Skip to main content
NCBI home page
Neurotherapeutics logoLink to Neurotherapeutics
. 2007 Oct;4(4):676–692. doi: 10.1016/j.nurt.2007.07.003

Emerging therapies for multiple sclerosis

Paolo A Muraro 1,✉, Bibiana Bielekova 3,✉
PMCID: PMC7479682  PMID: 17920549

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.

Key Words: Multiple sclerosis, hematopoietic stem cell transplantation, fingolimod, monoclonal antibodies, remyelination

Contributor Information

Paolo A. Muraro, Email: p.muraro@imperial.ac.uk

Bibiana Bielekova, Email: bibi.bielekova@uc.edu.

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. doi: 10.1073/pnas.0336479100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1126/science.290.5497.1779. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1073/pnas.0337659100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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;297:1299–1299. doi: 10.1126/science.297.5585.1299. [DOI] [PubMed] [Google Scholar]
  • 5.Wagers AJ, Sherwood RI, Christensen JL, Weissman IL. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science. 2002;297:2256–2259. doi: 10.1126/science.1074807. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1172/JCI116648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. [PubMed] [Google Scholar]
  • 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. doi: 10.1016/j.bbmt.2005.07.009. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/sj.bmt.1700666. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1084/jem.20041679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Muraro PA, Douek DC. Renewing the T cell repertoire to arrest autoimmune aggression. Trends Immunol. 2006;27:61–67. doi: 10.1016/j.it.2005.12.003. [DOI] [PubMed] [Google Scholar]
  • 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;1:1–1. doi: 10.1182/blood-2005-07-2800. [DOI] [PubMed] [Google Scholar]
  • 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;13:34–34. doi: 10.1016/j.bbmt.2006.12.090. [DOI] [Google Scholar]
  • 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. doi: 10.1177/1352458506071301. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1023/A:1006686426090. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1182/blood-2002-12-3908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1182/blood-2003-03-0877. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1212/wnl.62.2.282. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1182/blood-2004-08-3205. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1111/j.1399-0012.2006.00510.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1136/jnnp.2005.063883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1212/wnl.57.1.62. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1212/wnl.56.8.1084. [DOI] [PubMed] [Google Scholar]
  • 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. [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1212/01.wnl.0000219816.44094.f8. [DOI] [PubMed] [Google Scholar]
  • 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]. [DOI] [PubMed]
  • 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;27:27–27. doi: 10.1007/s00415-005-0934-5. [DOI] [PubMed] [Google Scholar]
  • 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–S9. [Google Scholar]
  • 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. doi: 10.1097/nen.0b013e318093f3ef. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1007/s004150050605. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1586/14737175.6.3.357. [DOI] [PubMed] [Google Scholar]
  • 32.Bielekova B, Kadom N, Fisher E, et al. MRI as a marker for disease heterogeneity in multiple sclerosis. Neurology. 2005;65:1071–1076. doi: 10.1212/01.wnl.0000178984.30534.f9. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1177/1352458506073502. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.7326/0003-4819-129-12-199812150-00007. [DOI] [PubMed] [Google Scholar]
  • 35.Weiner HL, Cohen JA. Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects. Mult Scler. 2002;8:142–154. doi: 10.1191/1352458502ms790oa. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/j.jneuroim.2003.10.036. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1001/archneur.63.10.noc60076. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.7164/antibiotics.47.208. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1074/jbc.C200176200. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/nature02284. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.4049/jimmunol.178.6.3437. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1096/fj.01-0625fje. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1002/eji.200425556. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1172/JCI28295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. [PubMed] [Google Scholar]
  • 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. doi: 10.1124/jpet.102.045658. [DOI] [PubMed] [Google Scholar]
  • 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. [PubMed] [Google Scholar]
  • 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. doi: 10.1016/j.jneuroim.2004.04.015. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1182/blood-2006-03-011437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.4049/jimmunol.178.4.2458. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.4049/jimmunol.178.9.5425. [DOI] [PubMed] [Google Scholar]
  • 52.Osinde M, Mullershausen F, Dev KK. Phosphorylated FTY720 stimulates ERK phosphorylation in astrocytes via S1P receptors. Neuropharmacology. 2007;52:1210–1218. doi: 10.1016/j.neuropharm.2006.11.010. [DOI] [PubMed] [Google Scholar]
  • 53.Mullershausen F, Craveiro LM, Shin Y, et al. Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors. J Neurochem 2007. [DOI] [PubMed]
  • 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. doi: 10.1096/fj.06-7420com. [DOI] [PubMed] [Google Scholar]
  • 55.Budde K, Schutz M, Glander P, et al. FTY720 (fingolimod) in renal transplantation. Clin Transplant. 2006;20(suppl 17):17–24. doi: 10.1111/j.1399-0012.2006.00596.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1097/01.tp.0000251718.95622.b3. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1111/j.1600-6143.2006.01552.x. [DOI] [PubMed] [Google Scholar]
