Summary
This review examines the mode of action, safety profile and clinical efficacy of some of the most promising new therapeutic strategies for multiple sclerosis. Autologous hematopoietic stem cell transplantation can regenerate a new and tolerant immune system and is a potentially effective rescue therapy in a subset of patients with aggressive forms of MS refractory to approved immunomodulatory and immunosuppressive agents. High-dose cyclophosphamide without stem cell support is suggested to induce prolonged remissions through similar immunological mechanisms with less toxicity. Fingolimod (FTY720) is a novel oral immunomodulating agent that acts through preventing lymphocyte recirculation from lymphoid organs. Monoclonal antibody therapy has provided scientists and clinicians the opportunity to rationally direct the therapeutic intervention against specific molecules. Targeting molecules of the immune system such as CD52 (alemtuzumab), CD25 (daclizumab), VLA-4 (natalizumab) and CD20 (rituximab) have resulted in potent immunomodulatory effects through sometimes unpredicted mechanisms. The potential of immunoglobulins to induce remyelination in the CNS is being investigated in an attempt to develop therapies promoting tissue repair and functional recovery. The evidence supporting the potential of these emerging immunotherapies suggests that strong progress is being made in the development of effective cures for multiple sclerosis.
References
- 1.
Mezey E, Key S, Vogelsang G, Szalayova I, Lange GD, Crain B. Transplanted bone marrow generates new neurons in human brains. Proc Natl Acad Sci U S A 2003;100:1364–1369.
- 2.
Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 2000;290:1779–1782.
- 3.
Weimann JM, Charlton CA, Brazelton TR, Hackman RC, Blau HM. Contribution of transplanted bone marrow cells to Purkinje neurons in human adult brains. Proc Natl Acad Sci U S A 2003; 100:2088–2093.
- 4.
Castro RF, Jackson KA, Goodell MA, Robertson CS, Liu H, Shine HD. Failure of bone marrow cells to transdifferentiate into neural cells in vivo. Science 2002;297:1299.
- 5.
Wagers AJ, Sherwood RI, Christensen JL, Weissman IL. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002;297:2256–2259.
- 6.
Karussis DM, Vourka-Karussis U, Lehmann D, et al. Prevention and reversal of adoptively transferred, chronic relapsing experimental autoimmune encephalomyelitis with a single high dose cytoreductive treatment followed by syngeneic bone marrow transplantation. J Clin Invest 1993;92:765–772.
- 7.
Burt RK, Padilla J, Begolka WS, Canto MC, Miller SD. Effect of disease stage on clinical outcome after syngeneic bone marrow transplantation for relapsing experimental autoimmune encephalomyelitis. Blood 1998;91: 2609–2616.
- 8.
Griffith LM, Pavletic SZ, Tyndall A, et al. Feasibility of allogeneic hematopoietic stem cell transplantation for autoimmune disease: position statement from a National Institute of Allergy and Infectious Diseases and National Cancer Institute-Sponsored International Workshop, Bethesda, MD, March 12 and 13, 2005. Biol Blood Marrow Transplant 2005;11:862–870.
- 9.
McAllister LD, Beatty PG, Rose J. Allogeneic bone marrow transplant for chronic myelogenous leukemia in a patient with multiple sclerosis. Bone Marrow Transplant 1997;19:395–397.
- 10.
Muraro PA, Douek DC, Packer A, et al. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. J Exp Med 2005; 201:805–816.
- 11.
Muraro PA, Douek DC. Renewing the T cell repertoire to arrest autoimmune aggression. Trends Immunol 2006;27:61–67.
- 12.
de Kleer I, Vastert B, Klein M, et al. Autologous stem cell transplantation for autoimmunity induces immunologie self-tolerance by reprogramming autoreactive T-cells and restoring the CD4+CD25+ immune regulatory network. Blood 2005;1:1.
- 13.
McSweeney P, Pasquini MC, Krukeia M, et al. Hematopoietic stem cell transplantation (HCT) for autoimmune diseases (AI): review of transplants performed in North and South America and reported to the Center for International Blood and Marrow Transplantation (CIBMTR). Biol Blood Marrow Transplant 2007; 13:34.
- 14.
Saccardi R, Kozak T, Bocelli-Tyndall C, et al. Autologous stem cell transplantation for progressive multiple sclerosis: update of the European group for blood and marrow transplantation auto immune diseases working party database. Mult Scler 2006;12:1–10.
- 15.
