Abstract
Experimental autoimmune encephalomyelitis (EAE) and Theiler’s Murine Encephalitis Virus-Induced Demyelinating Disease (TMEV-IDD) are two clinically relevant murine models of multiple sclerosis (MS). Like MS, both are characterized by mononuclear cell infiltration into the CNS and demyelination. EAE is induced by either the administration of myelin protein or peptide in adjuvant or by the adoptive transfer of encephalitogenic T cell blasts into naïve recipients. The relative merits of each of these protocols are compared. Depending on the type of question being asked, different mouse strains and peptides are used. Different disease courses are observed with different strains and different peptides in active EAE. These variations are also addressed. Additionally, issues relevant to clinical grading of EAE in mice are discussed. In addition to EAE induction, useful references for other disease indicators such as DTH, in vitro proliferation, and immunohistochemistry are provided. TMEV-IDD is a useful model for understanding the possible viral etiology of MS. This section provides detailed information on the preparation of viral stocks and subsequent intracerebral infection of mice. Additionally, virus plaque assay and clinical disease assessment are discussed. Recently, recombinant TMEV strains have been created for the study of molecular mimicry which incorporate various 30 amino acid myelin epitopes within the leader region of TMEV.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Brown A, McFarlin DE, Raine CS (1982) Chronologic neuropathology of relapsing experimental allergic encephalomyelitis in the mouse. Lab Invest 46:171–185
Karcher D, Lassmann H, Lowenthal A, Kitz K, Wisniewski HM (1982) Antibodies-restricted heterogeneity in serum and cerebrospinal fluid of chronic relapsing experimental allergic encephalomyelitis. J Neuroimmunol 2:93–106
Lassmann H (1983) Chronic relapsing experimental allergic encephalomyelitis: its value as an experimental model for multiple sclerosis. J Neurol 229:207–220
Tan LJ, Kennedy MK, Miller SD (1992) Regulation of the effector stages of experimental autoimmune encephalomyelitis via neuroantigen-specific tolerance induction. II. Fine specificity of effector T cell inhibition. J Immunol 148:2748–2755
Eng LF, Ghirnikar RS, Lee YL (1996) Inflammation in EAE: role of chemokine/cytokine expression by resident and infiltrating cells. Neurochem Res 21:511–525
Miller SD, Karpus WJ (1994) The immunopathogenesis and regulation of T-cell mediated demyelinating diseases. Immunol Today 15:356–361
Williams KC, Ulvestad E, Hickey WF (1994) Immunology of multiple sclerosis [Review) [300 refs). Clin Neurosci 2:229–245
Lublin FD (1985) Relapsing experimental allergic encephalomyelitis. An autoimmune model of multiple sclerosis. Springer Semin Immunopathol 8:197–208
Arnason BG (1983) Relevance of experimental allergic encephalomyelitis to multiple sclerosis. Neurol Clin 1:765–782
Traugott U, Stone SH, Raine CS (1979) Chronic relapsing experimental allergic encephalomyelitis. Correlation of circulating lymphocyte fluctuations with disease activity in suppressed and unsuppressed animals. J Neurol Sci 41:17–29
Traugott U, McFarlin DE, Raine CS (1986) Immunopathology of the lesion in chronic relapsing experimental autoimmune encephalomyelitis in the mouse. Cell Immunol 99:395–410
