Promoting remyelination following injury to the central nervous system (CNS) promises to be an effective neuroprotective strategy to limit the loss of surviving axons and prevent disability. Studies confirm that multiple sclerosis (MS) and spinal cord injury lesions contain myelinating cells and their progenitors. Recruiting these endogenous cells to remyelinate may be of therapeutic value. This review addresses the use of antibodies reactive to CNS antigens to promote remyelination. Antibody-induced remyelination in a virus-mediated model of chronic spinal cord injury was initially observed in response to treatment with CNS reactive antisera. Monoclonal mouse and human IgMs, which bind to the surface of oligodendrocytes and myelin, were later identified that were functionally equivalent to antisera. A recombinant form of a human remyelination-promoting IgM (rHIgM22) targets areas of CNS injury and promotes maximal remyelination within 5 weeks after a single low dose (25 μg/kg). The IgM isoform of this reparative antibody is required for in vivo function. We hypothesize that the IgM clusters membrane domains and associated signaling molecules on the surface of target cells. Current therapies for MS are designed to modulate inflammation. In contrast, remyelination promoting IgMs are the first potential therapeutic molecules designed to induce tissue repair by acting within the CNS at sites of damage on the cells responsible for myelin synthesis.
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References
Aarum J, Sandberg K, Haeberlein SL, Persson MA (2003) Migration and differentiation of neural precursor cells can be directed by microglia. Proc Natl Acad Sci USA 100:15983–15988
Akiyama Y, Radtke C, Honmou O, Kocsis JD (2002) Remyelination of the spinal cord following intravenous delivery of bone marrow cells. Glia 39:229–236
Akiyama Y, Radtke C, Kocsis JD (2002) Remyelination of the rat spinal cord by transplantation of identified bone marrow stromal cells. J Neurosci 22:6623–6630
Almazan G, Honegger P, Matthieu JM (1985) Triiodothyronine stimulation of oligodendroglial differentiation and myelination. A developmental study. Dev Neurosci 7:45–54
Annunziata P, Pluchino S, Martino T, Guazzi G (1997) High levels of cerebrospinal fluid IgM binding to myelin basic protein are associated with early benign course in multiple sclerosis. J Neuroimmunol 77:128–133
Armstrong RC, Dorn HH, Kufta CV, Friedman E, Dubois-Dalcq ME (1992) Pre-oligodendrocytes from adult human CNS. J Neurosci 12:1538–1547
Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, Ting JP (2001) TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci 4:1116–1122 Remyelination-Promoting Human IgMs 231
Asakura K, Miller DJ, Murray K, Bansal R, Pfeiffer SE, Rodriguez M (1996) Monoclonal autoantibody SCH94.03, which promotes central nervous system remyelination, recognizes an antigen on the surface of oligodendrocytes. J Neurosci Res 43:273–281
Asakura K, Miller DJ, Pease LR, Rodriguez M (1998) Targeting of IgM kappa antibodies to oligodendrocytes promotes CNS remyelination. J Neurosci 18:7700–7708
Bansal R (2002) Fibroblast growth factors and their receptors in oligodendrocyte development: implications for demyelination and remyelination. Dev Neurosci 24:35–46
Bansal R, Winkler S, Bheddah S (1999) Negative regulation of oligodendrocyte differentiation by galactosphingolipids. J Neurosci 19:7913–7924
Barouch R, Schwartz M (2002) Autoreactive T cells induce neurotrophin production by immune and neural cells in injured rat optic nerve: implications for protective autoimmunity. FASEB J 16:1304–1306
Barres BA, Lazar MA, Raff MC (1994) A novel role for thyroid hormone, glucocorticoids and retinoic acid in timing oligodendrocyte development. Development 120:1097–1108
Barres BA, Schmid R, Sendnter M, Raff MC (1993) Multiple extracellular signals are required for long-term oligodendrocyte survival. Development 118:283–295
Ben-Hur T, Einstein O, Mizrachi-Kol R, Ben-Menachem O, Reinhartz E, Karussis D, Abramsky O (2003) Transplanted multipotential neural precursor cells migrate into the inflamed white matter in response to experimental autoimmune encephalomyelitis. Glia 41:73–80
Bieber AJ, Kerr S, Rodriguez M (2003) Efficient central nervous system remyelination requires T cells. Ann Neurol 53:680–684