Fassas A, Anagnostopoulos A, Kazis A, et al. Autologous stem cell transplantation in progressive multiple sclerosis—an interim analysis of efficacy. J Clin Immunol 2000;20:24–30.
- 16.
Nash RA, Bowen JD, McSweeney PA, et al. High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis. Blood 2003;102:2364–2372.
- 17.
Burt RK, Cohen BA, Russell E, et al. Hematopoietic stem cell transplantation for progressive multiple sclerosis: failure of a total body irradiation-based conditioning regimen to prevent disease progression in patients with high disability scores. Blood 2003; 102:2373–2378.
- 18.
Saiz A, Blanco Y, Carreras E, et al. Clinical and MRI outcome after autologous hematopoietic stem cell transplantation in MS. Neurology 2004;62:282–284.
- 19.
Saccardi R, Mancardi GL, Solari A, et al. Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life. Blood 2005;105:2601–2607.
- 20.
Ni XS, Ouyang J, Zhu WH, Wang C, Chen B. Autologous hematopoietic stem cell transplantation for progressive multiple sclerosis: report of efficacy and safety at three yr of follow up in 21 patients. Clin Transplant 2006;20:485–489.
- 21.
Samijn JP, te Boekhorst PA, Mondria T, et al. Intense T cell depletion followed by autologous bone marrow transplantation for severe multiple sclerosis. J Neurol Neurosurg Psychiatry 2006;77:46–50.
- 22.
Mancardi GL, Saccardi R, Filippi M, et al. Autologous hematopoietic stem cell transplantation suppresses Gd-enhanced MRI activity in MS. Neurology 2001;57:62–68.
- 23.
Saiz A, Carreras E, Berenguer J, et al. MRI and CSF oligoclonal bands after autologous hematopoietic stem cell transplantation in MS. Neurology 2001;56:1084–1089.
- 24.
Inglese M, Mancardi GL, Pagani E, et al. Brain tissue loss occurs after suppression of enhancement in patients with multiple sclerosis treated with autologous haematopoietic stem cell transplantation. J Neurol Neurosurg Psychiatry 2004;75: 643–644.
- 25.
Chen JT, Collins DL, Atkins HL, Freedman MS, Galal A, Arnold DL. Brain atrophy after immunoablation and stem cell transplantation in multiple sclerosis. Neurology 2006;66:1935–1937.
- 26.
Roccatagliata L, Rocca MA, Valsasina P, et al. The long-term effect of AHSCT on MRI measures of MS evolution: a five-year follow-up study. Mult Scler 2007 Apr 27; [Epub ahead of print].
- 27.
Coles AJ, Cox A, Le Page E, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol 2005;27:27.
- 28.
Metz I, Lucchinetti CF, Openshaw H, et al. Multiple sclerosis pathology after autologous stem cell transplantation: ongoing de-myelination and neurodegeneration despite suppressed inflammation. Mult Scler 2006;12:S9.
- 29.
Cassiani-Ingoni R, Muraro PA, Magnus T, et al. Disease progression after bone marrow transplantation in a model of multiple sclerosis is associated with chronic microglial and glial progenitor response. J Neurol Exp Neuropathol 2007;66: 637–649.
- 30.
Comi G, Kappos L, Clanet M, et al. Guidelines for autologous blood and marrow stem cell transplantation in multiple sclerosis: a consensus report written on behalf of the European Group for Blood and Marrow Transplantation and the European Charcot Foundation. BMT-MS Study Group. J Neurol 2000;247:376–382.
- 31.
Bergamaschi R. Prognosis of multiple sclerosis: clinical factors predicting the late evolution for an early treatment decision. Expert Rev Neurother 2006;6:357–364.
- 32.
Bielekova B, Kadom N, Fisher E, et al. MRI as a marker for disease heterogeneity in multiple sclerosis. Neurology 2005;65:1071–1076.
- 33.
Portaccio E, Amato MP, Siracusa G, et al. Autologous hematopoietic stem cell transplantation for very active relapsing-remitting multiple sclerosis: report of two cases. Mult Scler 2007;13:676–678.
- 34.
Brodsky RA, Petri M, Smith BD, et al. Immunoablative high-dose cyclophosphamide without stem-cell rescue for refractory, severe autoimmune disease. Ann Intern Med 1998;129:1031–1035.
- 35.
Weiner HL, Cohen JA. Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects. Mult Scler 2002;8:142–154.
- 36.
