Abstract
Experimental autoimmune encephalomyelitis (EAE) is a model of the neuroimmune system responding to priming with central nervous system (CNS)-restricted antigens. It is an excellent model of post-vaccinal encephalitis and a useful model of many aspects of multiple sclerosis. EAE has been established in numerous species and is induced by priming with a large number of CNS-derived antigens. As a consequence, the pathogenesis, pathology and clinical signs vary significantly between experimental protocols. As I describe in this Timeline article, the reductionist approach taken in some lines of investigation of EAE resulted in a reliance on results obtained under a narrow range of conditions. Although such studies made important contributions to our molecular understanding of inflammation, T-cell activation, and MHC restriction, they did not advance as effectively our knowledge of the polyantigenic responses that usually occur in CNS immunopathology and autoimmunity.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
References
Gold, R., Linington, C. & Lassmann, H. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129, 1953–1971 (2006).
Sriram, S. & Steiner, I. Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis. Ann. Neurol. 58, 939–945 (2005).
Stuart, G. & Krikorian, K. S. The neuro-paralytic accidents of anti-rabies treatment. Ann. Trop. Med. 22, 327–377 (1928).
Balaguer, D. D. G. Un caso de rabia paralítica. Gaceta Médica Catalana 11, 45–57 (1888)(in Spanish).
Bassoe, P. & Grinker, R. R. Human rabies and rabies vaccine encephalomyelitis. Arch. Neurol. Psych. 4, 1138–1160 (1930).
Koritschoner, R. & Schweinburg, F. Klinisch und experimentelle beobachtungen über Lähmungen nach Wutschutzimpfung. Z. Immunitats Forsh 42, 217–283 (1925)(in German).
Stuart, G. & Krikorian, K. S. A fatal neuro-paralytic accident of antirabies treatment. Lancet 1, 1123–1125 (1930).
Rivers, T. M., Sprunt, D. H. & Berry, G. P. Observations on attempts to produce acute disseminated encephalomyelitis in monkeys. J. Exp. Med. 58, 39–53 (1933).
Rivers, T. M. & Schwentker, F. F. Encephalomyelitis accompanied by myelin destruction experimentally produced in monkeys. J. Exp. Med. 61, 689–702 (1935).
Schwentker, F. F. & Rivers, T. M. The antibody reseponse of rabbits to injection of emulsions and extracts of homologous brain. J. Exp. Med. 60, 559–574 (1934).
Freund, J. & McDermott, K. Sensitisation to horse serum by means of adjuvants. Proc. Soc. Exp. Biol. 49, 548–553 (1942).
Kabat, E. A., Wolf, A. & Bezer, A. E. The rapid production of acute disseminated encephalomyelitis in rhesus monkeys by injection of heterologous and homologous brain tissue with adjuvants. J. Exp. Med. 85, 117–130 (1947).
Morgan, I. M. Allergic encephalomyelitis in monkeys in response to injection of normal monkey nervous tissue. J. Exp. Med. 85, 131–140 (1947).
Freund, J., Stern, E. R. & Pisini, T. M. Isoallergic encephalomyelitis and radiculitis in guinea pigs after one injection of brain and mycobacteria in water-in-oil emulsion. J. Immunol. 57, 179–194 (1947).
Wolf, A., Kabat, E. A. & Bezer, A. E. The pathology of acute disseminated encephalomyelitis produced experimentally in the rhesus monkey and its resemblance to human demyelinating disease. J. Neuropath. Exp. Neurol. 6, 333–357 (1947).
Morrison, L. R. Disseminated encephalomyelitis experimentally produced by the use of homologous antigen. Arch. Neurol. Psychiat. 58, 391–416 (1947).
Lumsden, C. E. Experimental allergic encephalomyelitis II — on the nature of the encephalitogenic agent. Brain 27, 517–537 (1949).
Olitsky, P. K. & Yager, R. H. Experimental disseminated encephalomyelitis in white mice. J. Exp. Med. 90, 213–223 (1949).
Lipton, M. M. & Freund, J. Encephalomyelitis in the rat following intracutaneous injection of central nervous system tissue with adjuvant. Proc. Soc. Exp. Biol. NY 81, 260–261 (1952).