Bieber AJ, Ure DR, Rodriguez M (2005) Genetically dominant spinal cord repair in a murine model of chronic progressive multiple sclerosis. J Neuropathol Exp Neurol 64:46–57
Bieber AJ, Warrington A, Asakura K, Ciric B, Kaveri SV, Pease LR, Rodriguez M (2002) Human antibodies accelerate the rate of remyelination following lysolecithin-induced demyelination in mice. Glia 37:241–249
Bieber AJ, Warrington A, Pease LR, Rodriguez M (2001) Humoral autoimmunity as a mediator of CNS repair. Trends Neurosci 24:S39–S44
Bjartmar C, Trapp BD (2001) Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences. Curr Opin Neurol 14:271–278
Blakemore WF (1973) Demyelination of the superior cerebellar peduncle in the mouse induced by cuprizone. J Neurol Sci 20:63–72
Blakemore WF, Crang AJ (1988) Extensive oligodendrocyte remyelination following injection of cultured central nervous system cells into demyelinating lesions in adult central nervous system. Dev Neurosci 10:1–11
Bogler O, Wren D, Barnett SC, Land H, Noble M (1990) Cooperation between two growth factors promotes extended self-renewal and inhibits differentiation of oligodendrocyte-type- 2 astrocyte (O-2A) progenitor cells. Proc Natl Acad Sci U S A 87:6368–6372
Bregman BS, Kunkel-Bagden E, Schnell L, Dai HN, Gao D, Schwab ME (1995) Recovery from spinal cord injury mediated by antibodies to neurite growth inhibitors. Nature 378:498–501
Brenner T, Arnon R, Sela M, Abramsky O, Meiner Z, Riven-Kreitman R, Tarcik N, Teitelbaum D (2001) Humoral and cellular immune responses to Copolymer 1 in multiple sclerosis patients treated with Copaxone. J Neuroimmunol 115:152–160
Bruck W, Kuhlmann T, Stadelmann C (2003) Remyelination in multiple sclerosis. J Neurol Sci 206:181–185
Brustle O, Jones KN, Learish RD, Karram K, Choudhary K, Wiestler OD, Duncan ID, McKay RD (1999) Embryonic stem cell-derived glial precursors: a source of myelinating transplants. Science 285:754–756
Caroni P, Schwab ME (1988) Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. Neuron 1:85–96
. Chang A, Nishiyama A, Peterson J, Prineas J, Trapp BD (2000) NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J Neurosci 20:6404–6412 232 A.E. Warrington, M. Rodriguez
Chang A, Tourtellotte WW, Rudick R, Trapp BD (2002) Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med 346:165–173
Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Spillmann AA, Christ F, Schwab ME (2000) Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403:434–439
Ciric B, Howe CL, Paz Soldan M, Warrington AE, Bieber AJ, Van Keulen V, Rodriguez M, Pease LR (2003) Human monoclonal IgM antibody promotes CNS myelin repair independent of Fc function. Brain Pathol 13:608–616
Ciric B, VanKeulen V, Rodriguez M, Kyle RA, Gertz MA, Pease LR (2001) Clonal evolution in Waldenstrom macroglobulinemia highlights functional role of B-cell receptor. Blood 97:321–323
Cohen IR, Schwartz M (1999) Autoimmune maintenance and neuroprotection of the central nervous system. J Neuroimmunol 100:111–114
Dal Canto MC, Lipton HL (1977) Multiple sclerosis. Animal model: Theiler’s virus infection in mice. Am J Pathol 88:497–500
Dodel R, Hampel H, Depboylu C, Lin S, Gao F, Schock S, Jackel S, Wei X, Buerger K, Hoft C, Hemmer B, Moller HJ, Farlow M, Oertel WH, Sommer N, Du Y (2002) Human antibodies against amyloid beta peptide: a potential treatment for Alzheimer’s disease. Ann Neurol 52:253–256
Duncan ID (1996) Glial cell transplantation and remyelination of the central nervous system. Neuropathol Appl Neurobiol 22:87–100
Dyer CA (1993) Novel oligodendrocyte transmembrane signaling systems. Investigations utilizing antibodies as ligands. Mol Neurobiol 7:1–22
Dyer CA, Benjamins JA (1988) Redistribution and internalization of antibodies to galactocerebroside by oligodendroglia. J Neurosci 8:883–891
Einstein O, Karussis D, Grigoriadis N, Mizrachi-Kol R, Reinhartz E, Abramsky O, Ben-Hur T (2003) Intraventricular transplantation of neural precursor cell spheres attenuates acute experimental allergic encephalomyelitis. Mol Cell Neurosci 24:1074–1082
Ellezam B, Bertrand J, Dergham P, McKerracher L (2003) Vaccination stimulates retinal ganglion cell regeneration in the adult optic nerve. Neurobiol Dis 12:1–10
