Journal of Neuroimmune Pharmacology

, Volume 5, Issue 2, pp 220–230 | Cite as

Experimental Autoimmune Encephalomyelitis in the Common Marmoset, a Bridge Between Rodent EAE and Multiple Sclerosis for Immunotherapy Development

  • Yolanda S. Kap
  • Jon D. Laman
  • Bert A. ‘t Hart
Invited Review


The attrition rate of new drugs for central nervous system diseases including multiple sclerosis (MS) is very high. A widely recognized bottleneck in the selection of promising central nervous system drug candidates from the development pipeline is the lack of sufficiently predictive animal models. Here, we review how the experimental autoimmune encephalomyelitis (EAE) model in the Neotropical primate “common marmoset” can help to bridge the gap between rodent EAE models and MS. The EAE model in the marmoset closely resembles MS in the clinical as well as pathological presentation and can be used for fundamental research into immunopathogenic mechanisms and for therapy development. We discuss recent insights arising from this model, both on novel therapeutics and immunopathogenesis.


non-human primate CD40 IL-23 IL-12 B-cells NK-CTL 


Conflicts of interest

The authors of this review do not report conflict of interest.


  1. Barnett MH, Parratt JD, Cho ES, Prineas JW (2009) Immunoglobulins and complement in postmortem multiple sclerosis tissue. Ann Neurol 65:32–46CrossRefPubMedGoogle Scholar
  2. Bielekova B, Richert N, Howard T, Blevins G, Markovic-Plese S, McCartin J, Frank JA, Wurfel J, Ohayon J, Waldmann TA, McFarland HF, Martin R (2004) Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta. Proc Natl Acad Sci USA 101:8705–8708CrossRefPubMedGoogle Scholar
  3. Blezer EL, Bauer J, Brok HP, Nicolay K, ‘t Hart BA (2007) Quantitative MRI-pathology correlations of brain white matter lesions developing in a non-human primate model of multiple sclerosis. NMR Biomed 20:90–103CrossRefPubMedGoogle Scholar
  4. Bo L, Geurts JJ, Mork SJ, van der Valk P (2006) Grey matter pathology in multiple sclerosis. Acta Neurol Scand Suppl 183:48–50CrossRefPubMedGoogle Scholar
  5. Boon L, Brok HP, Bauer J, Ortiz-Buijsse A, Schellekens MM, Ramdien-Murli S, Blezer E, van Meurs M, Ceuppens J, de Boer M, ‘t Hart BA, Laman JD (2001) Prevention of experimental autoimmune encephalomyelitis in the common marmoset (Callithrix jacchus) using a chimeric antagonist monoclonal antibody against human CD40 is associated with altered B cell responses. J Immunol 167:2942–2949PubMedGoogle Scholar
  6. Brok HP, Uccelli A, Kerlero De Rosbo N, Bontrop RE, Roccatagliata L, de Groot NG, Capello E, Laman JD, Nicolay K, Mancardi GL, Ben-Nun A, Hart BA (2000) Myelin/oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis in common marmosets: the encephalitogenic T cell epitope pMOG24–36 is presented by a monomorphic MHC class II molecule. J Immunol 165:1093–1101PubMedGoogle Scholar
  7. Brok HP, van Meurs M, Blezer E, Schantz A, Peritt D, Treacy G, Laman JD, Bauer J, ‘t Hart BA (2002) Prevention of experimental autoimmune encephalomyelitis in common marmosets using an anti-IL-12p40 monoclonal antibody. J Immunol 169:6554–6563PubMedGoogle Scholar
  8. Brok HP, Boven L, van Meurs M, Kerlero de Rosbo N, Celebi-Paul L, Kap YS, Jagessar A, Hintzen RQ, Keir G, Bajramovic J, Ben-Nun A, Bauer J, Laman JD, Amor S, ‘t Hart BA (2007) The human CMV-UL86 peptide 981–1003 shares a crossreactive T-cell epitope with the encephalitogenic MOG peptide 34–56, but lacks the capacity to induce EAE in rhesus monkeys. J Neuroimmunol 182:135–152CrossRefPubMedGoogle Scholar
