Experimental Models of Relapsing-Remitting Multiple Sclerosis: Current Concepts and Perspective

Abstract

Multiple sclerosis (MS) and its model experimental autoimmune encephalomyelitis (EAE) are debilitating paralytic diseases caused by inflammation, demyelination and axonal degeneration of the central nervous system (CNS). Whilst the autoimmune nature of MS is strongly suggested by evidence of myelin specific autoreactive T cells and antibodies, EAE is an experimentally induced CNS specific autoimmune disease. As opposed to the majority of MS patients, which exhibit a relapsing-remitting course of the disease, only a handful of available EAE models displays relapsingremitting course. In this review, we will summarize differences in regulation of acute and relapsing disease with emphasis on relapsing-remitting EAE models, and outline advantages and limitations of available relapsing EAE models pertinent for studies of relapsing human disease. We will discuss current concepts of relapse regulation by focusing on immune and molecular mechanisms of neuroinflammation, oligodendrocyte damage, myelin loss and axonal degeneration. This review will compare our present understanding of relapse regulation in human versus experimental autoimmune disease. Translation of mechanisms learned from relapsing EAE into development of new therapies for MS will be evaluated. Finally, perspectives in further optimization and development of more suitable experimental models to study human relapsingremitting MS will be discussed.

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

“…Despite these drawbacks, it has provided essential information regarding T-cell-mediated immune damage in the CNS (Croxford et al 2011;Gold et al 2006;Skundric 2005), the contribution of the humoral response to demyelination (Del Pilar Martin and Monson 2007;Marta et al 2010;Rivero et al 1999;Tsunoda et al 2000), as well as the role of cytokines (Pierson et al 2012;Robinson et al 2014), reactive oxygen species and nitric oxide radicals in demyelination and axonal injury (Emerson et al 2009;Lassmann 2010b). Therefore, although other experimental models are also used in MS research, including Theiler's murine encephalomyelitis virus (TMEV)-induced infection (Dal Canto and Lipton 1979;Nelson et al 2004) and demyelination by the use of toxins (for example cuprizone or lysolecithin) (Blakemore and Franklin 2008;Matsushima and Morell 2001;Praet et al 2014;van Engelen et al 1997), the EAE model remains by far the most consistently used one.…”

Necrosis and myelomalaic lesions in acute experimental allergic encephalomyelitis in guinea pigs

“…Whilst the autoimmune nature of MS is strongly suggested by evidence of myelin specific autoreactive T cells and antibodies, EAE is an experimentally induced CNS specific autoimmune disease. 16 The histopathology of EAE is characterized by perivascular infiltrates of mononuclear inflammatory cells. Invasion of the neural parenchyma by inflammatory cells is accompanied by demyelination but not usually by necrosis.…”

Effect of intranasal administration of Semliki Forest virus recombinant particles expressing interferon-β on the progression of experimental autoimmune encephalomyelitis

“…A treatment regime was therefore developed that targeted the effector stage of the disease, which fell between days 12 and 17, when the T-cell response to the encephalitogenic peptide had already developed but significant accumulation in the CNS had not yet occurred (14). Treatment of mice prior to this effector phase resulted in significant improvement in the disease.…”

“…Vector RNA was detected in the nasal passage of infected animals MOLECULAR MEDICINE REPORTS 1: 335-342, 2008 Effect of intranasal administration of Semliki Forest virus recombinant particles expressing interferon-ß on the progression of experimental autoimmune encephalomyelitis + T helper (Th1) cells infiltrating the brain and attacking the myelin sheath (13,14). The other CD4 + MHC class II restricted cells, Th2 cells, are associated with disease recovery (13)(14)(15)(16)(17). The type of EAE induced is dependent on the immunization protocol, the animal strain and the antigen used.…”

“…The type of EAE induced is dependent on the immunization protocol, the animal strain and the antigen used. Myelin oligodendrocyte glycoprotein (MOG)-induced EAE, utilised in this study, consists of an initial induction phase, an effector phase at which T-cell response to the encephalitogenic peptide has fully developed but T-cell accumulation in the CNS has not yet occurred (days 12-17 in this study) (5) and a recovery phase (14).…”