Feigin I, Popoff N (1966) Regeneration of myelin in multiple sclerosis. The role of mesenchymal cells in such regeneration and in myelin formation in the peripheral nervous system. Neurology 16:364–372
Fernandez M, Giuliani A, Pirondi S, D’Intino G, Giardino L, Aloe L, Levi-Montalcini R, Calza L (2004) Thyroid hormone administration enhances remyelination in chronic demyelinating inflammatory disease. Proc Natl Acad Sci U S A 101:16363–16368
Franklin RJ (2002) Why does remyelination fail in multiple sclerosis? Nat Rev Neurosci 3:705–714
Franklin RJ, Gilson JM, Blakemore WF (1997) Local recruitment of remyelinating cells in the repair of demyelination in the central nervous system. J Neurosci Res 50:337–344
Franklin RJ, Hinks GL, Woodruff RH, O’Leary MT (2001) What roles do growth factors play in CNS remyelination? Prog Brain Res 132:185–193
Gaiano N, Fishell G (1998) Transplantation as a tool to study progenitors within the vertebrate nervous system. J Neurobiol 36:152–161
Goddard DR, Berry M, Butt AM (1999) In vivo actions of fibroblast growth factor-2 and insulin-like growth factor-I on oligodendrocyte development and myelination in the central nervous system. J Neurosci Res 57:74–85
GrandPre T, Nakamura F, Vartanian T, Strittmatter SM (2000) Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature 403:439–444
Guimond SE, Turnbull JE (1999) Fibroblast growth factor receptor signalling is dictated by specific heparan sulphate saccharides. Curr Biol 9:1343–1346
Hall SM (1972) The effect of injections of lysophosphatidyl choline into white matter of the adult mouse spinal cord. J Cell Sci 10:535–546
Hammarberg H, Lidman O, Lundberg C, Eltayeb SY, Gielen AW, Muhallab S, Svenningsson A, Linda H, van Der Meide PH, Cullheim S, Olsson T, Piehl F (2000) Neuroprotection by encephalomyelitis: rescue of mechanically injured neurons and neurotrophin production by CNS-infiltrating T and natural killer cells. J Neurosci 20:5283-5291
Herndon RM, Price DL, Weiner LP (1977) Regeneration of oligodendroglia during recovery from demyelinating disease. Science 195:693-694
Hohlfeld R, Kerschensteiner M, Stadelmann C, Lassmann H, Wekerle H (2000) The neuro- protective effect of inflammation: implications for the therapy of multiple sclerosis. J Neuroimmunol 107:161-166
Howe CL, Bieber AJ, Warrington AE, Pease LR, Rodriguez M (2004) Antiapoptotic signal- ing by a remyelination-promoting human antimyelin antibody. Neurobiol Dis 15:120-131
Howe CL, Mayoral S, Rodriguez M (2006) Activated microglia stimulate transcriptional changes in primary oligodendrocytes via IL-1beta. Neurobiol Dis 23:731-739
Huang DW, McKerracher L, Braun PE, David S (1999) A therapeutic vaccine approach to stimulate axon regeneration in the adult mammalian spinal cord. Neuron 24:639-647
Hunter SF, Miller DJ, Rodriguez M (1997) Monoclonal remyelination-promoting natural autoantibody SCH 94.03: pharmacokinetics and in vivo targets within demyelinated spinal cord in a mouse model of multiple sclerosis. J Neurol Sci 150:103-113
Imitola J, Comabella M, Chandraker AK, Dangond F, Sayegh MH, Snyder EY, Khoury SJ (2004) Neural stem/progenitor cells express costimulatory molecules that are differentially regulated by inflammatory and apoptotic stimuli. Am J Pathol 164:1615-1625
Jeffery ND, Blakemore WF (1995) Remyelination of mouse spinal cord axons demyelinated by local injection of lysolecithin. J Neurocytol 24:775-781
Jeffery ND, Blakemore WF (1997) Locomotor deficits induced by experimental spinal cord demyelination are abolished by spontaneous remyelination. Brain 120:27-37
Jeffery ND, Crang AJ, O’Leary M T, Hodge SJ, Blakemore WF (1999) Behavioural conse- quences of oligodendrocyte progenitor cell transplantation into experimental demyelinating lesions in the rat spinal cord. Eur J Neurosci 11:1508-1514
Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, Myers LW, Panitch HS, Rose JW, Schiffer RB (1995) Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind pla- cebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 45:1268-1276
Johnson KP, Brooks BR, Ford CC, Goodman A, Guarnaccia J, Lisak RP, Myers LW, Panitch HS, Pruitt A, Rose JW, Kachuck N, Wolinsky JS (2000) Sustained clinical benefits of glati- ramer acetate in relapsing multiple sclerosis patients observed for 6 years. Copolymer 1 Multiple Sclerosis Study Group. Mult Scler 6:255-266
