Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Significant progress has been made in our understanding of the etiology of MS. MS is widely believed to be an autoimmune disease that results from aberrant immune responses to CNS antigens. T cells are considered to be crucial in orchestrating an immunopathological cascade that results in damage to the myelin sheath. This review summarizes the currently available data supporting the idea that myelin reactive T cells are actively involved in the immunopathogenesis of MS. Some of the therapeutic strategies for MS are discussed with a focus on immunotherapies that aim to specifically target the myelin reactive T cells.
Similar content being viewed by others
References
Poser CM: The epidemiology of multiplesclerosis: A general overview. Ann Neurol 1994;36(S2): S180-S193.
Acheson ED: Epidemiology of multiple sclerosis. Br Med Bull 1977;33:9–14.
Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW: New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13: 227–231.
Raine CS, Scheinberg LC: On the immunopathology of plaquedevelopment and repair in multiplesclerosis. J Neuroimmunol 1988;20:189–201.
Prineas J: Pathology of the early lesion in multiple sclerosis. Hum Pathol 1975;6:531–554.
Raine CS: Multiplesclerosis: a pivotal role for the T cell in lesion development. Neuropathol Appl Neurobiol 1991;17:265–274.
Bruck W, Schmied M, Suchanek G, Bruck Y, Breitschopf H, Poser S, Piddlesden S, Lassmann H: Oligo dendrocytes in the early course of multiple sclerosis. Ann Neurol 1994;35:65–73.
Sadovnick AD, Bulman D, Ebers GC: Parent-child concordance in multiple sclerosis. Ann Neurol 1991;29:252–255.
Ebers GC, Koopman WJ, Hader W, Sadovnick AD, Kremenchutzky M, Mandalfino P, Wingerchuk DM, Baskerville J, Rice GP: The natural history of multiple sclerosis: a geographically based study: 8: familial multiple sclerosis. Brain 2000;123Pt3:641–649.
Ebers GC, Bulman DE, Sadovnick AD, Paty DW, Warren S, Hader W, Murray TJ, Seland TP, Duquette P, Grey T: A population-based study of multiple sclerosis in twins. N Engl J Med 1986;315:1638–1642.
Sadovnick AD, Armstrong H, Rice GP, Bulman D, Hashimoto L, Paty DW, Hashimoto SA, Warren S, Hader W, Murray TJ: A population-based study of multiple sclerosis in twins: update. Ann Neurol 1993; 33:281–285.
Fogdell A, Olerup O, Fredrikson S, Vrethem M, Hillert J: Linkage analysis of HLA class II genes in Swedish multiplex families with multiple sclerosis. Neurology 1997;48:758–762.
Olerup O, Hillert J: HLA class II-associated genetic susceptibility in multiple sclerosis: a critical evaluation. Tissue Antigens 1991;38: 1–15.
Serjeantson SW, Gao X, Hawkins BR, Higgins DA, Yu YL: Novel HLA-DR2-related haplotypes in Hong Kong Chinese implicate the DQB1*0602 allele in susceptibility to multiple sclerosis. Eur J Immunogenet 1992;19: 11–19.
Fogdell-Hahn A, Ligers A, Gronning M, Hillert J, Olerup O: Multiple sclerosis: a modifying influence of HLA class 1 genes in an HLA class II associated autoimmune disease. Tissue Antigens 2000;55:140–148.
Seboun E, Robinson MA, Doolittle TH, Ciulla TA, Kindt TJ, Hauser SL: A susceptibility locus for multiplesclerosis is linked to the T cell receptor beta chain complex. Cell 1989;57:1095–1100.
Oksenberg JR, Gaiser CN, Cavalli-Sforza LL, Steinman L: Polymorphic markers of human T-cell receptor alpha and beta genes. Family studies and comparison of frequencies in healthy individuals and patients with multiple sclerosis and myasthenia gravis. Hum Immunol 1988;22:111–121.
Oksenberg JR, Sherritt M, Begovich AB, Erlich HA, Bemard CC, Cavalli-Sforza LL, Steinman L: T-cell receptor V alpha and C alpha alleles associated with multiple and myast henia gravis. Proc Natl Acad Sci USA 1989;86: 988–992.
Vandevyver C, Buyse I, Philippaerts L, Ghabanbasani Z, Medaer R, Carton H, Cassiman JJ, Raus J: HLA and T-cell receptor polymorphisms in Belgian multiple sclerosis patients: noevidence for disease association with the T-cell receptor. J Neuroimmunol 1994;52:25–32.
Hillert J, Olerup O: Germ-line polymorphism of TCR genes and disease susceptibility—fact or hypothesis? Immunol Today 1992; 13:47–49.
Hillert J, Leng C, Olerup O: No association with germline T cell receptor beta-chain gene alleles or haplotypes in Swedish patients with multiple sclerosis. J Neuroimmunol 1991;32:141–147.
Tienari PJ, Wikstrom J, Sajantila A, Palo J, Peltonen L: Genetic susceptibility to multiple sclerosis linked to myelin basic protein gene. Lancet 1992;340:987–991.
Ibsen SN, Clausen J: Genetic susceptibility to multiple sclerosis may be linked to polymorphism of the myelin basic protein gene. J Neurol Sci 1995;131:96–98.
Vandevyver C, Stinissen P, Cassiman JJ, Raus J: Myelin basic protein gene polymorphism is not associated with chronic progressive multiple sclerosis. J Neuroimmunol 1994;52:97–99.
Rose J, Gerken S, Lynch S, Pisani P, Varvil T, Otterud B, Leppert M: Genetic susceptibility in familial multiple sclerosis not linked to the myelin basic protein gene. Lancet 1993;341:1179–1181.
Seboun E, Oksenberg JR, Rombos A, Usuku K, Goodkin DE, Lincoln RR, Wong M, Pham-Dinh D, Boesplug-Tanguy O, Carsique R, Fitoussi R, Gartioux C, Reyes C, Ribierre F, Faure S, Fizames C, Gyapay G, Weissenbach J, Dautigny A, Rimmler JB, Garcia ME, Pericak-Vance MA, Haines JL, Hauser SL: Linkage analysis of candidate myelin genes in familial multiple sclerosis. Neurogenetics 1999;2:155–162.