  9. Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, Norris K, Tandon PK (2008) Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 359:1786–1801CrossRefPubMedGoogle Scholar
  10. Compston A, Coles A (2008) Multiple sclerosis. Lancet 372:1502–1517CrossRefPubMedGoogle Scholar
  11. Cross AH, Lyons JA, San M, Keeling RM, Ku G, Racke MK (1999) T cells are the main cell type expressing B7–1 and B7–2 in the central nervous system during acute, relapsing and chronic experimental autoimmune encephalomyelitis. Eur J Immunol 29:3140–3147CrossRefPubMedGoogle Scholar
  12. Friese MA, Montalban X, Willcox N, Bell JI, Martin R, Fugger L (2006) The value of animal models for drug development in multiple sclerosis. Brain 129:1940–1952CrossRefPubMedGoogle Scholar
  13. Gausas J, Paterson PY, Day ED, Dal Canto MC (1982) Intact B-cell activity is essential for complete expression of experimental allergic encephalomyelitis in Lewis rats. Cell Immunol 72:360–366CrossRefPubMedGoogle Scholar
  14. Genain CP, Hauser SL (2001) Experimental allergic encephalomyelitis in the New World monkey Callithrix jacchus. Immunol Rev 183:159–172CrossRefPubMedGoogle Scholar
  15. Genain CP, Nguyen MH, Letvin NL, Pearl R, Davis RL, Adelman M, Lees MB, Linington C, Hauser SL (1995) Antibody facilitation of multiple sclerosis-like lesions in a nonhuman primate. J Clin Invest 96:2966–2974CrossRefPubMedGoogle Scholar
  16. Gerritse K, Laman JD, Noelle RJ, Aruffo A, Ledbetter JA, Boersma WJ, Claassen E (1996) CD40-CD40 ligand interactions in experimental allergic encephalomyelitis and multiple sclerosis. Proc Natl Acad Sci USA 93:2499–2504CrossRefPubMedGoogle Scholar
  17. Gold R, Linington C, Lassmann H (2006) Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129:1953–1971CrossRefPubMedGoogle Scholar
  18. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A, Panzara M, Sarkar N, Agarwal S, Langer-Gould A, Smith CH (2008) B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 358:676–688CrossRefPubMedGoogle Scholar
  19. Hedegaard CJ, Krakauer M, Bendtzen K, Lund H, Sellebjerg F, Nielsen CH (2008) T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis. Immunology 125:161–169CrossRefPubMedGoogle Scholar
  20. Hjelmstrom P, Juedes AE, Fjell J, Ruddle NH (1998) B-cell-deficient mice develop experimental allergic encephalomyelitis with demyelination after myelin oligodendrocyte glycoprotein sensitization. J Immunol 161:4480–4483PubMedGoogle Scholar
  21. Jagessar SA, Smith PA, Blezer E, Delarasse C, Pham-Dinh D, Laman JD, Bauer J, Amor S, ‘t Hart B (2008) Autoimmunity against myelin oligodendrocyte glycoprotein is dispensable for the initiation although essential for the progression of chronic encephalomyelitis in common marmosets. J Neuropathol Exp Neurol 67:326–340CrossRefPubMedGoogle Scholar
  22. Kap YS, Smith P, Jagessar SA, Remarque E, Blezer E, Strijkers GJ, Laman JD, Hintzen RQ, Bauer J, Brok HP, ‘t Hart BA (2008) Fast progression of recombinant human myelin/oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis in marmosets is associated with the activation of MOG34–56-specific cytotoxic T cells. J Immunol 180:1326–1337PubMedGoogle Scholar