Tal, C., Laufer, A. & Behar, A. J. An experimental demyelinative disease in the Syrian hamster. Br. J. Exp. Pathol. 39, 158–164 (1958).
Thomas, L., Paterson, P. Y. & Smithwick, B. Acute disseminated encephalomyelitis following immunization with homologous brain extracts: I. Studies on the role of a circulating antibody in the production of the condition in dogs. J. Exp. Med. 92, 133–152 (1950).
Innes, J. R. M. Experimental allergic encephalitis: attempts to produce the disease in sheep and goats. J. Comp. Path. 61, 241–250 (1951).
Genain, C. P. et al. Antibody facilitation of multiple sclerosis-like lesions in a nonhuman primate. J. Clin. Invest. 96, 2966–2974 (1995).
Ranzenhofer, E. R., Lipton, M. M. & Steigman, A. J. Effect of homologous spinal cord in Freund's adjuvant on cockerel comb, testicular and body growth. Proc. Soc. Exp. Biol. NY 99, 280–282 (1958).
Adams, R. D. & Kubik, C. S. The morbid anatomy of the demyelinative diseases. Am. J. Med. 12, 510–546 (1952).
Ferraro, A. Pathology of demyelinating diseases as an allergic reaction of the brain. Arch. Neurol. Psych. 4, 443–483 (1944).
Steinman, L. & Zamvil, S. S. How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis. Ann. Neurol. 60, 12–21 (2006).
Teitelbaum, D., Meshorer, A., Hirshfeld, T., Arnon, R. & Sela, M. Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide. Eur. J. Immunol. 1, 242–248 (1971).
Lublin, F. D., Lavasa, M., Viti, C. & Knobler, R. L. Suppression of acute and relapsing experimental allergic encephalomyelitis with mitoxantrone. Clin. Immunol. Immunopathol. 45, 122–128 (1987).
Yednock, T. A. et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin. Nature 356, 63–66 (1992).
Langer-Gould, A., Atlas, S. W., Green, A. J., Bollen, A. W. & Pelletier, D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N. Engl. J. Med. 353, 375–381 (2005).
Bielekova, B. et al. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nature Med. 6, 1167–1175 (2000).
van Oosten, B. W. et al. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology 47, 1531–1534 (1996).
Waksman, B. H., Porter, H., Lees, M. D., Adams, R. D. & Folch, J. A study of the chemical nature of components of bovine white matter effective in producing allergic encephalomyelitis in the rabbit. J. Exp. Med. 100, 451–471 (1954).
Ferraro, A. & Roizin, L. Production of experimental encephalomyelitis with calcium acetate compound extracted from brain tissue. J. Neuropath. Exp. Neurol. 10, 394–407 (1951).
Laatsch, R. H., Kies, M. W., Gordon, S. & Alvord, E. C. Jr. The encephalomyelitic activity of myelin isolated by ultracentrifugation. J. Exp. Med. 115, 777–788 (1962).
Einstein, E. R., Robertson, D. M., DiCaprio, J. M. & Moore, W. The isolation from bovine spinal cord of a homogeneous protein with encephalitogenic activity. J. Neurochem. 9, 353–361 (1962).
Kibler, R. F. et al. Immune response of Lewis rats to peptide C1 (residues 68–88) of guinea pig and rat myelin basic proteins. J. Exp. Med. 146, 1323–1331 (1977).
Fritz, R. B., Chou, C. H. & McFarlin, D. E. Induction of experimental allergic encephalomyelitis in PL/J and (SJL/J × PL/J)F1 mice by myelin basic protein and its peptides: localization of a second encephalitogenic determinant. J. Immunol. 130, 191–194 (1983).
Fritz, R. B., Skeen, M. J., Chou, C. H., Garcia, M. & Egorov, I. K. Major histocompatibility complex-linked control of the murine immune response to myelin basic protein. J. Immunol. 134, 2328–2332 (1985).
Zamvil, S. S. et al. T-cell epitope of the autoantigen myelin basic protein that induces encephalomyelitis. Nature 324, 258–260 (1986).