He B, Xu C, Yang B, Landthlom AM, Fredrikson S, Hillert J: Link-age and association analysis of genes encoding cytokines and myelin proteins in multiple sclerosis. J Neuroimmunol 1998;86:13–19.
Pickard C, Mann C, Simnott P, Boggild M, Hawkins C, Strange RC, Hutchinson IV, Ollier WE, Donn RP: Interleukin-10 (IL 10) promoter polymorphisms and multiple sclerosis. J Neuroimmunol 1999;101:207–210.
Reboul J, Mertens C, Levillayer F, Eichenbaum-Voline S, Vilkoren T, Cournu I, Babron MC, Lyon-Caen O, Clerget-Darpoux F, Edan G, Clanet M, Brahic M, Bureau JF, Fontaine B, Liblau R: cytokines in genetic susceptibility to multiple sclerosis: a candidate gene approach. French Multiple Sclerosis Genetics Group. J Neuroimmunol 2000;102:107–112.
Killestein J, Schrijver HM, Crusius JB, Perez C, Uitdehaag BM, Pena AS, Polman CH: Intracellular adhesion molecule-I polymorphisms and genetic susceptibility to multiple sclerosis: additional data and meta-analysis. Ann Neurol 2000;47:277–279.
Mycko MP, Kwinkowski M, Tronczynska E, Szymanska B, Selmaj KW: Multiple sclerosis: the increased frequency of the ICAM-1 exon 6 gene point mutation genetic type K469. Ann Neurol 1998;44:70–75.
Gaiser CN, Johnson MJ, de Lange G, Rassenti L, Cavalli-Sforza LL, Steinman L: Susceptibility to multiple sclerosis associated with an immunoglobulin gamma 3 restriction fragment length polymorphism. J Clin Invest 1987;79: 309–313.
Huang QR, Teutsch SM, Buhler MM, Bennetts BH, Heard RN, Manolios N, Stewart GJ: Evaluation of the apo-1/Fas promotermva I polymorphism in multiple sclerosis. Mult Scler 2000;6:14–18.
Ebers GC, Kukay K, Bulman DE, Sadovnick AD, Rice G, Anderson C, Armstrong H, Cousin K, Bell RB, Hader W, Paty DW, Hashimoto S, Oger J, Duquette P, Warren S, Gray T, O'Connor P, Nath A, Auty A, Metz L, Francis G, Paulseth JE, Murray TJ, Pryse-Phillips W, Risch N: A full genome search in multiple sclerosis. Nat Genet 1996; 13:472–476.
Sawcer S, Jones HB, Feakes R, Gray J, Smaldon N, Chataway J, Robertson N, Clayton D, Goodfellow PN, Compston A: Agenome screen in multiple sclerosis reveals susceptibility locion chromosome 6p21 and 17q22. Nat Genet 1996; 13:464–468.
Haines JL, Ter Minassian M, Bazyk A, Gusella JF, Kim DJ, Terwedow H, Pericak-Vance MA, Rimmler JB, Haynes CS, Roses AD, Lee A, Shaner B, Menold M, Seboun E, Fitoussi RP, Gartioux C, Reyes C, Ribierre F, Gyapay G, Weissenbach J, Hauser SL, Goodkin DE, Lincoln R, Usuku K, Oksenberg JR: A complete genomic screen for multiple sclerosis underscores a role for the major histocompatability complex. The Multiple Sclerosis Genetics Group. Nat Genet 1996;13: 469–471.
Kurtzke JF: Epidemiologic evidence for multiple sclerosis as an infection. Clin Microbiol Rev 1993;6:382–427.
Sadovnick AD, Ebers GC: Epidemiology of multiple sclerosis: a critical overview. Can J Neurol Sci 1993;20:17–29.
Dean G, Kurtzke JF: On the risk of multiplesclerosis according to age at immigration to South Africa. Br Med J 1971;3:725–729.
Rice GP. Virus-induced demyelination in man: models for multiple sclerosis. Curr Opin Neurol Neurosurg 1992;5:188–194.
Weiss RA, Schulz TF: Viruses and multiple sclerosis. Mult Scler 1995;1:59–60.
Perron H, Garson JA, Bedin F, Beseme F, Paranhos-Baccala G, Komurian-Pradel F, Mallet F, Tuke PW, Voisset C, Blond JL, Lalande B, Seigneurin JM, Mandrand B: Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. The Collaborative Research Group on Multiple Sclerosis. Proc Natl Acad Sci USA 1997;94:7583–7588.
Rieger F, Piergi R, Cifuentes-Diaz C, Menard A, Belladi L, Alliel PM, Perin JP: New perspectives in multiple sclerosis: retroviral involvement and glial cell death. Pathol Biol (Paris) 2000;48:15–24.
Menard A, Amouri R, Michel M, Marcel F, Brouillet A, Belliveau J, Geny C, Deforges L, Malcus-Vocanson C, Armstrong M, Lyon-Caen O, Mandrand B; Dobransky T, Rieger F, Perron H: Gliotoxicity, reverse transcriptase activity and retroviral RNA in monocyte/macrophage culture supernatants from patients with multiple sclerosis. FEBS Lett 1997;413: 477–485.
Menard A, Pierig R, Pelletier J, Bensa P, Belliveau J, Mandrand B, Perron H, Rieger F: Detection of a gliotoxic activity in the cerebrospinal fluid from multiple sclerosis patients. Neurosci Lett 1998; 245:49–52.
Challoner PB, Smith KT, Parker JD, MacLeod DL, Coulter SN, Rose TM, Schultz ER, Bemmett JL, Garber, RL, Chang M: Plaque-associated expression of human herpesvirus 6 in multiple sclerosis. Proc Nalt Acad Sci USA 1995; 92:7440–7444.
Friedman JE, Lyons MJ, Cu G, Ablashl DV, Whitman JE, Edgar M, Koskiniemi M, Vaheri A, Zabriskie JB: The association of the human herpesivirus-6 and MS. Mult Scler 1999;5:355–362.