Jones TB, Basso DM, Sodhi A, Pan JZ, Hart RP, MacCallum RC, Lee S, Whitacre CC, Popovich PG (2002) Pathological CNS autoimmune disease triggered by traumatic spinal cord injury: implications for autoimmune vaccine therapy. J Neurosci 22:2690-2700
Kasahara K, Watanabe K, Takeuchi K, Kaneko H, Oohira A, Yamamoto T, Sanai Y (2000) Involvement of gangliosides in glycosylphosphatidylinositol-anchored neuronal cell adhe- sion molecule TAG-1 signaling in lipid rafts. J Biol Chem 275:34701-34709
Kasahara K, Watanabe Y, Yamamoto T, Sanai Y (1997) Association of Src family tyrosine kinase Lyn with ganglioside GD3 in rat brain. Possible regulation of Lyn by glycosphingoli- pid in caveolae-like domains. J Biol Chem 272:29947-29953
Keegan BM, Noseworthy JH (2002) Multiple sclerosis. Annu Rev Med 53:285-302
Keegan M, Konig F, McClelland R, Bruck W, Morales Y, Bitsch A, Panitch H, Lassmann H, Weinshenker B, Rodriguez M, Parisi J, Lucchinetti CF (2005) Relation between humoral pathologi- cal changes in multiple sclerosis and response to therapeutic plasma exchange. Lancet 366:579-582
Keirstead HS, Blakemore WF (1999) The role of oligodendrocytes and oligodendrocyte pro- genitors in CNS remyelination. Adv Exp Med Biol 468:183-197
Kerschensteiner M, Gallmeier E, Behrens L, Leal VV, Misgeld T, Klinkert WE, Kolbeck R, Hoppe E, Oropeza-Wekerle RL, Bartke I, Stadelmann C, Lassmann H, Wekerle H, Hohlfeld R (1999) Activated human T cells, B cells, and monocytes produce brain-derived neuro- trophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflamma- tion? J Exp Med 189:865-870
Khalili K, White MK, Lublin F, Ferrante P, Berger JR (2007) Reactivation of JC virus and development of PML in patients with multiple sclerosis. Neurology 68:985-990
Kohama I, Lankford KL, Preiningerova J, White FA, Vollmer TL, Kocsis JD (2001) Transplantation of cryopreserved adult human Schwann cells enhances axonal conduction in demyelinated spinal cord. J Neurosci 21:944-950
Koshizuka S, Okada S, Okawa A, Koda M, Murasawa M, Hashimoto M, Kamada T, Yoshinaga K, Murakami M, Moriya H, Yamazaki M (2004) Transplanted hematopoietic stem cells from bone marrow differentiate into neural lineage cells and promote functional recovery after spinal cord injury in mice. J Neuropathol Exp Neurol 63:64-72
Kotter MR, Setzu A, Sim FJ, Van Rooijen N,Franklin RJ (2001) Macrophage depletion impairs oligodendrocyte remyelination following lysolecithin-induced demyelination. Glia 35:204-212
Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, Nakashima I, Weinshenker BG (2004) A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 364:2106-2112
Lisak RP, Zweiman B, Blanchard N, Rorke LB (1983) Effect of treatment with Copolymer 1 (Cop-1) on the in vivo and in vitro manifestations of experimental allergic encephalomy- elitis (EAE). J Neurol Sci 62:281-293
Liu S, Qu Y, Stewart TJ, Howard MJ, Chakrabortty S, Holekamp TF, McDonald JW (2000) Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation. Proc Natl Acad Sci U S A 97:6126-6131
Lucchinetti C, Bruck W (2004) The pathology of primary progressive multiple sclerosis. Mult Scler 10 [Suppl 1]:S23-S30
Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (1999) A quan- titative analysis of oligodendrocytes in multiple sclerosis lesions. A study of 113 cases. Brain 122:2279-2295
Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (2000) Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47:707-717
Lucchinetti CF, Brueck W, Rodriguez M, Lassmann H (1998) Multiple sclerosis: lessons from neuropathology. Semin Neurol 18:337-349
Marta CB, Montano MB, Taylor CM, Taylor AL, Bansal R, Pfeiffer SE (2005) Signaling cascades activated upon antibody cross-linking of myelin oligodendrocyte glycoprotein: potential implications for multiple sclerosis. J Biol Chem 280:8985-8993
Marta CB, Taylor CM, Coetzee T, Kim T, Winkler S, Bansal R, Pfeiffer SE (2003) Antibody cross-linking of myelin oligodendrocyte glycoprotein leads to its rapid repartitioning into detergent-insoluble fractions, and altered protein phosphorylation and cell morphology. J Neurosci 23:5461-5471
