Modelling MS: Chronic-Relapsing EAE in the NOD/Lt Mouse Strain

Abstract

Modelling complex disorders presents considerable challenges, and multiple sclerosis (MS) is no exception to this rule. The aetiology of MS is unknown, and its pathophysiology is poorly understood. Moreover, the last two decades have witnessed a dramatic revision of the long-held view of MS as an inflammatory demyelinating white matter disease. Instead, it is now regarded as a global central nervous system (CNS) disorder with a neurodegenerative component. Currently, there is no animal model recapitulating MS immunopathogenesis. Available models are based on autoimmune-mediated demyelination, denoted experimental autoimmune encephalomyelitis (EAE) or virally or chemically induced demyelination. Of these, the EAE model has been the most commonly used. It has been extensively improved since its first description and now exists as a number of variants, including genetically modified and humanized versions. Nonetheless, EAE is a distinct disease, and each variant models only certain facets of MS. Whilst the search for more refined MS models must continue, it is important to further explore where mechanisms underlying EAE provide proof-of-principle for those driving MS pathogenesis. EAE variants generated with the myelin component myelin oligodendrocyte glycoprotein (MOG) have emerged as the preferred ones, because in this particular variant disease is associated with both T- and B-cell effector mechanisms, together with demyelination. MOG-induced EAE in the non-obese diabetic (NOD) mouse strain exhibits a chronic-relapsing EAE clinical profile and high disease incidence. We describe the generation of this variant, its contribution to the understanding of MS immune and pathogenetic mechanisms and potential for evaluation of candidate therapies.

Multiple sclerosis animal models: a clinical and histopathological perspective

“…Disease progression is not a feature of MOG (136) nor is it characteristic of PLP 139-151induced EAE (139) and as such might, thus, be best studied in the Biozzi ABH EAE model. Another option is to use MOG-induced EAE in the non-obese diabetic (NOD) mouse strain (8,34,88), where continuous progression has been reported after the initial inflammatory attack. Disease progression can as well be studied in the cuprizone model, although this is less well appreciated by the community.…”

Autoimmune encephalomyelitis in NOD mice is not initially a progressive multiple sclerosis model

“…32 Animal procedures were approved by the Institutional Animal Care and Use Committee at the La Trobe Institute, Australia. 23,32…”

“…16,33 Alternatively, animals (9-12 week) were immunized with 200 lg MOG residues 35-55 (MOG ) peptide emulsified in Freunds complete adjuvant supplemented with 4 mg/mL M. tuberculosis on day 0 and 350 ng intravenous B. pertussis toxin on day 0 and day 2. 23,32 These mice were scored as: 0 = no signs, 1 = limp tail, 2 = hindlimb weakness, 3 = hindlimb weakness with at least one paralyzed hindlimb, 4 = paralysis of both hindlimbs and weakness of one forelimb, 5 = moribund. 23 Animals were randomly assigned to treatments and the studies were scored blinded to induction agent.…”

“…[17][18][19][20] The nonobese diabetic (NOD) mouse develops spontaneous or induced diabetes and other endocrine gland-associated autoimmunities. [21][22][23] This mouse strain has also been reported to develop progressive neurological disease that mimics progressive MS. 24,25 Progressive worsening appears to develop within 20-30 days postinduction following immunization with myelin oligodendrocyte glycoprotein (MOG) peptide residues 35-55 (MOG ). [24][25][26][27][28][29][30][31] Thus, this EAE model could have significant utility for screening potential neuroprotective and repair agents.…”

Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation

“…EAE induced in NOD mice by immunization with myelin oligodendrocyte glycoprotein 35-55 (MOG ) peptide recapitulates several features of SPMS, including the progressive accumulation of neurodegeneration and axonal loss and the chronic activation of the innate immune system in the CNS (3,33,34). Thus, to assess the therapeutic potential of S1P receptor modulators in SPMS, we evaluated the effects of FTY720 on NOD EAE.…”