Soldan SS, Berti R, Salem N, Secchiero P, Flamand L, Calabresi PA, Brennan MB, Maloni HW, McFarland HF, Lin HC, Patnaik M, Jacobson S: Association of human herpes virus 6 (HH V-6) with multiple sclerosis: increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA. Nat Med 1997;3:1394–1397.
Sola P, Merelli E, Marasca R, Poggi M, Luppi M, Montorsi M, Torelli G: Human herpesvirus 6 and multiple sclerosis: survey of anti-HHV-6 antibodies by immuno-fluorescence analysis and of viral sequences by polymerase chain reaction. J Neurol Neurosurg Psychiatry 1993;56:917–919.
Mirandonla P, Stefan A, Brambilla E, Campadelli-Fiume G, Grimaldi LM: Absence of human herpesvirus 6 and 7 from spinal fluid and serum of multiple sclerosis patients. Neurology 1999;53: 1367–1368.
Enbom M, Wang FZ, Fredrikson S, Martin C, Dahl H, Linde A: Similar humoral and cellular immunological reactivities to human herpesvirus 6 in patients with multiple sclerosis and controls. Clin Diagn Lab Immunol 1999;6: 545–549.
Martin C, Enbom M, Soderstrom M, Fredrikson S, Dahl H, Lycke J, Bergstrom T, Linde A: Absence of seven human herpesviruses, including HHV-6, by polymerase chain reaction in SCF and blood from patients with multiple sclerosis and optic neuritis. Acta Neurol Scand 1997;95:280–283.
Taus C, Pucci E, Cartechnini E, Fie A, Giuliani G, Clementi M, Menzo S: Absence of HHV-6 and HHV-7 increrebrospinal fluid in relapsing-remitting multiple sclerosis. Acta Neurol Scand 2000;101:224–228.
Merelli E, Sola P, Barozzi P, Torelli G: An encephalitic episode in a multiple sclerosis patient with human herpesvirus 6 latent infection. J Neurol Sci 1996;137:42–46.
Ferrante P, Mancuso R, Pagani E, Guerini FR, Calvo MG, Saresella M, Speciale L, Caputo D: Molecular evidences for a role of HSV-1 in multiple sclerosis clinical acute attack. J Neurovirol 2000;6; Suppl 2:S109-S114.
Wucherpfennig KW, Strominger JL: Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basis protein. Cell 1995;80:695–705.
Miller SD, Vanderlugt CL, Begolka WS, Pao W, Yauch RL, Neville KL, Katz-Levy Y, Carrizosa A, Kim BS: Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreading. Nat Med 1997;3: 1133–1136.
Allen I, Brankin B: Pathogenesis of multiple sclerosis—the immune diathesis and the role of viruses. J Neuropathol Exp Neurol 1993; 52:95–105.
Hafler DA, Weiner HL: In vivo labeling of blood T cells: rapid traffic into cerebrospinal fluid in multiple sclerosis. Ann Neurol 1987; 22:89–93.
Hickey WF: Migration of hematogenous cells through the blood-brain barrier and the initiation of CNS inflammation. Brain Pathol 1991;1:97–105.
Hickey WF, Hsu BL, Kimura H: T-lymphocyte entry into the central nervousystem. J Neurosci Res 1991;28:254–260.
Butcher EC, Picker LJ: Lymphocyte homing and homeostasis. Science 1996;272:60–66.
Shrikant P, Beneniste EN: The central nervous system as an immuno competent organ: role of glial cells in antigen presentation. J Immunol 1996;157:1819–1822
Freedman MS, Ruijs TC, Selin LK, Antel JP: Peripherlablood gamma-delta T cells, lyse fresh human brain-derived oligodenocytes. Ann Neurol 1991;30:794–800.
LeVine SM: The role of reactive oxygen species in the pathogenesis of multiple sclerosis. Med Hypotheses 1992;39:271–274.
Xiao BG, Linington C, Link H: Antibodies to myelin-oligodedrocyte glyco protein incerebrospinal fluid from patients with multiple sclerosis and controls. J Neuroimmunol 1991;31:91–96.
Selmaj KW, Raine CS: Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann Neurol 1988;23: 339–346.
Opdenakker G, Van Damme J: Cytokine-regulated proteases in autoimmune diseases. Immunol Today 1994;15:103–107.
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.
Zamvil SS, Steimann L: The T lymphocyte in experimental allergic encephalomylitis. Annu Rev Immunol 1990;8:579–621.
Paterson PY: Experimental allergicencephalomy elitis and autoimmune disease. Adv Immunol 1966; 5:131–208.
Bernard CC, Leydon J, Mackay IR: T cell necessity in the pathogenesis of experimental autoimmune encephalomy elitis in mice. Eur J Immunol 1976;6:655–660.
Martin R, McFarland HF, McFarlin DE: Immunological aspects of demyelinating diseases. Annu Rev Immunol 1992;10:153–187.
Ben Nun A, Wekerle H, Cohen IR: The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis. Eur J Immunol 1981;11:195–199.
Zamvil S, Nelson P, Trotter J, Mitchell D, Knobler R, Fritz R, Steinman L: T-cell clones specific for myelin basis protein induce chronic relapsing, paralysis and demyelination. Nature 1985;317:355–358.
Wucherpfennig KW, Sette A, Southwood S, Oseroff C, Matsui M, Strominger JL, Hafler DA: Structural requirements forbinding of an immunodominant myelin basis protein peptide to DR2 isotypes and for its recognition by human T cell clones. J Exp Med 1994;179:279–290.
Chou YK, Vainiene M, Whitham R, Bourdette D, Chou CH, Hashim G, Offner H, Vandenbark AA: Response of human T lymphocyte lines to myelin basis protein: association of dominant epitopes with HLA class II restriction molecules. J Neurosci Res 1989;23:207–216.
Martin R, Howell MD, Jaraquemada D, Flerlage M, Richert J, Brostoff S, Long EO, McFarlin DE, McFarland HF: A myelin basis protein peptide is recognized by cytotoxic T cells in the context of four HLA-DR types associated with multiple sclerosis. J Exp Med 1991;173:19–24.