Mason JL, Toews A, Hostettler JD, Morell P, Suzuki K, Goldman JE, Matsushima GK (2004) Oligodendrocytes and progenitors become progressively depleted within chronically demyelinated lesions. Am J Pathol 164:1673-1682
Matthews AE, Weiss SR, Paterson Y (2002) Murine hepatitis virus - a model for virus- induced CNS demyelination. J Neurovirol 8:76-85
Mayer M, Bhakoo K, Noble M (1994) Ciliary neurotrophic factor and leukemia inhibitory factor promote the generation, maturation and survival of oligodendrocytes in vitro. Development 120:143-153
McDonald JW, Liu XZ, Qu Y, Liu S, Mickey SK, Turetsky D, Gottlieb DI, Choi DW (1999) Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nat Med 5:1410-1412
McGavern DB, Murray PD, Rivera-Quinones C, Schmelzer JD, Low PA, Rodriguez M (2000) Axonal loss results in spinal cord atrophy, electrophysiological abnormalities and neurological deficits following demyelination in a chronic inflammatory model of multiple sclerosis. Brain 123:519-531
McMorris FA, Dubois-Dalcq M (1988) Insulin-like growth factor I promotes cell prolifera- tion and oligodendroglial commitment in rat glial progenitor cells developing in vitro. J Neurosci Res 21:199-209
McMorris FA, Mozell RL, Carson MJ, Shinar Y, Meyer RD, Marchetti N (1993) Regulation of oligodendrocyte development and central nervous system myelination by insulin-like growth factors. Ann N Y Acad Sci 692:321-334
McTigue DM, Horner PJ, Stokes BT, Gage FH (1998) Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord. J Neurosci 18:5354-5365
Mews I, Bergmann M, Bunkowski S, Gullotta F, Bruck W (1998) Oligodendrocyte and axon pathology in clinically silent multiple sclerosis lesions. Mult Scler 4:55-62
Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR (2000) Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 290:1779-1782
Mikami Y, Okano H, Sakaguchi M, Nakamura M, Shimazaki T, Okano HJ, Kawakami Y, Toyama Y, Toda M (2004) Implantation of dendritic cells in injured adult spinal cord results in activation of endogenous neural stem/progenitor cells leading to de novo neurogenesis and functional recovery. J Neurosci Res 76:453-465
Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GP, Libonati MA, Willmer- Hulme AJ, Dalton CM, Miszkiel KA, O’Connor PW (2003) A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 348:15-23
Miller DJ, Sanborn KS, Katzmann JA, Rodriguez M (1994) Monoclonal autoantibodies pro- mote central nervous system repair in an animal model of multiple sclerosis. J Neurosci 14:6230-6238
Mitsunaga Y, Ciric B, Van Keulen V, Warrington AE, Paz Soldan M, Bieber AJ, Rodriguez M, Pease LR (2002) Direct evidence that a human antibody derived from patient serum can promote myelin repair in a mouse model of chronic-progressive demyelinating disease. FASEB J 16:1325-1327
Moalem G, Monsonego A, Shani Y, Cohen IR, Schwartz M (1999) Differential T cell response in central and peripheral nerve injury: connection with immune privilege. FASEB J 13:1207-1217
Muir DA, Compston DA (1996) Growth factor stimulation triggers apoptotic cell death in mature oligodendrocytes. J Neurosci Res 44:1-11
Murray PD, Pavelko KD, Leibowitz J, Lin X, Rodriguez M (1998) CD4(+) and CD8(+) T cells make discrete contributions to demyelination and neurologic disease in a viral model of multiple sclerosis. J Virol 72:7320-7329
Nait-Oumesmar B, Decker L, Lachapelle F, Avellana-Adalid V, Bachelin C, Van Evercooren AB (1999) Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination. Eur J Neurosci 11:4357-4366
Nait-Oumesmar B, Picard-Riera N, Kerninon C, Decker L, Seilhean D, Hoglinger GU, Hirsch EC, Reynolds R, Baron-Van Evercooren A (2007) Activation of the subventricular zone in multiple sclerosis: evidence for early glial progenitors. Proc Natl Acad Sci USA 104:4694-4699
Njenga MK, Murray PD, McGavern D, Lin X, Drescher KM, Rodriguez M (1999) Absence of spontaneous central nervous system remyelination in class II-deficient mice infected with Theiler’s virus. J Neuropathol Exp Neurol 58:78-91
Noble M, Murray K, Stroobant P, Waterfield MD, Riddle P (1988) Platelet-derived growth fac- tor promotes division and motility and inhibits premature differentiation of the oligodendrocyte/ type-2 astrocyte progenitor cell. Nature 333:560-562