Boyle EA, McGeer PL (1990) Cellular immune response in multiple sclerosis plaques. Am J Pathol 137:575–584
McCallum K, Esiri MM, Tourtellotte WW, Booss J (1987) T cell subsets in multiple sclerosis. Gradients at plaque borders and differences in nonplaque regions. Brain 110:1297–1308
Renno T, Krakowski M, Piccirillo C, Lin JY, Owens T (1995) TNF-alpha expression by resident microglia and infiltrating leukocytes in the central nervous system of mice with experimental allergic encephalomyelitis. Regulation by Th1 cytokines. J Immunol 154:944–953
Swanborg RH (1995) Experimental autoimmune encephalomyelitis in rodents as a model for human demyelinating disease [see comments) [Review) [99 refs). Clin Immunol Immnopathol 77:4–13
Epstein LG, Prineas JW, Raine CS (1983) Attachment of myelin to coated pits on macrophages in experimental allergic encephalomyelitis. J Neurol Sci 61:341–348
Smith ME (1993) Phagocytosis of myelin by microglia in vitro. J Neurosci Res 35:480–487
Sommer MA, Forno LS, Smith ME (1992) EAE cerebrospinal fluid augments in vitro phagocytosis and metabolism of CNS myelin by macrophages. J Neurosci Res 32:384–394
Colover J (1988) Immunological and cytological studies of autoimmune demyelination and multiple sclerosis. Brain Behav Immun 2:341–345
Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N (1992) Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin. Nature 356:63–66
Kawakami N, Lassmann S, Li Z, Odoardi F, Ritter T, Ziemssen T, Klinkert WE, Ellwart JW, Bradl M, Krivacic K, Lassmann H, Ransohoff RM, Volk HD, Wekerle H, Linington C, Flugel A (2004) The activation status of neuroantigen-specific T cells in the target organ determines the clinical outcome of autoimmune encephalomyelitis. J Exp Med 199:185–197
Lees JR, Golumbek PT, Sim J, Dorsey D, Russell JH (2008) Regional CNS responses to IFN-gamma determine lesion localization patterns during EAE pathogenesis. J Exp Med 205:2633–2642
Kroenke MA, Carlson TJ, Andjelkovic AV, Segal BM (2008) IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J Exp Med 205:1535–1541
Cross AH, Raine CS (1990) Serial adoptive transfer of murine experimental allergic encephalomyelitis: successful transfer is dependent on active disease in the donor. J Neuroimmunol 28:27–37
Raine CS, Mokhtarian F, McFarlin DE (1984) Adoptively transferred chronic relapsing experimental autoimmune encephalomyelitis in the mouse. Neuropathologic analysis. Lab Invest 51:534–546
Zamvil S, Nelson P, Trotter J, Mitchell D, Knobler R, Fritz R, Steinman L (1985) T-cell clones specific for myelin basic protein induce chronic relapsing paralysis and demyelination. Nature 317:355–358
Kim C, Tse HY (1993) Adoptive transfer of murine experimental autoimmune encephalomyelitis in SJL.Thy-1 congenic mouse strains. J Neuroimmunol 46:129–136
Howard LM, Miller SD (2001) Autoimmune intervention by CD154 blockade prevents T cell retention and effector function in the target organ. J Immunol 166:1547–1553
Dal Canto M, Lipton HL, Miller SD, Melvold RW, Capen CC, Jones TC, Migaki G (1986) Theiler’s murine encephalomyelitis virus (TMEV) infection in mice as a model for MS. In: Capen CC, Jones TC, Migaki G (eds.). In Registry of comparative pathology, handbook of animal models of human disease, VIIth fascicle. AFIP, Washington, D.C.