  23. Kappos L, Antel J, Comi G, Montalban X, O’Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW (2006) Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 355:1124–1140CrossRefPubMedGoogle Scholar
  24. Kasran A, Boon L, Wortel CH, Hogezand RA, Schreiber S, Goldin E, Boer M, Geboes K, Rutgeerts P, Ceuppens JL (2005) Safety and tolerability of antagonist anti-human CD40 Mab ch5D12 in patients with moderate to severe Crohn’s disease. Aliment Pharmacol Ther 22:111–122CrossRefPubMedGoogle Scholar
  25. Kleinschnitz C, Meuth SG, Wiendl H (2008) The trials and errors in MS therapy. Int MS J 15:79–90PubMedGoogle Scholar
  26. Kola I, Landis J (2004) Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3:711–715CrossRefPubMedGoogle Scholar
  27. Krishnamoorthy G, Holz A, Wekerle H (2007) Experimental models of spontaneous autoimmune disease in the central nervous system. J Mol Med 85:1161–1173CrossRefPubMedGoogle Scholar
  28. Kroenke MA, Segal BM (2007) Th17 and Th1 responses directed against the immunizing epitope, as opposed to secondary epitopes, dominate the autoimmune repertoire during relapses of experimental autoimmune encephalomyelitis. J Neurosci Res 85:1685–1693CrossRefPubMedGoogle Scholar
  29. Laman JD, Claassen E, Noelle RJ (1996) Functions of CD40 and its ligand, gp39 (CD40L). Crit Rev Immunol 16:59–108PubMedGoogle Scholar
  30. Laman JD, ‘t Hart BA, Brok H, Meurs M, Schellekens MM, Kasran A, Boon L, Bauer J, Boer M, Ceuppens J (2002) Protection of marmoset monkeys against EAE by treatment with a murine antibody blocking CD40 (mu5D12). Eur J Immunol 32:2218–2228CrossRefPubMedGoogle Scholar
  31. Lassmann H, Ransohoff RM (2004) The CD4-Th1 model for multiple sclerosis: a critical [correction of crucial] re-appraisal. Trends Immunol 25:132–137CrossRefPubMedGoogle Scholar
  32. Longbrake EE, Racke MK (2009) Why did IL-12/IL-23 antibody therapy fail in multiple sclerosis? Expert Rev Neurother 9:319–321CrossRefPubMedGoogle Scholar
  33. Lopez-Diego RS, Weiner HL (2008) Novel therapeutic strategies for multiple sclerosis—a multifaceted adversary. Nat Rev Drug Discov 7:909–925CrossRefPubMedGoogle Scholar
  34. Lunemann JD, Munz C (2009) EBV in MS: guilty by association? Trends Immunol 30:243–248CrossRefPubMedGoogle Scholar
  35. Mancardi G, ‘t Hart B, Roccatagliata L, Brok H, Giunti D, Bontrop R, Massacesi L, Capello E, Uccelli A (2001) Demyelination and axonal damage in a non-human primate model of multiple sclerosis. J Neurol Sci 184:41–49CrossRefPubMedGoogle Scholar
  36. Massacesi L, Genain CP, Lee-Parritz D, Letvin NL, Canfield D, Hauser SL (1995) Active and passively induced experimental autoimmune encephalomyelitis in common marmosets: a new model for multiple sclerosis. Ann Neurol 37:519–530CrossRefPubMedGoogle Scholar
  37. McFarland HI, Lobito AA, Johnson MM, Nyswaner JT, Frank JA, Palardy GR, Tresser N, Genain CP, Mueller JP, Matis LA, Lenardo MJ (1999) Determinant spreading associated with demyelination in a nonhuman primate model of multiple sclerosis. J Immunol 162:2384–2390PubMedGoogle Scholar
  38. Merkler D, Boscke R, Schmelting B, Czeh B, Fuchs E, Bruck W, Stadelmann C (2006a) Differential macrophage/microglia activation in neocortical EAE lesions in the marmoset monkey. Brain Pathol 16:117–123CrossRefPubMedGoogle Scholar