Noseworthy JH, Gold R, Hartung HP (1999) Treatment of multiple sclerosis: recent trials and future perspectives. Curr Opin Neurol 12:279-293
Nunes MC, Roy NS, Keyoung HM, Goodman RR, McKhann G 2nd, Jiang L, Kang J, Nedergaard M, Goldman SA (2003) Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain. Nat Med 9:439-447
Pannu R, Christie DK, Barbosa E, Singh I, Singh AK (2007) Post-trauma Lipitor treatment prevents endothelial dysfunction, facilitates neuroprotection, and promotes locomotor recovery following spinal cord injury. J Neurochem 101:182-200
Patrikios P, Stadelmann C, Kutzelnigg A, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Bruck W, Lucchinetti C, Lassmann H (2006) Remyelination is extensive in a subset of multiple sclerosis patients. Brain 129:3165-3172
Pavelko KD, van Engelen BG, Rodriguez M (1998) Acceleration in the rate of CNS remyelination in lysolecithin-induced demyelination. J Neurosci 18:2498-2505
Paz Soldan MM, Warrington AE, Bieber AJ, Ciric B, Van Keulen V, Pease LR, Rodriguez M (2003) Remyelination-promoting antibodies activate distinct Ca2+ influx pathways in astrocytes and oligodendrocytes: relationship to the mechanism of myelin repair. Mol Cell Neurosci 22:14-24
Penderis J, Shields SA, Franklin RJ (2003) Impaired remyelination and depletion of oligodendrocyte progenitors does not occur following repeated episodes of focal demyelination in the rat central nervous system. Brain 126:1382-1391
Perier O, Gregoire A (1965) Electron microscopic features of multiple sclerosis lesions. Brain 88:937-952
Pirko I, Ciric B, Gamez J, Bieber AJ, Warrington AE, Johnson AJ, Hanson DP, Pease LR, Macura SI, Rodriguez M (2004) A human antibody that promotes remyelination enters the CNS and decreases lesion load as detected by T2-weighted spinal cord MRI in a virusinduced murine model of MS. FASEB J 18:1577-1579
Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, Galli R, Del Carro U, Amadio S, Bergami A, Furlan R, Comi G, Vescovi AL, Martino G (2003) Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 422:688-694
Prabhakar S, D’Souza S, Antel JP, McLaurin J, Schipper HM, Wang E (1995) Phenotypic and cell cycle properties of human oligodendrocytes in vitro. Brain Res 672:159-169
Prineas JW, Barnard RO, Kwon EE, Sharer LR, Cho ES (1993) Multiple sclerosis: remyelination of nascent lesions. Ann Neurol 33:137-151
Prineas JW, Wright RG (1978) Macrophages, lymphocytes, and plasma cells in the perivascular compartment in chronic multiple sclerosis. Lab Invest 38:409-421
Qian X, Davis AA, Goderie SK, Temple S (1997) FGF2 concentration regulates the generation of neurons and glia from multipotent cortical stem cells. Neuron 18:81-93
Raine CS, Stone SH (1977) Animal model for multiple sclerosis. Chronic experimental allergic encephalomyelitis in inbred guinea pigs. N Y State J Med 77:1693-1696
Rapalino O, Lazarov-Spiegler O, Agranov E, Velan GJ, Yoles E, Fraidakis M, Solomon A, Gepstein R, Katz A, Belkin M, Hadani M, Schwartz M (1998) Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med 4:814-821
Rapraeger AC, Krufka A, Olwin BB (1991) Requirement of heparan sulfate for bFGF-mediated fibroblast growth and myoblast differentiation. Science 252:1705-1758
Richardson WD, Pringle N, Mosley MJ, Westermark B, Dubois-Dalcq M (1988) A role for platelet-derived growth factor in normal gliogenesis in the central nervous system. Cell 53:309-319
Riggott MJ, Matthew WD (1997) Neurite outgrowth is enhanced by anti-idiotypic monoclonal antibodies to the ganglioside GM1. Exp Neurol 145:278-287
Rivera-Quinones C, McGavern D, Schmelzer JD, Hunter SF, Low PA, Rodriguez M (1998) Absence of neurological deficits following extensive demyelination in a class I-deficient murine model of multiple sclerosis. Nat Med 4:187-193
Robinson S, Tani M, Strieter RM, Ransohoff RM, Miller RH (1998) The chemokine growthregulated oncogene-alpha promotes spinal cord oligodendrocyte precursor proliferation. J Neurosci 18:10457-10563
Rodriguez M (1991) Immunoglobulins stimulate central nervous system remyelination: electron microscopic and morphometric analysis of proliferating cells. Lab Invest 64:358-370
Rodriguez M (2003) A function of myelin is to protect axons from subsequent injury: implications for deficits in multiple sclerosis. Brain 126:751-752