Zhang J, Medaer R, Hashim GA, Chin Y, van den Berg-Loonen E Raus J: Myelin basis protein-specific T lymphocytes in multiple sclerosis and controls: precursor frequency, fine specificity, and cytotoxicity. Ann Neurol 1992;32:330–338.
Ota K, Matsui M, Milford EL, Mackin GA, Weiner HL, Hafler DA: T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature 1990;346:183–187.
Pette M, Fujita K, Wilkinson D, Altmann DM, Trowsdale J, Giegerich G, Hinkkanen A, Epplen JT, Kappos L, Wekerle H: Myelin autoreactivity in multiple sclerosis recognition of myelin basis protein in the context of HLA-DR2 products by T lymphocytes of multiple-sclerosis patients and healthy donors. Proc Natl Acad Sci USA 1990;87:7986–7972.
Zhang J, Markovic-Plese S, Lacet B, Raus J, Weiner HL, Hafler DA: Increased frequency of interleukin 2-responsive T cells specific for myelin basis protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. J Exp Med 1994;179:973–984.
Lee SJ, Wucherpfennig KW, Brod SA, Benjamin D, Weiner HL, Hafler DA: Common T-cell receptor V beta usage in oligoclonal T lymphocytes derived from cerebrospinal fluid and blood of patients with multiple sclerosis. Ann Neurol 1991;29:33–40.
Hafler DA, Duby AD, Lee SJ, Benjamin D, Seidman JG, Weiner HL: Oligoclonal T lymphocytes in the cerebrospinal fluid of patients with multiple sclerosis. J Exp Med 1988;167:1313–1322.
Oksenberg JR, Panzara MA, Begovich AB, Mitchell D, Erlich HA, Murray RS, Shimonkevitz R, Sherritt M, Rothbard J, Bernard CC: Selection for T-cell receptor V beta-D beta-J beta gene rearrangements with specificity for a myelin basic protein peptide in brain lesions of multiple sclerosis. Nature 1993;362:68–70.
Allegretta M, Albertini RJ, Howell MD, Smith LR, Martin R, McFarland HF, Sriram S, Brostoff S, Steinman L: Homologies between T cell receptor junctional sequences unique to multiple sclerosis and T cells mediating experimental allergic encephalomyelitis. J Clin Invest 1994;94:105–109.
Kondo T, Yamamura T, Inobe J, Ohashi T, Takahashi K, Tabira T: TCR reportoire to proteolipid protein (PLP) in multiple sclerosis (MS): homologies between PLP-specific T cells and MS-associated T cells in TCR junctional sequences. Int Immunol 1996;8:123–130.
Wucherpfennig KW, Newcombe J, Li H, Keddy C, Cuzner ML, Hafler DA: T cell receptor V alpha-V beta repertoire and cytokine gene expression in active multiple sclerosis lesions. J Exp Med 1992;175:993–1002.
Babbe H, Roers A, Waisman A, Lassmann H, Goebels N, Hohlfeld R, Friese M, Schroder R, Deckert M, Schmidt S, Ravid R, Rajewsky K: Clonal expansions of CD8(+)T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J Exp Med 2000;192:393–404.
Allegretta M, Nicklas JA, Sriram S, Albertini RJ: T cells responsive to myelin basis protein in patients with multiple sclerosis. Science 1990;247:718–721.
Trotter JL, Damico CA, Cross AH, Pelfrey CM, Karr RW, Fu XT, McFarland HF: HPRT mutant T-cell lines from multiple sclerosis patients recognize myelin proteolipid protein peptides. J Neuroimmunol 1997;75:95–103.
Sun J, Link H, Olsson T, Xiao BG, Andersson G, Ekre HP, Linington C, Diener P: T and B cell responses to myelin-oligodendrocyte glyco-protein in multiple sclerosis. J Immunol 1991;146:1490–1495.
Sun JB, Olsson T, Wang WZ, Xiao BG, Kostulas V, Fredrikson S, Ekre HP, Link H: Autoreactive T cell B cells responding to myelin proteolipid protein in multiple sclerosis and controls. Eur J Immunol 1991;21:1461–1468.
Lu CZ, Fredrikson S, Xiao BG, Link H: Interleukin-2 secreting cells in multiple sclerosis and controls. J Neurol Sci 1993;120:99–106.
Vandevyver C, Mertends N, van den Elsen P, Mecher R, Raus J, Zhang J: Clonal expansion of myelin basic protein-reactive T cells in patients with multiple sclerosis: restricted T cell receptor V gene rearrangements and CDR3 sequence. Eur J Immunol 1995;25:958–968.
Wucherpfennig KW, Zhang J, Witek C, Matsui M, Modabber Y, Ota K, Hafler DA: Clonal expansion and persistence of human T cells specific for an immunodominant myelin basic protein peptide. J Immunol 1994;152:5581–5592.
Hafler DA, Saadeh MG, Kuchroo VK, Milford E, Steinman L: TCR usage in human and experimental demyelinating disease. Immunol Today 1996;17:152–159.
Ando DG, Clayton J, Kono D, Urban JL, Sercarz EE: Encephali-togenic T cells in the B10.PL model of experimental allergic encephalomy elitis (EAE) are of the Th-1 lymphokine subtype. Cell Immunol 1989;124:132–143.
Vartanian T, Li Y, Zhao M, Stefansson K: Interferon-gamma-induced oligodendrocyte cell death: implications for the pathogenesis of multiple sclerosis. Mol Med 1995;1:732–743.
Hofman FM, Hinton DR, Johnson K, Merrill JE: Tumor necrosis factor identified in multiple sclerosis brain. J Exp Med 1989;170:607–612.
Hermans G, Stinissen P, Hauben L, Berg-Loonen E, Raus J, Zhang J: Cytokine profile of myelin basic protein-reactive T cells in multiple sclerosis and healthy individuals. Ann Neurol 1997;42:18–27.
Hemmer B, Vergelli M, Calabresi P, Huang T, McFarland HF, Martin R: Cytokine phenotype of human autoreactive T cell clones specific for the immunodominant myelin basic protein peptide (83–99). J Neurosci Res 1996;45:852–862.