Miller SD (1995) Pathogenesis of Theiler’s murine encephalomyelitis virus-induced demyelinating disease – a model of multiple sclerosis. ACLAD Newslett 16:4–6
Pevear DC, Borkowski J, Luo M, Lipton H (1988) Sequence comparison of a highly virulent and a less virulent strain of Theiler’s virus. Amino acid differences on a three- dimensional model identify the location of possible immunogenic sites. Ann NY Acad Sci 540:652–653
Pevear DC, Calenoff M, Rozhon E, Lipton HL (1987) Analysis of the complete nucleotide sequence of the picornavirus Theiler’s murine encephalomyelitis virus indicates that it is closely related to cardioviruses. J Virol 61:1507–1516
Lipton HL (1980) Persistent Theiler’s murine encephalomyelitis virus infection in mice depends on plaque size. J Gen Virol 46:169–177
Clatch RJ, Miller SD, Metzner R, Dal Canto MC, Lipton HL (1990) Monocytes/macrophages isolated from the mouse central nervous system contain infectious Theiler’s murine encephalomyelitis virus (TMEV). Virology 176:244–254
Peterson JD, Karpus WJ, Clatch RJ, Miller SD (1993) Split tolerance of Th1 and Th2 cells in tolerance to Theiler’s murine encephalomyelitis virus. Eur J Immunol 23:46–55
Katz-Levy Y, Neville KL, Padilla J, Rahbe SM, Begolka WS, Girvin AM, Olson JK, Vanderlugt CL, Miller SD (2000) Temporal development of autoreactive Th1 responses and endogenous antigen presentation of self myelin epitopes by CNS-resident APCs in Theiler’s virus-infected mice. J Immunol 165:5304–5314
Miller SD, Vanderlugt CL, Begolka WS, Pao W, Yauch RL, Neville KL, Katz-Levy Y, Carrizosa A, Kim BS (1997) Persistent infection with Theiler’s virus leads to CNS autoimmunity via epitope spreading. Nat Med 3:1133–1136
Prineas J (1975) Pathology of the early lesion in multiple sclerosis. Hum Pathol 6:531–554
Dal Canto MC, Lipton HL (1975) Primary demyelination in Theiler’s virus infection. An ultrastructural study. Lab Invest 33:626–637
Nathanson N, Miller A (1978) Epidemiology of multiple sclerosis: critique of evidence for a viral etiology. Am J Epidemiol 107:451–461
Kurtzke JF, Raine CS, McFarlin HF, Tourtellotte WW (1997) The epidemiology of multiple sclerosis. In: Multiple sclerosis: clinical and pathogenetic basis. Chapman and Hall, London, pp 91–139
Lipton HL (1975) Theiler’s virus infection in mice: an unusual biphasic disease process leading to demyelination. Infect Immun 11:1147–1155
Walker MR, Mannie MD (2002) Acquisition of functional MHC class II/peptide complexes by T cells during thymic development and CNS-directed pathogenesis. Cell Immunol 218:13–25
Segal BM, Shevach EM (1996) IL-12 unmasks latent autoimmune disease in resistant mice. J Exp Med 184:771–775
Axtell RC, de Jong BA, Boniface K, van der Voort LF, Bhat R, De Sarno P, Naves R, Han M, Zhong F, Castellanos JG, Mair R, Christakos A, Kolkowitz I, Katz L, Killestein J, Polman CH, de Waal Malefyt R, Steinman L, Raman C (2010) T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med 16:406–412
Stromnes IM, Cerretti LM, Liggitt D, Harris RA, Goverman JM (2008) Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells. Nat Med 14:337–342
Dal Canto MC, Melvold RW, Kim BS, Miller SD (1995) Two models of multiple sclerosis: experimental allergic encephalomyelitis (EAE) and Theiler’s murine encephalomyelitis virus (TMEV) infection – a pathological and immunological comparison. Microsc Res Tech 32:215–229
Olson JK, Croxford JL, Calenoff M, Dal Canto MC, Miller SD (2001) A virus-induced molecular mimicry model of multiple sclerosis. J Clin Invest 108:311–318
Clatch RJ, Lipton HL, Miller SD (1986) Characterization of Theiler’s murine encephalomyelitis virus (TMEV)-specific delayed-type hypersensitivity responses in TMEV-induced demyelinating disease: correlation with clinical signs. J Immunol 136:920–927