  39. Merkler D, Schmelting B, Czeh B, Fuchs E, Stadelmann C, Bruck W (2006b) Myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in the common marmoset reflects the immunopathology of pattern II multiple sclerosis lesions. Mult Scler 12:369–374CrossRefPubMedGoogle Scholar
  40. Mestas J, Hughes CC (2004) Of mice and not men: differences between mouse and human immunology. J Immunol 172:2731–2738PubMedGoogle Scholar
  41. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354:899–910CrossRefPubMedGoogle Scholar
  42. Pomeroy IM, Matthews PM, Frank JA, Jordan EK, Esiri MM (2005) Demyelinated neocortical lesions in marmoset autoimmune encephalomyelitis mimic those in multiple sclerosis. Brain 128:2713–2721CrossRefPubMedGoogle Scholar
  43. Pomeroy IM, Jordan EK, Frank JA, Matthews PM, Esiri MM (2008) Diffuse cortical atrophy in a marmoset model of multiple sclerosis. Neurosci Lett 437:121–124CrossRefPubMedGoogle Scholar
  44. Ransohoff RM (2006) EAE: pitfalls outweigh virtues of screening potential treatments for multiple sclerosis. Trends Immunol 27:167–168CrossRefPubMedGoogle Scholar
  45. Reboldi A, Coisne C, Baumjohann D, Benvenuto F, Bottinelli D, Lira S, Uccelli A, Lanzavecchia A, Engelhardt B, Sallusto F (2009) C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol 10:514–523CrossRefPubMedGoogle Scholar
  46. Robinson WH, Fontoura P, Lee BJ, de Vegvar HE, Tom J, Pedotti R, DiGennaro CD, Mitchell DJ, Fong D, Ho PP, Ruiz PJ, Maverakis E, Stevens DB, Bernard CC, Martin R, Kuchroo VK, van Noort JM, Genain CP, Amor S, Olsson T, Utz PJ, Garren H, Steinman L (2003) Protein microarrays guide tolerizing DNA vaccine treatment of autoimmune encephalomyelitis. Nat Biotechnol 21:1033–1039CrossRefPubMedGoogle Scholar
  47. Schafer S, Kolkhof P (2008) Failure is an option: learning from unsuccessful proof-of-concept trials. Drug Discov Today 13:913–916CrossRefPubMedGoogle Scholar
  48. Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH (2008) Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol 7:796–804CrossRefPubMedGoogle Scholar
  49. Sekiguchi Y, Ichikawa M, Takamoto M, Ota H, Koh CS, Muramatsu M, Honjo T, Agematsu K (2009) Antibodies to myelin oligodendrocyte glycoprotein are not involved in the severity of chronic non-remitting experimental autoimmune encephalomyelitis. Immunol Lett 122:145–149CrossRefPubMedGoogle Scholar
  50. Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, Cinque P, Andreoni L, Trivedi P, Salvetti M, Faggioni A, Aloisi F (2007) Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med 204:2899–2912CrossRefPubMedGoogle Scholar
  51. Sriram S, Steiner I (2005) Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis. Ann Neurol 58:939–945CrossRefPubMedGoogle Scholar
  52. Steinman L, Zamvil SS (2006) How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis. Ann Neurol 60:12–21CrossRefPubMedGoogle Scholar
  53. ‘t Hart BA, Amor S (2003) The use of animal models to investigate the pathogenesis of neuroinflammatory disorders of the central nervous system. Curr Opin Neurol 16:375–383CrossRefPubMedGoogle Scholar
  54. ‘t Hart BA, Massacesi L (2009) Clinical, pathological, and immunologic aspects of the multiple sclerosis model in common marmosets (Callithrix jacchus). J Neuropathol Exp Neurol 68:341–355CrossRefPubMedGoogle Scholar