Dubois-Dalcq M, Armstrong R: The cellular and molecular events of central nervous system remyelination. Bioessays 1990;12:569–576.
Williams KA and Deber CM: The structure and function of central nervous system myelin. Crit Rev Clin Lab Sci 1993;30:29–64.
Deibler GE, Burlin TV, Stone AL: Three isoforms of human myelin basic protein: purification and structure. J Neurosci Res 1995;41:819–827.
Chou FC, Chou CH, Shapira R, Kibler RF: Basis of microheterogeneity of myelin basic protein. J Biol Chem 1976;251:2671–2679.
Meinl E, Weber F, Drexler K, Morelle C, Ott M, Saruhan-Direskeneli G, Goebels N, Ertl B, Jechart G, Giegerich G: Myelin basic protein-specific T lymphocyte repertoire in multiple sclerosis. Complexity of the response and dominance of nested epitopes due to recruitment of multiple T cell clones. J Clin Invest 1993;92:2633–2643.
Olsson T, Sun J, Hillert J, Hojeberg B, Ekre HP, Andersson G, Olerup O, Link H: Increased numbers of T cells recognizing multiple myelin basic protein epitopes in multiple sclerosis. Eur J Immunol 1992;22:1083–1087.
Chou YK, Bourdette DN, Offner H, Whitham R, Wang RY, Hashim GA, Vandenbark AA: Frequency of T cells specific for myelin basic protein and myelin proteolipid protein in blood and cerebrospinal fluid in multiple sclerosis. J Neuroimmunol 1992;38:105–113.
Hellings N, Barée M, Verhoeven C, D'Hooghe MB, Medaer R, Bernard CC, Raus J, Stinissen P: T cell reactivity to multiple myelin antigens in multiple sclerosis patients and healthy controls. J Neurosci Res 2001;63:290–302.
Scholz C, Patton KT, Anderson DE, Freeman GJ, Hafler DA: Expansion of autoreactive T cells in multiplesc lerosis in dependent of exogenous B7 constimulation. J Immunol 1998;160:1532–1538.
Lovett-Racke AE, Trotter JL, Lauber J, Perrin PJ, June CH, Racke MK: Decreased dependence of myelin basic protein-reactive T cells on CD28-mediated costimulation in multiple sclerosis patients. A marker of activated/memory T cells. J Clin Invest 1998;101:725–730.
Sobel RA, Greer JM, Kuchroo VK: Minireview: autoimmune responses to myelin proteolipid protein. Neurochem Res 1994;19:915–921.
Martin R, McFarland HF: Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis. Crit Rev Clin Lab Sci 1995;32:121–182.
Pelfrey CM, Trotter JL, Tranquill LR, McFarland HF: Identification of a second T cell epitope of human proteolipid protein (residues 89–106) recognized by proliferative and cytolytic CD4+T cells from multiple sclerosis patients. J Neuroimmunol 1994;53:153–161.
Markovic-Plese S, Fukaura H, Zhang J, al Sabbagh A, Southwood S, Sette A, Kuchroo VK, Hafler DA: T cell recognition of immunodominant and cryptic proteolipid protein epitopes in humans. J Immunol 1995;155:982–992.
Pelfrey CM, Trotter JL, Tranquill LR, McFarland HF: Identification of a novel T cell epitope of human proteolipid protein (residues 40–60) recognized by proliferative and cytolytic CD4+T cells from multiple sclerosis patients. J Neuroimmunol 1993;46:33–42.
Pelfrey CM, Tranquill LR, Vogt AB, McFarland HF: T cell response to two immunodominant proteolipid protein (PLP) peptides in multiple sclerosis patients and healthy controls. Mult Scler 1996; 1:270–278.
Greer JM, Csurhes PA, Cameron KD, McCombe PA, Good MF, Pender MP: Increased immunore-activity to two overlapping peptides of myelin proteolipid protein in multiple sclerosis. Brain 1997;120(Pt8):1447–1460.
Correale J, McMillan M, McCarthy K, Le T, Weiner LP: Isolation and characterization of autoreactive propeolipid protein-peptide specific T-cell clones from multiple sclerosis patients. Neurology 1995;45:1370–1378.
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 an myelin/oligodendrocyte glycoprotein. Am J Pathol 1988;130:443–454.
Brunner C, Lassmann H, Waehneldt TV, Matthieu JM, Linington C: Differential ultrastructural localization of myelin basic protein, myelin/oligodendroglial glycoprotein, and 2′,3′-cyclic nucleotide 3′-phosphodiesterase in the CNS of adult rats. J Neurochem 1989;52:296–304.
Linington C, Engelhardt B, Kapocs G, Lassman H: Induction of persistently demyelinated lesions in the rat following the repeated adoptive transfer of encephalitogenic T cells and demyelimating antibody. J Neuroimmunol 1992;40:219–224.
Linington C, Berger T, Perry L, Weerth S, Hinze-Selch D, Zhang Y, Lu HC, Lassmann H, Wekerle H: T cells specific for the myelin oligodendrocyte glycoprotein mediate an umusual autoimmune inflammatory response in the central nervous system. Eur J Immunol 1993;23:1364–1372.
Genain CP, Hauser SL: Creation of a model for multiple sclerosis in Callithrix jacchus marmosets. J Mol Med 1997;75:187–197.
Lassmann H, Brunner C, Bradl M, Linington C: Experimental allergic encephalomyelitis: the balance between encephalitogenic T lymphocytes and demyelinating antibodies determines size and structure of demyelinated lesions. Acta Neuropathol (Berl) 1988;75:566–576.
Kerlero de Rosbo N, Honegger P, Lassmann H, Matthieu JM: Demyelination induced in aggregating brain cell cultures by a monoclonal antibody against myelin/oligodendrocyte glycoprotein. J Neurochem 1990;55:583–587.
Genain CP, Abel K, Belmar N, Villinger F, Rosenberg DP, Linington C, Raine CS, Hauser SL: Late complications of immune deviation therapy in a non human primate. Science 1996;274:2054–2057.