Zamvil, S. S. et al. Predominant expression of a T cell receptor Vβ gene subfamily in autoimmune encephalomyelitis. J. Exp. Med. 167, 1586–1596 (1988).
Acha-Orbea, H. et al. Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell 54, 263–273 (1988).
Burns, F. R. et al. Both rat and mouse T cell receptors specific for the encephalitogenic determinant of myelin basic protein use similar V α and V β chain genes even though the major histocompatibility complex and encephalitogenic determinants being recognized are different. J. Exp. Med. 169, 27–39 (1989).
Heber-Katz, E. & Acha-Orbea, H. The V-region disease hypothesis: evidence from autoimmune encephalomyelitis. Immunol. Today 10, 164–169 (1989).
Sakai, K. et al. Involvement of distinct murine T-cell receptors in the autoimmune encephalitogenic response to nested epitopes of myelin basic protein. Proc. Natl Acad. Sci. USA 85, 8608–8612 (1988).
Behlke, M. A., Chou, H. S., Huppi, K. & Loh, D. Y. Murine T-cell receptor mutants with deletions of βchain variable region genes. Proc. Natl Acad. Sci. USA 83, 767–771 (1986).
Wraith, D. C., Smilek, D. E., Mitchell, D. J., Steinman, L. & McDevitt, H. O. Antigen recognition in autoimmune encephalomyelitis and the potential for peptide-mediated immunotherapy. Cell 59, 247–255 (1989).
Sakai, K. et al. Prevention of experimental encephalomyelitis with peptides that block interaction of T cells with major histocompatibility complex proteins. Proc. Natl Acad. Sci. USA 86, 9470–9474 (1989).
Kappos, L. et al. Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial. Nature Med. 6, 1176–1182 (2000).
Crowe, P. D., Qin, Y., Conlon, P. J. & Antel, J. P. NBI-5788, an altered MBP83–99 peptide, induces a T-helper 2-like immune response in multiple sclerosis patients. Ann. Neurol. 48, 758–765 (2000).
Lyons, G. A. Letter to shareholders, Neurocrine Biosciences Annual Report [online], (2003).
Sharma, S. D. et al. Antigen-specific therapy of experimental allergic encephalomyelitis by soluble class II major histocompatibility complex-peptide complexes. Proc. Natl Acad. Sci. USA 88, 11465–11469 (1991).
Spack, E. G. Antigen-specific therapies for the treatment of multiple sclerosis: a clinical trial update. Expert Opin. Investig. Drugs 6, 1715–1727 (1997).
Goodkin, D. E. et al. A phase I trial of solubilized DR2:MBP84–102 (AG284) in multiple sclerosis. Neurology 54, 1414–1420 (2000).
Warren, K. G., Catz, I., Ferenczi, L. Z. & Krantz, M. J. Intravenous synthetic peptide MBP8298 delayed disease progression in an HLA Class II-defined cohort of patients with progressive multiple sclerosis: results of a 24-month double-blind placebo-controlled clinical trial and 5 years of follow-up treatment. Eur. J. Neurol. 13, 887–895 (2006).
Bornstein, M. B. et al. A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N. Engl. J. Med. 317, 408–414 (1987).
Johnson, K. P. et al. 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 45, 1268–1276 (1995).
Sela, M., Mozes, E. Therapeutic vaccines in autoimmunity. Proc. Natl Acad. Sci. USA 101 (Suppl. 2), 14586–14592 (2004).
Racke, M. K., Martin, R., McFarland, H. & Fritz, R. B. Copolymer-1-induced inhibition of antigen-specific T cell activation: interference with antigen presentation. J. Neuroimmunol. 37, 75–84 (1992).
Kies, M. W. Panel discussion on species variability and multiple antigens in EAE: summary statement. Ann. NY Acad. Sci. 122, 242–244 (1965).
Steinman, L. The coming of age for antigen-specific therapy of multiple sclerosis. Eur. J. Neurol. 13, 793–794 (2006).
Kuerten S. et al. MBP–PLP fusion protein-induced EAE in C57BL/6 mice. J. Neuroimmunol. 177, 99–111 (2006).
Check, E. Nerve inflammation halts trial for Alzheimer's drug. Nature 415, 462 (2002).
