The Experimental Autoimmune Encephalomyelitis (EAE) Model: A Gateway to Successful Translation of Multiple Sclerosis Therapies
,
Abstract
Multiple sclerosis (MS) is a neuroinflammatory disorder that is characterized by demyelination, neurodegeneration, and immune dysregulation. The experimental autoimmune encephalomyelitis (EAE) model has helped to elucidate MS pathophysiology and test therapies. This review synthesizes current literature on the development, applications, and translational significance of EAE models in MS research. It discusses various EAE induction protocols, including active and passive immunization, and highlights advancements such as humanized mice and induced pluripotent stem cell (iPSC)-derived neuronal models. The review evaluates the role of EAE in identifying immune pathways, validating therapeutic agents like glatiramer acetate and natalizumab, and exploring precision medicine approaches through biomarker discovery. The EAE model replicated the key features of MS, including inflammation, demyelination, and axonal loss, facilitating therapy development. However, its predictive validity faces limitations, such as heterogeneity in disease induction, underrepresentation of chronic progression, and species differences. Innovations, such as humanized mouse models and iPSC-derived neurons, show promise in addressing these challenges. EAE research has advanced biomarker-based personalized treatments, although further validation is required. Despite its widespread use, EAE has limitations in terms of variability in disease induction, incomplete MS feature replication, species-specific responses, and clinical translation. Addressing these limitations remains crucial for therapeutic development, focusing on analyzing model limitations and strategies to overcome translational barriers. This review offers immunologists a comprehensive overview of EAE's contributions of EAE to MS research and its potential to inform the development of novel therapeutic approaches for this debilitating disease.
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2. Papiri G, D’Andreamatteo G, Cacchiò G, Alia S, Silvestrini M, Paci C, et al. Multiple Sclerosis: Inflammatory and Neuroglial Aspects. Curr Issues Mol Biol. 2023;45(2):1443-70.
3. McGinley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and treatment of multiple sclerosis: a review. Jama. 2021; 325(8):765-79.
4. Ford H. Clinical presentation and diagnosis of multiple sclerosis. Clin Med (Lond). 2020;20(4):380-3.
5. Goodin DS, Khankhanian P, Gourraud P-A, Vince N. The nature of genetic and environmental susceptibility to multiple sclerosis. PLoS One. 2021;16(3):e0246157.
6. Talanki Manjunatha R, Habib S, Sangaraju SL, Yepez D, Grandes XA. Multiple Sclerosis: Therapeutic Strategies on the Horizon. Cureus. 2022;14(5):e24895.
7. Yang JH, Rempe T, Whitmire N, Dunn-Pirio A, Graves JS. Therapeutic Advances in Multiple Sclerosis. Front Neurol. 2022;13.
8. Gadhave DG, Sugandhi VV, Jha SK, Nangare SN, Gupta G, Singh SK, et al. Neurodegenerative disorders: Mechanisms of degeneration and therapeutic approaches with their clinical relevance. Ageing Res Rev. 2024; 99:102357.
9. 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. 2006;129(8):1953-71.
10. Khoy K, Mariotte D, Defer G, Petit G, Toutirais O, Le Mauff B. Natalizumab in multiple sclerosis treatment: from biological effects to immune monitoring. Frontiers in immunology. 2020;11:549842.
11. Voskuhl RR, MacKenzie-Graham A. Chronic experimental autoimmune encephalomyelitis is an excellent model to study neuroaxonal degeneration in multiple sclerosis. Front Mol Neurosci. 2022;15.
12. Hamilton AM, Forkert ND, Yang R, Wu Y, Rogers JA, Yong VW, et al. Central nervous system targeted autoimmunity causes regional atrophy: a 9.4T MRI study of the EAE mouse model of Multiple Sclerosis. Sci Rep. 2019;9(1):8488.
13. Kiani AK, Pheby D, Henehan G, Brown R, Sieving P, Sykora P, et al. Ethical considerations regarding animal experimentation. J Prev Med Hyg. 2022;63(2 Suppl 3):E255-e66.
14. Robinson AP, Harp CT, Noronha A, Miller SD. The experimental autoimmune encephalomyelitis (EAE) model of MS: utility for understanding disease pathophysiology and treatment. Handb Clin Neurol. 2014;122:173-89.
15. Lazarević M, Stanisavljević S, Nikolovski N, Dimitrijević M, Miljković Đ. Complete Freund's adjuvant as a confounding factor in multiple sclerosis research. Front Immunol. 2024;15:1353865.
16. Constantinescu CS, Farooqi N, O'Brien K, Gran B. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol. 2011;164(4):1079-106.
17. J. van der Star B, YS Vogel D, Kipp M, Puentes F, Baker D, Amor S. In vitro and in vivo models of multiple sclerosis. CNS Neurol Disord Drug Targets. 2012;11(5):570-88.
18. Yan Y, Zhao Q, Huang Y, Yang JY, Zou J, Ao C, et al. Experimental Autoimmune Encephalomyelitis Animal Models Induced by Different Myelin Antigens Exhibit Differential Pharmacologic Responses to Anti-Inflammatory Drugs. J Immunol Sci. 2022;6(1):18-24.
19. Kroenke MA, Carlson TJ, Andjelkovic AV, Segal BM. 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. 2008;205(7):1535-41.
18. Steinman L, Patarca R, Haseltine W. Experimental encephalomyelitis at age 90, still relevant and elucidating how viruses trigger disease. J Exp Med. 2023;220(2).
19. Nichols JM, Kaplan BLF. Age-Dependent Effects of Transgenic 2D2 Mice Used to Induce Passive Experimental Autoimmune Encephalomyelitis in C57BL/6 Mice. Neuroimmunomodulation. 2023;30(1):291-301.
20. deLuca LES, Pikor NB, O’Leary J, Galicia-Rosas G, Ward LA, Defreitas D, et al. Substrain differences reveal novel disease-modifying gene candidates that alter the clinical course of a rodent model of multiple sclerosis. J Immunology. 2010;184(6):3174-85.
21. Steinman L, Patarca R, Haseltine W. Experimental encephalomyelitis at age 90, still relevant and elucidating how viruses trigger disease. J Exp Med. 2023;220(2).
22. Nichols JM, Kaplan BLF. Age-Dependent Effects of Transgenic 2D2 Mice Used to Induce Passive Experimental Autoimmune Encephalomyelitis in C57BL/6 Mice. Neuroimmunomodulation. 2023;30(1):291-301.
23. Fazazi MR, Doss PMIA, Pereira R, Fudge N, Regmi A, Joly-Beauparlant C, et al. Myelin-reactive B cells exacerbate CD4+ T cell-driven CNS autoimmunity in an IL-23-dependent manner. Nat Comm. 2024;15(1):5404.
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| Keywords | ||
| Demyelination Experimental autoimmune encephalomyelitis Immunopathogenesis Inflammation Multiple sclerosis Precision medicine Translational research | ||
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How to Cite
1.
Aliyu M, Saboor-Yaraghi A, Sahraian MA, Noorbakhsh F. The Experimental Autoimmune Encephalomyelitis (EAE) Model: A Gateway to Successful Translation of Multiple Sclerosis Therapies. Iran J Allergy Asthma Immunol. 2025;:1-18.