Kerlerode Rosbo N, Milo R, Lees MB, Burger D, Bernard CC, Ben Nun A: Reactivity to myelinantigens in multiple sclerosis. Peripheral blood lymphocytes respond predominantly to myelin oligodendrocyte glycoprotein. J Clin Invest 1993;92:2602–2608.
Kerlero de Rosbo N, Hoffman M, Mendel I, Yust I, Kaye J, Bakimer R, Flechter S, Abramsky O, Milo R, Karni A, Ben Num A: Predominance of the auto immune response to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis: reactivity to the extracellular domain of MOG is directed against three main regions. Eur J Immunol 1997;27:3059–3069.
Wallstrom E, Khademi M, Andersson M, Weissert R, Linington C, Olsson T: Increased reactivity to myelin oligoden drocyte glycoprotein peptides and epitope mapping in HLA DR2(15)+multiple sclerosis. Eur J Immunol 1998;28:3329–3335.
Lindert RB, Haase CG, Brehm U, Linington C, Wekerle H, Hohlfeld R: Multiple sclerosis: B- and T-cell responses to the extracellular domain of the myelin oligoden-drocyte glycoprotein. Brain 1999;122(Ptl1):2089–2100.
Johnson D, Hafler DA, Fallis RJ, Lees MB, Brady RO, Quarles RH, Weiner HL: Cell-mediated immunity to myelin-associated glycoprotein, proteolipid protein, and myelin basic protein in multiple sclerosis. J Neuroimmunol 1986; 13:99–108.
Yamamoto Y, Mizuno R, Nishimura T, Ogawa Y, Yoshikawa H, Fujimura H, Adachi E, Kishimoto T, Yanagihara T, Sakoda S: Cloning and expression of myelin-associated oligodendrocytic basic protein. A novel basic protein constituting the central nervous system myelin. J Biol Chem 1994;269:31,725–31,730.
Bronstein JM, Popper P, Micevych PE, Farber DB: Isolation and characterization of a novel oligodendrocyte-specific protein. Neurology 1996;47:772–778.
Maatta JA, Kaldman MS, Sakoda S, Salmi AA, Hinkkanen AE: Encephali to genicity of myelin-associated oligodendrocytic basic protein and 2′,3′-cyclic nucleotide 3′-phosphodieste rase for BALB/c and SJL mice. Immunology 1998; 95:383–388.
Zhong MC, Cohen L, Meshorer A, Kerlero de Rosbo N, Ben Nun A: T-cells specific for soluble recombinant oligoden drocyte-specific protein induce severe clinical experimental autoimmune encephalomyelitis in H-2(b) and H-2(s) mice. J Neuroimmunol 2000;105:39–45.
Weerth S, Berger T, Lassmann H, Linington C: Encephalitogenic and neuritogenic T cell responses to the myelin- associated glycoprotein (MAG) in the Lew is rat. J Neuroimmunol 1999;95:157–164.
Zhang Y, Burger D, Saruhan G, Jeannet M, Steck AJ: The T-lymphocyte response against myelin-associated glycoprotein and myelin basic protein in patients with multiple sclerosis. Neurology 1993;43:403–407.
Kaye JF, Kerlero de Rosbo N, Mendel I, Flechter S, Hoffman M, Yust I, Ben Num A: The central nervous system-specific myelino ligodendrocytic basic protein (MOBP) is encephalitogenic and a potential target antigen in multiple sclerosis (MS). J Neuroimmunol 2000;102: 189–198.
Berger T, Weerth S, Kojima K, Linington C, Wekerle H, Lassmann H: Epxerimental autoimmune encephalomyelitis: the antigen specificity of T lymphocytes determines the topography of lesions in the central and peripheral nervous system. Lab Invest 1997;76:355–364.
Schmidt S, Linington C, Zipp F, Sotgiu S, de Waal MR, Wekerle H, Hohlfeld R: Multiple sclerosis: comparison of the human T-cell response to S100 beta and myelin basic protein reveals parallels to rat experimental autoimmune panencephalitis. Brain 1997;120 (Pt8):1437–1445.
van Noort JM, van Sechel AC, van Stipdonk MJ, Bajramovic JJ: The small heat shock protein alpha B-crystallin as key autoantigen in multiplesclerosis. Prog Brain Res 1998;117:435–452.
Bajramovic JJ, Plomp AC, Goes A, Koevoets C, Newcomhe J, Cuzner, ML, van Noort JM: Presentation of alpha B-crystallin to T cells in active multiple sclerosis lesions: an early event following inflammatory dem yelination. J Immunol 2000;164:4359–4366.
Banki K, Colombo E, Sia F, Halladay D, Mattson DH, Tatum AH, Massa PT, Phillips PE, Perl A: Oligodendrocyte-specific, expression and aut oantigenicity of transaldolase in multiple sclerosis. J Exp Med 1994;180:1649–1663.
Rosener M, Muraro PA, Riethmuller A, Kalbus M, Sappler G, Thompson RJ, lichtenfels R, Sommer N, McFarland HF, Martin R: 2′,3′-cyclicnucleotide 3′-phosphodiesterase: a novel candidale autoantigen in demyelinating diseases. J Neuroimmunol 1997;75: 28–34.
Tuoby VK, Yu M, Yin L, Kawczak JA, Johnson JM, Mathisen PM, Weinstock-Guttman B, Kinkel RP: The epitope spreading cascade during progression of experimental autoimmune encephalomy elitis and multiple sclerosis. Immunol Rev 1998;164:93–100.
Lehmann PV, Sercarz EE, Forsthuber T, Dayan CM, Gammon G: Determinant spreading and the dynamics of theautoimmunet, T-cell repertoire. Immunol Today 1993; 14:203–208.
Salvetti M, Ristori G, D'Amato M, Buttinelli C, Falcone M, Fieschi, C, Wekerle H, Pozzilli C: Predomirnat and stable T cell responses to regions, of myelinbasic proteincan be detected in individual patients with multiple sclerosis. Eur J Immunol 1993;23:1232–1239.
Goebels N, Hofstetter H, Schmidt S, Brumer, C, Wekerle H, Hohlfeld R: Repertoire dynamics of autoreactive T cells in multiple sclerosis patients and healthy subjects: epitope spreading versus clonal persistence. Brain 2000;123Pt3: 508–518.