Rogers, J., Strohmeyer, R., Kovelowski, C. J. & Li, R. Microglia and inflammatory mechanisms in the clearance of amyloid β peptide. Glia 40, 260–269 (2002).
Esch, T. R., Miskimins, R. & Heber-Katz, E. CAT induces encephalomyelitis in MBP-CAT transgenic mice expressing CAT in oligodendrocytes. Transgene 1, 11–18 (1993).
Hemachudha, T. et al. Myelin basic protein as an encephalitogen in encephalomyelitis and polyneuritis following rabies vaccination. N. Engl. J. Med. 316, 369–374 (1987).
Webster, L. T., & Clow, A. D. Propagation of rabies virus in tissue culture. J. Exp. Med. 66, 125–131 (1937).
Cao, Y. et al. Induction of experimental autoimmune encephalomyelitis in transgenic mice expressing ovalbumin in oligodendrocytes. Eur. J. Immunol. 36, 207–215 (2006).
Smallwood, L. & Baxter, A. G. On lawnmowers and lay-down miseres. Immunology 111, 252–253 (2004).
Levine, S. & Sowinski, R. Experimental allergic encephalomyelitis in inbred and outbred mice. J. Immunol. 110, 139–143 (1973).
Eylar, E. H., Caccam, J., Jackson, J. J., Westall, F. C. & Robinson, A. B. Experimental allergic encephalomyelitis: synthesis of disease-inducing site of the basic protein. Science 168, 1220–1223 (1970).
Shapira, R., Chou, F. C., McKneally, S., Urban, E. & Kibler, R. F. Biological activity and synthesis of an encephalitogenic determinant. Science 173, 736–738 (1971).
Chou, C. H., Chou, F. C., Kowalski, T. J., Shapira, R. & Kibler, R. F. The major site of guinea-pig myelin basic protein encephalitogenic in Lewis rats. J. Neurochem. 28, 115–119 (1977).
Pettinelli, C. B., Fritz, R. B., Chou, C. H. & McFarlin, D. E. Encephalitogenic activity of guinea pig myelin basic protein in the SJL mouse. J. Immunol. 129, 1209–1211 (1982).
Sakai, K. et al. Characterization of a major encephalitogenic T cell epitope in SJL/J mice with synthetic oligopeptides of myelin basic protein. J. Neuroimmunol. 19, 21–32 (1988).
Fritz, R. B., Chou, C. H. & McFarlin, D. E. Relapsing murine experimental allergic encephalomyelitis induced by myelin basic protein. J. Immunol. 130, 1024–1026 (1983).
Lennon, V. A., Wilks, A. V. & Carnegie, P. R. Immunologic properties of the main encephalitogenic peptide from the basic protein of human myelin. J. Immunol. 105, 1223–1230 (1970).
Carnegie, P. R. Amino acid sequence of the encephalitogenic basic protein from human myelin. Biochem. J. 123, 57–67 (1971).
Fujinami, R. S. & Oldstone, M. B. Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science 230, 1043–1045 (1985).
Goldstein, N. P., Kolb, L. C., Mason, H. L., Sayre, G. P. & Karlson, A. G. Relationship of homologous brain proteolipid to allergic encephalomyelitis in guinea pigs. Neurology 3, 609–614 (1953).
Furlan, R. et al. Vaccination with amyloid-β peptide induces autoimmune encephalomyelitis in C57/BL6 mice. Brain 126, 285–291 (2003).
Pellkofer, H. et al. Modelling paraneoplastic CNS disease: T-cells specific for the onconeuronal antigen PNMA1 mediate autoimmune encephalomyelitis in the rat. Brain 127, 1822–1830 (2004).
Kojima, K. et al. Experimental autoimmune panencephalitis and uveoretinitis transferred to the Lewis rat by T lymphocytes specific for the S100 beta molecule, a calcium binding protein of astroglia. J. Exp. Med. 180, 817–829 (1994).
Linington, C. et al. T cells specific for the myelin oligodendrocyte glycoprotein mediate an unusual autoimmune inflammatory response in the central nervous system. Eur. J. Immunol. 23, 1364–1372 (1993).