  55. ‘t Hart BA, Bauer J, Muller HJ, Melchers B, Nicolay K, Brok H, Bontrop RE, Lassmann H, Massacesi L (1998) Histopathological characterization of magnetic resonance imaging-detectable brain white matter lesions in a primate model of multiple sclerosis: a correlative study in the experimental autoimmune encephalomyelitis model in common marmosets (Callithrix jacchus). Am J Pathol 153:649–663Google Scholar
  56. ‘t Hart BA, Laman JD, Bauer J, Blezer E, van Kooyk Y, Hintzen RQ (2004) Modelling of multiple sclerosis: lessons learned in a non-human primate. Lancet Neurol 3:588–597CrossRefPubMedGoogle Scholar
  57. ‘t Hart BA, Bauer J, Brok HP, Amor S (2005a) Non-human primate models of experimental autoimmune encephalomyelitis: variations on a theme. J Neuroimmunol 168:1–12CrossRefPubMedGoogle Scholar
  58. ‘t Hart BA, Blezer EL, Brok HP, Boon L, de Boer M, Bauer J, Laman JD (2005b) Treatment with chimeric anti-human CD40 antibody suppresses MRI-detectable inflammation and enlargement of pre-existing brain lesions in common marmosets affected by MOG-induced EAE. J Neuroimmunol 163:31–39CrossRefPubMedGoogle Scholar
  59. ‘t Hart BA, Smith P, Amor S, Strijkers GJ, Blezer EL (2006) MRI-guided immunotherapy development for multiple sclerosis in a primate. Drug Discov Today 11:58–66CrossRefPubMedGoogle Scholar
  60. ‘t Hart BA, Jagessar A, Kap YS, Brok HPM (2007) Preclinical models of multiple sclerosis in nonhuman primates. Expert Rev Clin Immunol 3:749–761CrossRefPubMedGoogle Scholar
  61. ‘t Hart BA, Hintzen RQ, Laman JD (2008) Preclinical assessment of therapeutic antibodies against human CD40 and human interleukin-12/23p40 in a nonhuman primate model of multiple sclerosis. Neurodegener Dis 5:38–52CrossRefPubMedGoogle Scholar
  62. van Boxel-Dezaire AH, Hoff SC, van Oosten BW, Verweij CL, Drager AM, Ader HJ, van Houwelingen JC, Barkhof F, Polman CH, Nagelkerken L (1999) Decreased interleukin-10 and increased interleukin-12p40 mRNA are associated with disease activity and characterize different disease stages in multiple sclerosis. Ann Neurol 45:695–703CrossRefPubMedGoogle Scholar
  63. Van der Aa A, Hellings N, Bernard CC, Raus J, Stinissen P (2003) Functional properties of myelin oligodendrocyte glycoprotein-reactive T cells in multiple sclerosis patients and controls. J Neuroimmunol 137:164–176CrossRefPubMedGoogle Scholar
  64. van Kooten C, Banchereau J (1997) Functional role of CD40 and its ligand. Int Arch Allergy Immunol 113:393–399CrossRefPubMedGoogle Scholar
  65. Vollmer T, Key L, Durkalski V, Tyor W, Corboy J, Markovic-Plese S, Preiningerova J, Rizzo M, Singh I (2004) Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 363:1607–1608CrossRefPubMedGoogle Scholar
  66. von Herrath MG, Nepom GT (2005) Lost in translation: barriers to implementing clinical immunotherapeutics for autoimmunity. J Exp Med 202:1159–1162CrossRefGoogle Scholar
  67. Willis SN, Stadelmann C, Rodig SJ, Caron T, Gattenloehner S, Mallozzi SS, Roughan JE, Almendinger SE, Blewett MM, Bruck W, Hafler DA, O’Connor KC (2009) Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain (in press)Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Yolanda S. Kap
    • 1
    • 2
    • 3
  • Jon D. Laman
    • 2
    • 3
  • Bert A. ‘t Hart
    • 1
    • 2
    • 3
  1. 1.Department of ImmunobiologyBiomedical Primate Research CentreRijswijkThe Netherlands
  2. 2.Department of ImmunologyErasmus Medical Centre RotterdamRotterdamThe Netherlands
  3. 3.MS Centre ErasMSRotterdamThe Netherlands

Personalised recommendations