Hemmer B, Fleckenstein BT, Vergelli M, Jung G, McFarland H, Martin R, Wiesmuller KH: Identification of high potency microbial and self ligands for a human autoreactive class II-restricted T cell clone. J Exp Med 1997;185:1651–1659.
Hemmer B, Jacobsen M, Sommer N: Degeneracy in T-cell antigen recognition—implications for the pathogenesis of autoimmune diseases. J Neuroimmunol 2000;107: 148–153.
Zhang J, Vandevyver C, Stinissen P, Mertens N, Berg-Loonen E, Raus J: Activation and clonal expansion of human myelin basic protein-reactive T cells by bacterial superanti gens J Autoimmun 1995;8:615–632.
Segal BM, Dwyer BK, Shevach EM: An interleukin (IL)-10/IL-12 immunoregulatory circuitcontrols susceptibility to auto immune disease. J Exp Med 1998;187: 537–546.
Cohen IR: Thecognitiveparadigm and the immunological homumculus. Immunol Today 1992;13: 490–494.
Zipp F, Kerschensteiner M, Dornmair K, Malotka J, Schmidt S, Bender A, Giegerich G, de Waal MR, Wekerle H, Hohlfeld R: Diversity of the anti-T-cell receptor immune response and its implications for T-cell vaccination therapy of multiple sclerosis [see comments]. Brain 1998;121(Pt8): 1395–1407.
Broeren CP, Lucassen MA, van Stipdonk MJ, Van Der ZR, Boog CJ, Kusters JG, Van Eden W: CDRI T-cell receptor beta-chain peptide induces major histocompatibility complex class II-restricted T-T cell, interactions. Proc Natl Acad Sci USA 1994;91: 5997–6001.
Ben Nun A, Wekerle H, Cohen IR: Vaccination against autoimmuneencephalomy elitis with T-lymphocyte line cells reactive against myelin basic protein. Nature 1981;292:60–61.
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 1993;261: 1451–1454.
Offner H, Jacobs R, Beho BF, Jr., Vandenbark AA: Treatments targeting the T cell receptor (TCR): effects of TCR peptide-specific T cells on activation, migration, and encephalitogenicity of myelin basic protein-specific T cells. Springer Semin Immunopathol 1999;21:77–90.
Lider O, Reshef, T, Beraud E, Ben Nun A, Cohen IR: Anti-idiotypic network induced by T cell vaccination against experimental autoimmune encephalomyelitis. Science 1988;239:181–183.
Lohse AW, Mor F, Karin N, Cohen IR: Control of experimental autoimmune encephalomyelitis by T cells responding to activated T cells. Science 1989;244:820–822.
Zhang J, Vandevyver C, Stinissen P, Raus J: In vivo clonotypic regulation of human myelin basic protein-reactive T cells by T cell vaccination. J Immunol 1995;155: 5868–5877.
Hermans G, Denzer U, Lohse A, Raus J, Stinissen P: Cellular and Humoral Immune Responses Against Autoreactive T cells in Multiple Sclerosis Patients After T cell Vaccination. J Autoimmun 1999;13:233–246.
Stinissen P, Zhang J, Vandevyver C, Hermans G, Raus J: Gammadelta T cell responses to activated T cells in multiple sclerosis patients induced by T cell vaccination. J Neuroimmunol 1998;87: 94–104.
Saoudi A, Seddon B, Heath V, Fowell D, Mason D: The physiological role of regulatory T cells in the prevention of autoimmunity: the function of the thymus in the generation, of the regulatory T cell subset. Immunol Rev 1996;149: 195–216.
Seddon B, Mason D: Peripheral autoantigen induces regulatory T cells that preventautoimmunity. J Exp Med 1999;189:877–882.
Antel JP, Arnason BG, Medof ME: Suppressor cell function in multiplesclerosis: correlation with clinical disease activity. Ann Neurol 1979;5:338–342.
Zhang ZX, Yang L, Young KJ, DuTemple B, Zhang L: Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression. Nat Med 2000;6:782–789.
Schwartz M, Cohen IR: Autoimmunity can benefit selfmaintenance. Immunol Today 2000;21:265–268.
Cohen IR, Schwartz M: Autoimmune maintenance and neuroprotection of the central nervous system. J Neuroimmunol 1999; 100:111–114.
Moalem G, Leibowitz-Amit R, Yoles E, Mor F, Cohen IR, Schwartz M: Autoimmune T cells protec neurons from, secondary degeneration after central nervous system axotomy. Nat Med 1999; 5:49–55.
Hauben E, Nevo U, Yoles E, Moalem G, Agranov E, Mor F, Akselrod S, Neeman M, Cohen IR, Schwartz M: Autoimmune T cells as potential neuroprotective therapy for spinal cord injury. Lancet 2000;355:286–287.
Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, Fischer JS, Goodkin DE, Granger CV, Simon JH: A phase III trial of intramuscular recombinant interferon beta as treatment for exacerbatingremitting multiple sclerosis: design and conduct of study and baseline characteristics of patients. Multiple Sclerosis Collaborative Research Group (MSCRG). Mult Scler 1995;1:118–135.
The IFNB Multiple Sclerosis Study Group: In terferon beta-1 bis effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-bllind, placebocontrolled trial. Neurology 1993;43:655–661.
PRISMS (Prevention of Relapses and Disability by Interferon betala Subcutaneously in Multiple Scleorosis) Study Group: Randomised double-blind placebocontrolled study of interferon beta-1 a in relapsing/remitting multiple, sclerosis. Lancet 1998; 352:1498–1504.
Pette M, Pette DF, Muraro PA, Farnon E, Martin R, McFarland HF: Interferon-beta interfereswith the proliferation but not with the cytokinesecretion, of myelin basic protein-spectific, T-helper type I lymphocytes. Neurology 1997;49: 385–392.
Stuve O, Dooley NP, Uhm JH, Antel JP, Francis GS, Williams G, Yong VW: Interferon beta-1b decreases the migration of T lymphocytes in vitro: effects on matrix metalloproteinase-9. Ann Neurol 1996;40:853–863.