Rodriguez M (2007) Effectors of demyelination and remyelination in the CNS: Implications for multiple sclerosis. Brain Pathol 17:219-229
Rodriguez M, Karnes WE, Bartleson JD, Pineda AA (1993) Plasmapheresis in acute episodes of fulminant CNS inflammatory demyelination. Neurology 43:1100-1104
Rodriguez M, Lennon VA (1990) Immunoglobulins promote remyelination in the central nervous system. Ann Neurol 27:12-17
Rodriguez M, Lennon VA, Benveniste EN, Merrill JE (1987) Remyelination by oligodendrocytes stimulated by antiserum to spinal cord. J Neuropathol Exp Neurol 46:84-95
Rodriguez M, Miller DJ, Lennon VA (1996) Immunoglobulins reactive with myelin basic protein promote CNS remyelination. Neurology 46:538-545
Rodriguez M, Oleszak E, Leibowitz J (1987) Theiler’s murine encephalomyelitis: a model of demyelination and persistence of virus. Crit Rev Immunol 7:325-365
Rodriguez M, Scheithauer BW, Forbes G, Kelly PJ (1993) Oligodendrocyte injury is an early event in lesions of multiple sclerosis. Mayo Clin Proc 68:627-636
Rubin BP, Dusart I, Schwab ME (1994) A monoclonal antibody (IN-1) which neutralizes neurite growth inhibitory proteins in the rat CNS recognizes antigens localized in CNS myelin. J Neurocytol 23:209-217
Sasaki M, Honmou O, Akiyama Y, Uede T, Hashi K, Kocsis JD (2001) Transplantation of an acutely isolated bone marrow fraction repairs demyelinated adult rat spinal cord axons. Glia 35:26-34
Schluesener HJ, Sobel RA, Linington C, Weiner HL (1987) A monoclonal antibody against a myelin oligodendrocyte glycoprotein induces relapses and demyelination in central nervous system autoimmune disease. J Immunol 139:4016-4021
Schwab ME (1996) Structural plasticity of the adult CNS. Negative control by neurite growth inhibitory signals. Int J Dev Neurosci 14:379-385
Schwartz M, Moalem G, Leibowitz-Amit R, Cohen IR (1999) Innate and adaptive immune responses can be beneficial for CNS repair. Trends Neurosci 22:295-299
Setzu A, Lathia JD, Zhao C, Wells K, Rao MS, Ffrench-Constant C, Franklin RJ (2006) Inflammation stimulates myelination by transplanted oligodendrocyte precursor cells. Glia 54:297-303
Sindic CJ, Cambiaso CL, Depre A, Laterre EC, Masson PL (1982) The concentration of IgM in the cerebrospinal fluid of neurological patients. J Neurol Sci 55:339-350
Sindic CJ, Monteyne P, Laterre EC (1994) Occurrence of oligoclonal IgM bands in the cerebrospinal fluid of neurological patients: an immunoaffinity-mediated capillary blot study. J Neurol Sci 124:215-219
Smith EJ, Blakemore WF, McDonald WI (1979) Central remyelination restores secure conduction. Nature 280:395-396
Sommer I, Schachner M (1981) Monoclonal antibodies (O1 to O4) to oligodendrocyte cell surfaces: an immunocytological study in the central nervous system. Dev Biol 83:311-327
Spirman N, Sela BA, Gitler C, Calef E, Schwartz M (1984) Regenerative capacity of the goldfish visual system is affected by antibodies specific to gangliosides injected intraocularly. J Neuroimmunol 6:197-207
Spirman N, Sela BA, Schwartz M (1982) Antiganglioside antibodies inhibit neuritic outgrowth from regenerating goldfish retinal explants. J Neurochem 39:874-877
Stohlman SA, Hinton DR (2001) Viral induced demyelination. Brain Pathol 11:92-106
Suzuki K, Andrews JM, Waltz JM, Terry RD (1969) Ultrastructural studies of multiple sclerosis. Lab Invest 20:444-454
Teitelbaum D, Aharoni R, Sela M, Arnon R (1991) Cross-reactions and specificities of monoclonal antibodies against myelin basic protein and against the synthetic copolymer 1. Proc Natl Acad Sci U S A 88:9528-9532
Totoiu MO, Nistor GI, Lane TE, Keirstead HS (2004) Remyelination, axonal sparing, and locomotor recovery following transplantation of glial-committed progenitor cells into the MHV model of multiple sclerosis. Exp Neurol 187:254-265
Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278-285
Tripathi R, McTigue DM (2007) Prominent oligodendrocyte genesis along the border of spinal contusion lesions. Glia 55:698-711
Ure DR, Rodriguez M (2002) Polyreactive antibodies to glatiramer acetate promote myelin repair in murine model of demyelinating disease. FASEB J 16:1260-1262
Ure DR, Rodriguez M (2002) Preservation of neurologic function during inflammatory demyelination correlates with axon sparing in a mouse model of multiple sclerosis. Neuroscience 111:399-411