Kami A, Balashov K, Hancock WW, et al. Cyclophosphamide modulates CD4+ T cells into a T helper type 2 phenotype and reverses increased IFN-gamma production of CD8+ T cells in secondary progressive multiple sclerosis. J Neuroimmunol 2004; 146:189–198.
- 37.
Gladstone DE, Zamkoff KW, Krupp L, et al. High-dose cyclophosphamide for moderate to severe refractory multiple sclerosis. Arch Neurol 2006;63:1388–1393.
- 38.
Fujita T, Inoue K, Yamamoto S, et al. Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite. J Antibiot (Tokyo) 1994;47:208–215.
- 39.
Brinkmann V, Davis MD, Heise CE, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 2002;277:21453–21457.
- 40.
Matloubian M, Lo CG, Cinamon G, et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 2004;427:355–360.
- 41.
Maeda Y, Matsuyuki H, Shimano K, Kataoka H, Sugahara K, Chiba K. Migration of CD4 T cells and dendritic cells toward sphingosine 1-phosphate (S1P) is mediated by different receptor subtypes: S1P regulates the functions of murine mature dendritic cells via S1P receptor type 3. J Immunol 2007; 178:3437–3446.
- 42.
Idzko M, Panther E, Corinti S, et al. Sphingosine 1-phosphate induces chemotaxis of immature and modulates cytokine-release in mature human dendritic cells for emergence of Th2 immune responses. Faseb J 2002;16:625–627.
- 43.
Muller H, Hofer S, Kaneider N, et al. The immunomodulator FTY720 interferes with effector functions of human monocyte-derived dendritic cells. Eur J Immunol 2005;35:533–545.
- 44.
Idzko M, Hammad H, van Nimwegen M, et al. Local application of FTY720 to the lung abrogates experimental asthma by altering dendritic cell function. J Clin Invest 2006;116:2935–2944.
- 45.
Chiba K, Matsuyuki H, Maeda Y, Sugahara K. Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus. Cell Mol Immunol 2006; 3:11–19.
- 46.
Fujino M, Funeshima N, Kitazawa Y, et al. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J Pharmacol Exp Ther 2003;305:70–77.
- 47.
Kataoka H, Sugahara K, Shimano K, et al. FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. Cell Mol Immunol 2005;2:439–448.
- 48.
Webb M, Tham CS, Lin FF, et al. Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J Neuroimmunol 2004; 153:108–121.
- 49.
Payne SG, Oskeritzian CA, Griffiths R, et al. The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors. Blood 2007;109:1077–1085.
- 50.
Daniel C, Sartory N, Zahn N, Geisslinger G, Radeke HH, Stein JM. FTY720 ameliorates Th1-mediated colitis in mice by directly affecting the functional activity of CD4+CD25+ regulatory T cells. J Immunol 2007;178:2458–2468.
- 51.
Liao JJ, Huang MC, Goetzl EJ. Cutting edge: alternative signaling of TH17 cell development by sphingosine 1-phosphate. J Immunol 2007; 178:5425–5428.
- 52.
Osinde M, Mullershausen F, Dev KK. Phosphorylated FTY720 stimulates ERK phosphorylation in astrocytes via S1P receptors. Neuropharmacology 2007;52:1210–1218.
- 53.
Mullershausen F, Craveiro LM, Shin Y, et al. Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors. J Neurochem 2007.
- 54.
Novgorodov AS, El-Alwani M, Bielawski J, Obeid LM, Gudz TI. Activation of sphingosine-1-phosphate receptor S1P5 inhibits oligodendrocyte progenitor migration. Faseb J 2007;21:1503–1514.
- 55.
Budde K, Schutz M, Glander P, et al. FTY720 (fingolimod) in renal transplantation. Clin Transplant 2006;20(suppl 17): 17–24.
- 56.
Tedesco-Silva H, Pescovitz MD, Cibrik D, et al. Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation. Transplantation 2006;82:1689–1697.
- 57.
Salvadori M, Budde K, Charpentier B, et al. FTY720 versus MMF with cyclosporine in de novo renal transplantation: a 1-year, randomized controlled trial in Europe and Australasia. Am J Transplant 2006;6:2912–2921.
- 58.
Kappos L, Antel J, Comi G, et al. Oral fmgolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 2006;355:1124–1140.
- 59.
Hofmann M, Brinkmann V, Zerwes HG. FTY720 preferentially depletes naive T cells from peripheral and lymphoid organs. Int Immunopharmacol 2006;6:1902–1910.
