In 1935, Rivers and Schwenkter reported that an inflammatory demyelinating CNS disorder could be induced in monkeys with repeated injections of CNS tissue. The pathology of this disease had similarities to MS and its potential as a model for MS was immediately recognized (136). This model is known as experimental allergic (later autoimmune) encephalomyelitis (EAE). Although EAE does not identically replicate every aspect of MS, its similarities lend plausibility to the theory of auto-immunity as the cause of MS. Many components of the immune response in EAE have been corroborated in human MS, as will be discussed below. In the 1980s, it was demonstrated that this disease, induced readily in certain strains and species with whole spinal cord homogenate, could be induced with specific components of myelin (137). Later, Pettinelli and McFarlin (138) showed that CD4+ T-cells reactive with MBP could transfer the disease, confirming the primary role of T-cells. Moreover, following a single transfer of MBP-reactive T-cells, recipient mice displayed a relapsing-remitting phenotype (139). Zamvil et al. (140) demonstrated that the disease could be fully transferred by a single T-cell clone bearing a single T-cell receptor directed against an epitope of MBP. These studies unequivocally demonstrated that myelin-specific T-cells initiated this model for MS.
Similarities and differences exist between EAE and MS. EAE does not occur spontaneously in normal animals, but must be induced by evoking a strong antimyelin cellular immune response. A notable exception is that when mice were created that were transgenic for a T-cell receptor (TCR) directed against MBP, on rare occasions EAE did occur spontaneously, but only when the mice were maintained in "dirty" housing conditions (141) or lacked any other functioning T-cells (142). Mice expressing a transgenic TCR in most of their T-cells are not representative of humans with MS.
The course of EAE can be remarkably similar to certain clinical subtypes of MS. Some strains of mice, the SJL and PL strains in particular, have relapses and remissions, often remitting to neurologically normal between attacks. In mice with relapsing EAE, the frequency of relapses declines with time, as it does in MS (personal observations). For the SJL strain, female mice are more susceptible than males to EAE induction, another similarity to MS (143). Pregnant mice are less susceptible to EAE than nonpregnant littermates, reminiscent of the well-documented decline in MS activity during pregnancy (144). Susceptibility and clinical course of EAE are genetically determined, and linked to the MHC II, similar to MS (145). Some mouse strains, such as the C57BL/6, display a chronic EAE course without full recovery, but they seldom can be demonstrated to progress over time in the manner of primary progressive MS or secondary progressive MS.
Histologically, EAE is similar to MS with inflammation comprising T-cells and macrophages, as well as smaller numbers of B-cells and plasma cells. Lesions are centered on blood vessels, much like MS. Murine EAE involves the spinal cord and optic nerves to a greater extent than the cerebrum, more similar in localization to neuromyelitis optica than to typical MS. Often an early wave of polymorphonuclear cells (PMNs) is seen during the initial hours of an EAE relapse (146). This is dissimilar to MS, as it is distinctly rare to observe PMNs in MS lesions. In a marmoset model of EAE with chronic relapsing disease, vesiculated myelin was observed in lesions, similar to some acute MS lesions. In both the marmoset AE model and in human lesions, myelin specific antibodies bound to areas of active demyelination were observed (147).
Most therapies that are effective in MS are effective in EAE as well. In fact, two therapies used in RRMS, glatiramer acetate and nataluzimab (under FDA review), were developed based upon data from the EAE model (148,149). Though not initially developed using the EAE model, beta-interferons are effective at inhibiting EAE (150).
Despite limitations of the EAE model, its study has revealed a great deal about the development of an immune response within the CNS, and has led to new therapeutic agents for MS. The many similarities between EAE and MS support the case that MS is autoimmune in etiology. However, dissimilarities exist also. EAE is not MS, and some therapies that have clearly benefited certain models of EAE have not done so in humans. Inhibition of TNF-alpha is a case in point (151).
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