Gerety SJ, Clatch RJ, Lipton HL, Goswami RG, Rundell MK, Miller SD (1991) Class II-restricted T cell responses in Theiler’s murine encephalomyelitis virus-induced demyelinating disease. IV. Identification of an immunodominant T cell determinant on the N-terminal end of the VP2 capsid protein in susceptible SJL/J mice. J Immunol 146:2401–2408
Jin YH, Kang B, Kim BS (2009) Theiler’s virus infection induces a predominant pathogenic CD4+ T cell response to RNA polymerase in susceptible SJL/J mice. J Virol 83:10981–10992
Miller SD, Olson JK, Croxford JL (2001) Multiple pathways to induction of virus-induced autoimmune demyelination: lessons from Theiler’s virus infection. J Autoimmun 16:219–227
Duong TT, Finkelman FD, Singh B, Strejan GH (1994) Effect of anti-interferon-gamma monoclonal antibody treatment on the development of experimental allergic encephalomyelitis in resistant mouse strains. J Neuroimmunol 53:101–107
Zamvil SS, Steinman L (1990) The T lymphocyte in experimental allergic encephalomyelitis. Annu Rev Immunol 8:579–621
McRae BL, Vanderlugt CL, Dal Canto MC, Miller SD (1995) Functional evidence for epitope spreading in the relapsing pathology of experimental autoimmune encephalomyelitis. J Exp Med 182:75–85
Begolka WS, Vanderlugt CL, Rahbe SM, Miller SD (1998) Differential expression of inflammatory cytokines parallels progression of central nervous system pathology in two clinically distinct models of multiple sclerosis. J Immunol 161:4437–4446
Sakai K, Zamvil SS, Mitchell DJ, Lim M, Rothbard JB, Steinman L (1988) Characterization of a major encephalitogenic T cell epitope in SJL/J mice with synthetic oligopeptides of myelin basic protein. J Neuroimmunol 19:21–32
Tuohy VK, Thomas DM (1993) A third encephalitogenic determinant of myelin proteolipid protein (PLP) for SJL/J mice. J Immunol 150:194A
Greer JM, Kuchroo VK, Sobel RA, Lees MB (1992) Identification and characterization of a second encephalitogenic determinant of myelin proteolipid protein (residues 178–191) for SJL mice. J Immunol 149:783–788
Greer JM, Sobel RA, Sette A, Southwood S, Lees MB, Kuchroo VK (1996) Immunogenic and encephalitogenic epitope clusters of myelin proteolipid protein. J Immunol 156:371–379
Amor S, Groome N, Linington C, Morris MM, Dornmair K, Gardinier MV, Matthieu JM, Baker D (1994) 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
Zamvil SS, Mitchell DJ, Moore AC, Kitamura K, Steinman L, Rothbard JB (1986) T-cell epitope of the autoantigen myelin basic protein that induces encephalomyelitis. Nature 324:258–260
Whitham RH, Jones RE, Hashim GA, Hoy CM, Wang RY, Vandenbark AA, Offner H (1991) Location of a new encephalitogenic epitope (residues 43 to 64) in proteolipid protein that induces relapsing experimental autoimmune encephalomyelitis in PL/J and (SJL × PL)F1 mice. J Immunol 147:3803–3808
Mendel I, Kerlero DR, Ben-Nun A (1995) A myelin oligodendrocyte glycoprotein peptide induces typical chronic experimental autoimmune encephalomyelitis in H-2b mice: fine specificity and T cell receptor V beta expression of encephalitogenic T cells. Eur J Immunol 25:1951–1959
Tompkins SM, Padilla J, Dal Canto MC, Ting JP, Van Kaer L, Miller SD (2002) De novo central nervous system processing of myelin antigen is required for the initiation of experimental autoimmune encephalomyelitis. J Immunol 168:4173–4183
Tuohy VK, Lu ZJ, Sobel RA, Laursen RA, Lees MB (1988) A synthetic peptide from myelin proteolipid protein induces experimental allergic encephalomyelitis. J Immunol 141:1126–1130
Endoh M, Kunishita T, Nihei J, Nishizawa M, Tabira T (1990) Susceptibility to proteolipid apoprotein and its encephalitogenic determinants in mice. Int Arch Allergy Appl Immunol 92:433–438