- 60.
Kimura A, Ohmori T, Ohkawa R, et al. Essential roles of sphingosine 1-phosphate/S1P1 receptor axis in the migration of neural stem cells toward a site of spinal cord injury. Stem Cells 2007; 25:115–124.
- 61.
Pavlou AK, Belsey MJ. The therapeutic antibodies market to 2008. Eur J Pharm Biopharm 2005;59: 389–396.
- 62.
Presta LG. Engineering of therapeutic antibodies to minimize immunogenicity and optimize function. Adv Drug Deliv Rev 2006;58:640–656.
- 63.
Hohlfeld R, Wekerle H. Drug Insight: using monoclonal antibodies to treat multiple sclerosis. Nat Clin Pract Neurol 2005; 1:34–44.
- 64.
Coles AJ, Cox A, Le Page E, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol 2006;253:98–108.
- 65.
Moreau T, Thorpe J, Miller D, et al. Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis. Lancet 1994;344:298–301.
- 66.
Coles AJ, Wing MG, Molyneux P, et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 1999;46:296–304.
- 67.
Waldmann T, Tagaya Y, Bamford R. Interleukin-2, interleukin-15, and their receptors. Int Rev Immunol 1998;16:205–226.
- 68.
Waldmann TA. The IL-2/IL-15 receptor systems: targets for immunotherapy. J Clin Immunol 2002;22:51–56.
- 69.
Goebel J, Stevens E, Forrest K, Roszman TL. Daclizumab (Zenapax) inhibits early interleukin-2 receptor signal transduction events. Transpl Immunol 2000;8:153–159.
- 70.
Tkaczuk J, Milford E, Yu C, et al. Intracellular signaling consequences of anti-IL-2Ralpha blockade by daclizumab. Transplant Proc 2001;33:212–213.
- 71.
Queen C, Schneider WP, Selick HE, et al. A humanized antibody that binds to the interleukin 2 receptor. Proc Natl Acad Sci U S A 1989;86:10029–10033.
- 72.
Waldmann TA, O’Shea J. The use of antibodies against the IL-2 receptor in transplantation. Curr Opin Immunol 1998;10:507–512.
- 73.
Nussenblatt RB, Fortin E, Schiffman R, 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 U S A 1999;96:7462–7466.
- 74.
Nussenblatt RB, Thompson DJ, Li Z, et al. Humanized antiinterleukin-2 (IL-2) receptor alpha therapy: long-term results in uveitis patients and preliminary safety and activity data for establishing parameters for subcutaneous administration. J Autoimmun 2003;21:283–293.
- 75.
Bielekova B, Richert N, Howard T, et al. Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon (beta). Proc Natl Acad Sci U S A 2004;101:8705–8708.
- 76.
Rose JW, Watt HE, White AT, Carlson NG. Treatment of multiple sclerosis with an anti-interleukin-2 receptor monoclonal antibody. Ann Neurol 2004;56:864–867.
- 77.
Bielekova B, Catalfamo M, Reichert-Scrivner S, et al. Regulatory CD56 bright natural killer cells mediate immunomodulatory effects of IL-2R {alpha}-targeted therapy (daclizumab) in multiple sclerosis. PNAS 2006;103: 5941–5946.
- 78.
Rice GP, Hartung HP, Calabresi PA. Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology 2005;64:1336–1342.
- 79.
Tubridy N, Behan PO, Capildeo R, et al. The effect of anti-alpha4 integrin antibody on brain lesion activity in MS. The UK Antegren Study Group. Neurology 1999;53:466–472.
- 80.
Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003; 348:15–23.
- 81.
O’Connor PW, Goodman A, Willmer-Hulme AJ, et al. Randomized multicenter trial of natalizumab in acute MS relapses: clinical and MRI effects. Neurology 2004;62:2038–2043.
- 82.
Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899–910.
- 83.
Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006;354:911–923.
- 84.
Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in multiple sclerosis. Ann Neurol 1996;39:285–294.
- 85.
Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006;354:924–933.
- 86.
Niino M, Bodner C, Simard ML, et al. Natalizumab effects on immune cell responses in multiple sclerosis. Ann Neurol 2006; 59:748–754.
- 87.
Stuve O, Marra CM, Jerome KR, et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol 2006;59:743–747.
- 88.
Cross AH, Stark JL, Lauber J, Ramsbottom MJ, Lyons JA. Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol 2006; 180:63–70.