Rudick RA, Ransohoff RM, Lee JC, Peppler R, Yu M, Mathisen PM, Tuohy VK: In vivo effects of interferon beta-1a on immunosuppressivecy tokines in multiplesclerosis. Neurology 1998;50:1294–1300.
Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, Myers LW, Panitch HS, Rose JW, Schiffer RB: Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995;45: 1268–1276.
Racke MK, Martin R, McFarland H, Fritz RB: Copolymer-1-induced inhibition of anti gen-specific T cell activation: interference with antigen presentation. J Neuroimmunol 1992;37:75–84.
Teitelbaum D, Fridkis-Hareli M, Arnon R, Sela M: Copolymer 1 inhibits chronic relapsing experimental allergic encephalomyelitis induced by proteolipid protein (PLP) peptides in mice and interferes with PLP-specific T cell responses. J Neuroimmunol 1996; 64:209–217.
Mecher 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 1995;346:807–808.
Hermans G, Medaer R, Raus J, Stinissen P: Myelinreactive T cells after T cell vaccination in multiple sclerosis: cytokine profile and depletion by additional immunizations. J Neuroimmunol 2000; 102:79–84.
Stinissen P, Medaer R, Raus J: Preliminary data of an extended open label phase I study of T cell vaccination in Multiple Sclerosis. J. Neuroimmunol 1998;99.
Vandenbark AA, Hashim G, Offner H: Immunization with a synthetic T-cell receptor V-region peptide protects against, experimental autoimmune encephalomyelitis. Nature 1989;341:541–544.
Howell MD, Winters ST, Olee T, Powell HC, Carlo DJ, Brostoff SW: Vaccination against experimental allergic encephalomyelitis with T cell receptor peptides. Science 1989;246:668–670.
Kotzin BL, Karuturi S, Chou YK, Lafferty J, Forrester JM, Better M, Nedwin GE, Offner H, Vandenbark AA: Preferential T-cell receptor beta-chain variable gene use in myelin basic protein-reactive T-cell clones from patients with multiple sclerosis. Proc Natl Acad Sci USA 1991;88:9161–9165.
Gold DP, Smith RA, Golding AB, Morgan EE, Dafashy T, Nelson J, Smith L, Diveley J, Laxer JA, Richieri SP, Carlo DJ, Brostoff SW, Wilson DB: Results of a phase I clinical trial of a T-cell receptor vaccine in patients with multiple sclerosis. II. Comparativeanalysis of TCR utilization in CSF T-cell populations before and after vaccination witha TCRV-beta 6CDR2 peptide. J Neuroimmunol 1997;76: 29–38.
Wilson DB, Golding AB, Smith RA, Dafashy T, Nelson J, Smith L, Carlo DJ, Brostoff SW, Gold DP: Results of a phase I clinical trial of a T-cell receptor peptide vaccine in patients with multiple sclerosis. 1. Analysis of T-cell receptor utilization in CSF cell populations. J Neuroimmunol 1997;76:15–28.
Waisman A, Ruiz PJ, Hirschberg DL, Gelman A, Oksenberg JR, Brocke S, Mor F, Cohen IR, Steinman L: Suppressive vaccination with DNA encoding a variable region gene of the T-cell receptor prevents autoimmune encephalomy elitis and activates Th2 immunity [see comments]. Nat Med 1996;2:899–905.
Youssef S, Wildbaum G, Karin N: Prevention of experimental autoimmune encephalomyelitis by MIP-lalpha and MCP-1 naked DNA vaccines. J Autoimmun 1999; 13:21–29.
Youssef S, Wildbaum G, Maor G, Lanir N, Gour-Lavie A, Grabie, N, Karin N: Long-lasting protective immunity to experimental autoimmune encephalomyelitis following vaccination with naked DNA encoding C-C chemokines. J Immunol 1998;161:3870–3879.
Wildbaum G, Karin N: Augmentation of natural immunity to a pro-inflammatory, cytokine (TNF-alpha) by targeted DNA vaccine confers long-lasting resistance to experimental autoimmune encephalomyelitis. Gene Ther 1999;6: 1128–1138.
Elliott EA, Cofiell R, Wilkins JA, Raine CS, Matis LA, Mueller, JP: Immune to lerance mediated by recombinant proteolipid protein prevents experimental autoimmune encephalomyelitis. J Neuroimmunol 1997;79:1–11.
Ruiz PJ, Garren H, Ruiz IU, Hirschberg DL, Nguyen LV, Karpuj MV, Cooper MT, Mitchell DJ, Fathman CG, Steinman L: Suppressive immunization with DNA encoding a self-peptide prevents autoimmune disease: modulation of T cell costimulation. J Immunol 1999;162:3336–3341.
Lobell A, Weissert R, Storch MK, Svanholm C, de Graaf KL, Lassmann H, Andersson R, Olsson T, Wigzell H: Vaccination with DNA encoding an immunodominant myelin basic protein peptide targeted to Fc of immunoglobul in G suppresses experimental autoimmune encephalomyelitis. J Exp Med 1998;187:1543–1548.
Weissert R, Lobell A, de Graaf KL, Eltayeb SY, Andersson R, Olsson T, Wigzell H: Protective DNA vaccination against organ-specific autoimmunity is highly specific and discriminates between single aminoacidsubstitutions in the peptide autoantigen. Proc Natl Acad Sci USA 2000;97:1689–1694.
Tuohy VK, Mathisen PM: T cell design for therapy in autoimmune demyelinating disease. J Neuroimmunol 2000;107:226–232.
Mathisen PM, Yu M, Johnson JM, Drazba JA, Tuohy VK: Treatment of experimental autoimmune encephalomyelitis with genetically modified memory T cells. J Exp Med 1997;186:159–164.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hellings, N., Raus, J. & Stinissen, P. Insights into the immunopathogenesis of multiple sclerosis. Immunol Res 25, 27–51 (2002). https://doi.org/10.1385/IR:25:1:27
Issue Date:
DOI: https://doi.org/10.1385/IR:25:1:27