Muller DM, Pender MP, Greer JM (2000) A neuropathological analysis of experimental autoimmune encephalomyelitis with predominant brain stem and cerebellar involvement and differences between active and passive induction. Acta Neuropathol (Berl) 100:174–182
Maron R, Hancock WW, Slavin A, Hattori M, Kuchroo V, Weiner HL (1999) Genetic susceptibility or resistance to autoimmune encephalomyelitis in MHC congenic mice is associated with differential production of pro- and anti-inflammatory cytokines. Int Immunol 11:1573–1580
Slavin A, Ewing C, Liu J, Ichikawa M, Slavin J, Bernard CC (1998) Induction of a multiple sclerosis-like disease in mice with an immunodominant epitope of myelin oligodendrocyte glycoprotein. Autoimmunity 28:109–120
McRae BL, Kennedy MK, Tan LJ, Dal Canto MC, Miller SD (1992) Induction of active and adoptive chronic-relapsing experimental autoimmune encephalomyelitis (EAE) using an encephalitogenic epitope of proteolipid protein. J Neuroimmunol 38:229–240
Miller SD, Tan LJ, Kennedy MK, Dal Canto MC (1991) Specific immunoregulation of the induction and effector stages of relapsing EAE via neuroantigen-specific tolerance induction. Ann NY Acad Sci 636:79–94
Tuohy VK, Thomas DM (1995) Sequence 104-117 of myelin proteolipid protein is a cryptic encephalitogenic T cell determinant for SJL/J mice. J Neuroimmunol 56:161–170
Skundric DS, Kim C, Tse HY, Raine CS (1993) Homing of T cells to the central nervous system throughout the course of relapsing experimental autoimmune encephalomyelitis in Thy-1 congenic mice. J Neuroimmunol 46:113–121
Fritz RB, Zhao ML (1994) Encephalitogenicity of myelin basic protein exon-2 peptide in mice. J Neuroimmunol 51:1–6
Segal BM, Raine CS, McFarlin DE, Voskuhl RR, McFarland HF (1994) Experimental allergic encephalomyelitis induced by the peptide encoded by exon 2 of the MBP gene, a peptide implicated in remyelination. J Neuroimmunol 51:7–19
Pettinelli CB, McFarlin DE (1981) Adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice after in vitro activation of lymph node cells by myelin basic protein: requirement for Lyt 1+ 2 – T lymphocytes. J Immunol 127:1420–1423
Pettinelli CB, Fritz RB, Chou CHJ, McFarlin DE (1982) Encephalitogenic activity of guinea pig myelin basic protein in the SJL mouse. J Immunol 129:1209–1211
Shaw MK, Kim C, Hao HW, Chen F, Tse HY (1996) Induction of myelin basic protein-specific experimental autoimmune encephalomyelitis in C57BL/6 mice: mapping of T cell epitopes and T cell receptor V beta gene segment usage. J Neurosci Res 45:690–699
Clark RB, Grunnet M, Lingenheld EG (1997) Adoptively transferred EAE in mice bearing the lpr mutation. Clin Immunol Immnopathol 85:315–319
Mendel I, Shevach EM (2002) Differentiated Th1 autoreactive effector cells can induce experimental autoimmune encephalomyelitis in the absence of IL-12 and CD40/CD40L interactions. J Neuroimmunol 122:65–73
Segal BM, Dwyer BK, Shevach EM (1998) An Interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J Exp Med 187:537–546
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media New York
About this protocol
Cite this protocol
McCarthy, D.P., Richards, M.H., Miller, S.D. (2012). Mouse Models of Multiple Sclerosis: Experimental Autoimmune Encephalomyelitis and Theiler’s Virus-Induced Demyelinating Disease. In: Perl, A. (eds) Autoimmunity. Methods in Molecular Biology, vol 900. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-720-4_19
Download citation
DOI: https://doi.org/10.1007/978-1-60761-720-4_19
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-60761-719-8
Online ISBN: 978-1-60761-720-4
eBook Packages: Springer Protocols