- 89.
Stuve O, Cepok S, Elias B, et al. Clinical stabilization and effective B-lymphocyte depletion in the cerebrospinal fluid and peripheral blood of a patient with fulminant relapsing-remitting multiple sclerosis. Arch Neurol 2005;62: 1620–1623.
- 90.
Soon D, Altmann DR, Fernando KT, et al. A study of subtle blood brain barrier disruption in a placebo-controlled trial of natalizumab in relapsing remitting multiple sclerosis. J Neurol 2007; 254:306–314.
- 91.
Stuve O, Marra CM, Bar-Or A, et al. Altered CD4+/CD8 + T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. Arch Neurol 2006;63:1383–1387.
- 92.
Rastetter W, Molina A, White CA. Rituximab: expanding role in therapy for lymphomas and autoimmune diseases. Annu Rev Med 2004;55:477–503.
- 93.
Tedder TF, Engel P. CD20: a regulator of cell-cycle progression of B lymphocytes. Immunol Today 1994;15: 450–454.
- 94.
McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998;16:2825–2833.
- 95.
Taylor RP, Lindorfer MA. Drug insight: the mechanism of action of rituximab in autoimmune disease—the immune complex decoy hypothesis. Nat Clin Pract Rheumatol 2007;3:86–95.
- 96.
Monson NL, Cravens PD, Frohman EM, Hawker K, Racke MK. Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis. Arch Neurol 2005;62: 258–264.
- 97.
Chang A, Tourtellotte WW, Rudick R, Trapp BD. Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med 2002;346:165–173.
- 98.
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.
- 99.
Bjartmar C, Wujek JR, Trapp BD. Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J Neurol Sci 2003;206:165–171.
- 100.
Trebst C, Stangel M. Promotion of remyelination by immunoglobulins: implications for the treatment of multiple sclerosis. Curr Pharm Des 2006;12:241–249.
- 101.
Rodriguez M, Lennon VA. Immunoglobulins promote remyelination in the central nervous system. Ann Neurol 1990;27:12–17.
- 102.
Stangel M, Boegner F, Klatt CH, Hofmeister C, Seyfert S. Placebo controlled pilot trial to study the remyelinating potential of intravenous immunoglobulins in multiple sclerosis. J Neurol Neurosurg Psychiatry 2000;68: 89–92.
- 103.
Noseworthy JH, O’Brien PC, Weinshenker BG, et al. IV immunoglobulin does not reverse established weakness in MS. Neurology 2000;55:1135–1143.
- 104.
Noseworthy JH, O’Brien PC, Petterson TM, et al. A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis. Neurology 2001;56:1514–1522.
- 105.
Hommes OR, Sorensen PS, Fazekas F, et al. Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial. Lancet 2004;364:1149–1156.
- 106.
Fazekas F, Sorensen PS, Filippi M, et al. MRI results from the European Study on Intravenous Immunoglobulin in Secondary Progressive Multiple Sclerosis (ESIMS). Mult Scler 2005;11:433–440.
- 107.
Warrington AE, Asakura K, Bieber AJ, et al. Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis. Proc Natl Acad Sci U S A 2000; 97:6820–6825.
- 108.
Warrington AE, Bieber AJ, Ciric B, et al. Immunoglobulin-mediated CNS repair. J Allergy Clin Immunol 2001;108:S121–125.
- 109.
Pirko I, Ciric B, Gamez J, et al. A human antibody that promotes remyelination enters the CNS and decreases lesion load as detected by T2-weighted spinal cord MRI in a virus-induced murine model of MS. Faseb J 2004;18:1577–1579.
- 110.
Warrington AE, Bieber AJ, Ciric B, Pease LR, Van Keulen V, Rodriguez M. A recombinant human IgM promotes myelin repair after a single, very low dose. J Neurosci Res 2007;85:967–976.
- 111.
Ciric B, Howe CL, Paz Soldan M, et al. Human monoclonal IgM antibody promotes CNS myelin repair independent of FC function. Brain Pathol 2003;13:608–616.
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Muraro, P.A., Bielekova, B. Emerging therapies for multiple sclerosis. Neurotherapeutics 4, 676–692 (2007). https://doi.org/10.1016/j.nurt.2007.07.003
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Key Words
- Multiple sclerosis
- hematopoietic stem cell transplantation
- fingolimod
- monoclonal antibodies
- remyelination