  • 58.Kappos L, Antel J, Comi G, et al. Oral fmgolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 2006;355:1124–1140. doi: 10.1056/NEJMoa052643. [DOI] [PubMed] [Google Scholar]
  • 59.Hofmann M, Brinkmann V, Zerwes HG. FTY720 preferentially depletes naive T cells from peripheral and lymphoid organs. Int Immunopharmacol. 2006;6:1902–1910. doi: 10.1016/j.intimp.2006.07.030. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1634/stemcells.2006-0223. [DOI] [PubMed] [Google Scholar]
  • 61.Pavlou AK, Belsey MJ. The therapeutic antibodies market to 2008. Eur J Pharm Biopharm. 2005;59:389–396. doi: 10.1016/j.ejpb.2004.11.007. [DOI] [PubMed] [Google Scholar]
  • 62.Presta LG. Engineering of therapeutic antibodies to minimize immunogenicity and optimize function. Adv Drug Deliv Rev. 2006;58:640–656. doi: 10.1016/j.addr.2006.01.026. [DOI] [PubMed] [Google Scholar]
  • 63.Hohlfeld R, Wekerle H. Drug Insight: using monoclonal antibodies to treat multiple sclerosis. Nat Clin Pract Neurol. 2005;1:34–44. doi: 10.1038/ncpneuro0016. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1007/s00415-005-0934-5. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0140-6736(94)91339-0. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1002/1531-8249(199909)46:3<296::AID-ANA4>3.0.CO;2-#. [DOI] [PubMed] [Google Scholar]
  • 67.Waldmann T, Tagaya Y, Bamford R. Interleukin-2, interleukin-15, and their receptors. Int Rev Immunol. 1998;16:205–226. doi: 10.3109/08830189809042995. [DOI] [PubMed] [Google Scholar]
  • 68.Waldmann TA. The IL-2/IL-15 receptor systems: targets for immunotherapy. J Clin Immunol. 2002;22:51–56. doi: 10.1023/A:1014416616687. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0966-3274(00)00021-6. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0041-1345(00)01978-3. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1073/pnas.86.24.10029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Waldmann TA, O’Shea J. The use of antibodies against the IL-2 receptor in transplantation. Curr Opin Immunol. 1998;10:507–512. doi: 10.1016/S0952-7915(98)80215-X. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1073/pnas.96.13.7462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0896-8411(03)00113-6. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1073/pnas.0402653101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1002/ana.20287. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1073/pnas.0601335103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Rice GP, Hartung HP, Calabresi PA. Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology. 2005;64:1336–1342. doi: 10.1212/01.WNL.0000158329.30470.D0. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1212/wnl.53.3.466. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1056/NEJMoa020696. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1212/01.wnl.0000128136.79044.d6. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1056/NEJMoa044397. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1056/NEJMoa044396. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1002/ana.410390304. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1056/NEJMoa054693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Niino M, Bodner C, Simard ML, et al. Natalizumab effects on immune cell responses in multiple sclerosis. Ann Neurol. 2006;59:748–754. doi: 10.1002/ana.20859. [DOI] [PubMed] [Google Scholar]
  • 87.Stuve O, Marra CM, Jerome KR, et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol. 2006;59:743–747. doi: 10.1002/ana.20858. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/j.jneuroim.2006.06.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1001/archneur.62.10.1620. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1007/s00415-006-0356-z. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1001/archneur.63.10.1383. [DOI] [PubMed] [Google Scholar]
  • 92.Rastetter W, Molina A, White CA. Rituximab: expanding role in therapy for lymphomas and autoimmune diseases. Annu Rev Med. 2004;55:477–503. doi: 10.1146/annurev.med.55.091902.104249. [DOI] [PubMed] [Google Scholar]
  • 93.Tedder TF, Engel P. CD20: a regulator of cell-cycle progression of B lymphocytes. Immunol Today. 1994;15:450–454. doi: 10.1016/0167-5699(94)90276-3. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1200/JCO.1998.16.8.2825. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/ncprheum0424. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1001/archneur.62.2.258. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1056/NEJMoa010994. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1002/1531-8249(200006)47:6<707::AID-ANA3>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0022-510X(02)00069-2. [DOI] [PubMed] [Google Scholar]
  • 100.Trebst C, Stangel M. Promotion of remyelination by immunoglobulins: implications for the treatment of multiple sclerosis. Curr Pharm Des. 2006;12:241–249. doi: 10.2174/138161206775193118. [DOI] [PubMed] [Google Scholar]
  • 101.Rodriguez M, Lennon VA. Immunoglobulins promote remyelination in the central nervous system. Ann Neurol. 1990;27:12–17. doi: 10.1002/ana.410270104. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1136/jnnp.68.1.89. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103.Noseworthy JH, O’Brien PC, Weinshenker BG, et al. IV immunoglobulin does not reverse established weakness in MS. Neurology. 2000;55:1135–1143. doi: 10.1212/wnl.55.8.1135. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1212/wnl.56.11.1514. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0140-6736(04)17101-8. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1191/1352458505ms1196oa. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1073/pnas.97.12.6820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108.Warrington AE, Bieber AJ, Ciric B, et al. Immunoglobulin-mediated CNS repair. J Allergy Clin Immunol. 2001;108:S121–125. doi: 10.1067/mai.2001.118301. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1096/fj.04-2026fje. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1002/jnr.21217. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1111/j.1750-3639.2003.tb00489.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Neurotherapeutics are provided here courtesy of Elsevier

RESOURCES