Utzschneider DA, Archer DR, Kocsis JD, Waxman SG, Duncan ID (1994) Transplantation of glial cells enhances action potential conduction of amyelinated spinal cord axons in the myelin-deficient rat. Proc Natl Acad Sci U S A 91:53-57
Vartanian T, Fischbach G, Miller R (1999) Failure of spinal cord oligodendrocyte development in mice lacking neuregulin. Proc Natl Acad Sci U S A 96:731-735
Vieira P, Rajewsky K (1988) The half-lives of serum immunoglobulins in adult mice. Eur J Immunol 18:313-316
Vincent A, Lily O, Palace J (1999) Pathogenic autoantibodies to neuronal proteins in neurological disorders. J Neuroimmunol 100:169-180
Vyas AA, Patel HV, Fromholt SE, Heffer-Lauc M, Vyas KA, Dang J, Schachner M, Schnaar RL (2002) Gangliosides are functional nerve cell ligands for myelin-associated glycoprotein (MAG), an inhibitor of nerve regeneration. Proc Natl Acad Sci U S A 99:8412-8417
Warrington AE, Asakura K, Bieber AJ, Ciric B, Van Keulen V, Kaveri SV, Kyle RA, Pease LR, Rodriguez M (2000) Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis. Proc Natl Acad Sci USA 97:6820-6825
Warrington AE, Barbarese E, Pfeiffer SE (1993) Differential myelinogenic capacity of specific developmental stages of the oligodendrocyte lineage upon transplantation into hypomyelinating hosts. J Neurosci Res 34:1-13
Warrington AE, Bieber AJ, Ciric B, Pease LR, Van Keulen V, Rodriguez M (2007) A recombinant human IgM promotes myelin repair after a single, very low dose. J Neurosci Res 85:967-976
Warrington AE, Bieber AJ, Van Keulen V, Ciric B, Pease LR, Rodriguez M (2004) Neuronbinding human monoclonal antibodies support central nervous system neurite extension. J Neuropathol Exp Neurol 63:461-473
Warrington AE, Pfeiffer SE (1992) Proliferation and differentiation of O4+ oligodendrocytes in postnatal rat cerebellum: analysis in unfixed tissue slices using anti-glycolipid antibodies. J Neurosci Res 33:338-353
Weibel D, Cadelli D, Schwab ME (1994) Regeneration of lesioned rat optic nerve fibers is improved after neutralization of myelin-associated neurite growth inhibitors. Brain Res 642:259-266
Weinshenker BG, O’Brien PC, Petterson TM, Noseworthy JH, Lucchinetti CF, Dodick DW, Pineda AA, Stevens LN, Rodriguez M (1999) A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol 46:878-886
Weinshenker BG, Wingerchuk DM, Pittock SJ, Lucchinetti CF, Lennon VA (2006) NMOIgG: a specific biomarker for neuromyelitis optica. Dis Markers 22:197-206
Windrem MS, Nunes MC, Rashbaum WK, Schwartz TH, Goodman RA, McKhann G 2nd, Roy NS, Goldman SA (2004) Fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain. Nat Med 10:93-97
Wolswijk G (1997) Oligodendrocyte precursor cells in chronic multiple sclerosis lesions. Mult Scler 3:168-169
Woodruff RH, Franklin RJ (1997) Growth factors and remyelination in the CNS. Histol Histopathol 12:459-466
Yajima K, Suzuki K (1979) Demyelination and remyelination in the rat central nervous system following ethidium bromide injection. Lab Invest 41:385-392
Yandava BD, Billinghurst LL, Snyder EY (1999) “Global” cell replacement is feasible via neural stem cell transplantation: evidence from the dysmyelinated shiverer mouse brain. Proc Natl Acad Sci U S A 96:7029-7034
Yao DL, Liu X, Hudson LD, Webster HD (1995) Insulin-like growth factor I treatment reduces demyelination and up-regulates gene expression of myelin-related proteins in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 92:6190-194
Yoles E, Hauben E, Palgi O, Agranov E, Gothilf A, Cohen A, Kuchroo V, Cohen IR, Weiner H, Schwartz M (2001) Protective autoimmunity is a physiological response to CNS trauma. J Neurosci 21:3740-3748
Ziemssen T, Ziemssen F (2005) The role of the humoral immune system in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Autoimmun Rev 4:460-467
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Warrington, A.E., Rodriguez, M. (2008). Remyelination-Promoting Human IgMs: Developing a Therapeutic Reagent for Demyelinating Disease. In: Rodriguez, M. (eds) Advances in multiple Sclerosis and Experimental Demyelinating Diseases. Current Topics in Microbiology and Immunology, vol 318. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-73677-6_9
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