is exacerbated in mice lacking the NOS2 gene. J. Immunol. 160, 2940-2946 (1998).
136. Cuzner ML, Loughlin AJ, Mosely K, Woodroofe MN. The role of microglia in the processes of inflammatory demyelination and remyelination. Neuropathol. Appl. Neurobiol. 20, 200-201 (1994).
137. Kerschensteiner M, Gallmeier E, Behrens L et al. Activated human T-cells, B-cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J. Exp. Med. 189, 865-870 (1999).
138. Ye P, D'Ercole AJ. Insulin-like growth Factor I protects oligodendrocytes from tumor necrosis factor-alpha-induced injury. Endocrinology 140, 3063-3072 (1999).
139. Wilczak N, De Keyser J. Insulin-like growth factor-I receptors in normal appearing white matter and chronic plaques in multiple sclerosis. Brain Res. 772, 243-246 (1997).
140. Gveric D, Cuzner ML, Newcombe J. Insulin-like growth factors and binding proteins in multiple sclerosis plaques. Neuropathol. Appl. Neurobiol. 25, 215-225 (1999).
141. Cannella B, Pitt D, Marchionni M, Raine CS. Neuregulin and erbB receptor expression in normal and diseased human white matter. J. Neuroimmunol. 100, 233-242 (1999).
142. Robertson NP, Clayton D, Fraser M, Deans J, Compston DA. Clinical concordance in sibling pairs with multiple sclerosis. Neurology 47, 347-352 (1996).
143. Jeffery ND, Blakemore WF. Locomotor deficits induced by experimental spinal cord demyelination are abolished by spontaneous remyelination. Brain 120(Pt 1), 27-37 (1997).
144. Brassat D, Azais-Vuillemin C, Yaouanq J et al. Familial factors influence disability in MS multiplex families. French Multiple Sclerosis Genetics Group. Neurology 52, 1632-1636 (1999).
145. Mann CL, Davies MB, Boggild MD et al. Glutathione S-transferase polymorphisms in MS: their relationship to disability. Neurology 54, 552-557 (2000).
146. Sciacca FL, Ferri C, Vandenbroeck K et al. Relevance of interleukin-1 receptor antagonist intron 2 polymorphism in Italian MS patients. Neurology 52, 1896-1898 (1999).
147. Evagelou N, Jackson M, Beeson D, Palace J. Association of the APOE epsilon 4 allele with disease activity in multiple sclerosis. J. Neurol. Neurosurg. Psychiat. 67, 203-205 (1999).
148. Chapman J, Sylantiev C, Nisipeanu P, Korczyn AD. Preliminary observations on APOE epsilon 4 allele and progression of disability in multiple sclerosis. Arch. Neurol. 56, 1484-1487 (1999).
149. Weatherby SJ, Mann CL, Davies MB et al. Polymorphisms of apolipoprotein E; outcome and susceptibility in multiple sclerosis. Multiple Sclerosis 6, 32-36 (2000).
150. Fazekas F, Strasser-Fuchs S, Schmidt H. Apolipoprotein E genotype related differences in brain lesions of multiple sclerosis. J. Neurol. Neurosurg. Psychiat. 69(1), 25-28 (2000).
151. Smith ME, Stone LA, Albert PS et al. Clinical worsening in multiple sclerosis is associated with increased frequency and area of gadopentetate dimeglumine-enhancing magnetic resonance imaging lesions. Ann. Neurol. 33, 480-489 (1993).
152. Masterman T, Ligers A, Zhang Z et al. CTLA4 dimorphisms and the multiple sclerosis phenotype. J. Neuroimmunol. 131, 208-212 (2002).
153. Maurer M, Ponath A, Kruse N, Rieckmann P. CTLA4 exon 1 dimorphism is associated with primary progressive multiple sclerosis. J. Neuroimmunol. 131, 213-215 (2002).
154. Colhoun HM, McKeigue PM, Smith GD. Problems of reporting genetic associations with complex outcomes. Lancet 361, 865-872 (2003).
155. Smith DR, Weinstock-Guttmann B, Cohen JA et al. Design of randomized, blinded, MRI trial of pulse cyclophosphamide rescue therapy in β-IFN resistant active MS. American Academy of Neurology 53rd Annual Meeting. PA, USA (2001).