Amor, S. et al. Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encephalomyelitis in SJL and Biozzi AB/H mice. J. Immunol. 153, 4349–4356 (1994).
Kaye, J. F. et al. The central nervous system-specific myelin oligodendrocytic basic protein (MOBP) is encephalitogenic and a potential target antigen in multiple sclerosis (MS). J. Neuroimmunol. 102, 189–198 (2000).
Zamvil, S. et al. T-cell clones specific for myelin basic protein induce chronic relapsing paralysis and demyelination. Nature 317, 355–358 (1985).
Kabat, E. A., Wolf, A., Bezer, A. E. Rapid production of acute disseminated encephalomyelitis in rhesus monkeys by injection of brain tissue with adjuvants. Science 104, 362–363 (1946).
Lipton, M. M. & Freund, J. The transfer of experimental allergic encephalomyelitis in the rat by means of parabiosis. J. Immunol. 71, 380–384 (1953).
Paterson, P. Y. Transfer of allergic encephalomyelitis in rats by means of lymph node cells. J. Exp. Med. 111, 119–136 (1960).
Waksman, B. H., Arbouys, S. & Arnason, B. G. The use of specific “lymphocyte” antisera to inhibit hypersensitive reactions of the “delayed” type. J. Exp. Med. 114, 997–1022 (1961).
Ben-Nun, A., Wekerle, H. & Cohen, I. R. The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis. Eur. J. Immunol. 11, 195–199 (1981).
Schluesener, H. J., Sobel, R. A., Linington, C. & Weiner, H. L. A monoclonal antibody against a myelin oligodendrocyte glycoprotein induces relapses and demyelination in central nervous system autoimmune disease. J. Immunol. 139, 4016–4021 (1987).
Fierz, W. et al. Synergism in the pathogenesis of EAE induced by an MBP-specific T-cell line and monoclonal antibodies to galactocerebroside or a myelin oligodendroglial glycoprotein. Ann. NY Acad. Sci. 540, 360–363 (1988).
Jiang, H., Zhang, S. I. & Pernis, B. Role of CD8+ T cells in murine experimental allergic encephalomyelitis. Science 256, 1213–1215 (1992).
Koh, D. R. et al. Less mortality but more relapses in experimental allergic encephalomyelitis in CD8−/− mice. Science 256, 1210–1213 (1992).
Genain, C. P. et al. In healthy primates, circulating autoreactive T cells mediate autoimmune disease. J. Clin. Invest. 94, 1339–1345 (1994).
Elliott, J. I., Douek, D. C. & Altmann, D. M. Mice lacking αβ+ T cells are resistant to the induction of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 70, 139–144 (1996).
Nataf, S., Carroll, S. L., Wetsel, R. A., Szalai, A. J. & Barnum, S. R. Attenuation of experimental autoimmune demyelination in complement-deficient mice. J. Immunol. 165, 5867–5873 (2000).
Acknowledgements
I thank H. Koerner for helpful discussion, M. Jordan for critical review, H. McDevitt for his comments on an early draft of the manuscript and D. Godfrey for his suggestions. This work was funded by the National Health and Medical Research Council of Australia.
Author information
Authors and Affiliations
Related links
Rights and permissions
About this article
Cite this article
Baxter, A. The origin and application of experimental autoimmune encephalomyelitis. Nat Rev Immunol 7, 904–912 (2007). https://doi.org/10.1038/nri2190
Issue Date:
DOI: https://doi.org/10.1038/nri2190
This article is cited by
-
Thinking outside the box: non-canonical targets in multiple sclerosis
Nature Reviews Drug Discovery (2022)
-
The Lung Microbiome: A Potential Target in Regulating Autoimmune Inflammation of the Brain
Neuroscience Bulletin (2022)
-
Metabolic regulation and function of T helper cells in neuroinflammation
Seminars in Immunopathology (2022)
-
CD8+ T cells specific for cryptic apoptosis-associated epitopes exacerbate experimental autoimmune encephalomyelitis
Cell Death & Disease (2021)
-
Passive transfer of allergic encephalomyelitis in rats: a tool for drug mechanism studies and detecting late-acting immunosuppressants
Inflammopharmacology (2021)