Abstract
Multiple sclerosis (MS) is the most common demyelinating and an autoimmune disease of the central nervous system characterized by immune-mediated myelin and axonal damage, and chronic axonal loss attributable to the absence of myelin sheaths. T cell subsets (Th1, Th2, Th17, CD8+, NKT, CD4+CD25+ T regulatory cells) and B cells are involved in this disorder, thus new MS therapies seek damage prevention by resetting multiple components of the immune system. The currently approved therapies are immunoregulatory and reduce the number and rate of lesion formation but are only partially effective. This review summarizes current understanding of the processes at issue: myelination, demyelination and remyelination—with emphasis upon myelin composition/architecture and oligodendrocyte maturation and differentiation. The translational options target oligodendrocyte protection and myelin repair in animal models and assess their relevance in human. Remyelination may be enhanced by signals that promote myelin formation and repair. The crucial question of why remyelination fails is approached is several ways by examining the role in remyelination of available MS medications and avenues being actively pursued to promote remyelination including: (i) cytokine-based immune-intervention (targeting calpain inhibition), (ii) antigen-based immunomodulation (targeting glycolipid-reactive iNKT cells and sphingoid mediated inflammation) and (iii) recombinant monoclonal antibodies-induced remyelination.
Highlights
Multiple sclerosis (MS) is a chronic disorder characterized by multifocal inflammatory infiltrates (T cells, B cells, macrophages) within the central nervous system (CNS) and with concomitant degradation of myelin, oligodendrocytes and axons, along with reactive astrogliosis and activated microglia [1]
The immunopathological events can be divided into: (i) an initial T cell priming, (ii) activation phase in the periphery, and a subsequent (iii) migration of the pro-inflammatory T cells and monocytes across the blood-brain barrier (BBB), (iv) amplification of local inflammation and activation of resident antigen presenting cells (APCs), such as microglia, (v) effector phase of the disease: invasion of CNS parenchyma resulting in damaging of oligodendrocytes, myelin sheath and axons [61]
Studies using in vivo models of demyelination and remyelination, as well as in vitro culture systems, have revealed a wealth of knowledge regarding the many sequential and necessary steps involved for oligodendrocyte progenitor cells (OPCs) to remyelinate a denuded axon
Summary
Multiple sclerosis (MS) is a chronic disorder characterized by multifocal inflammatory infiltrates (T cells, B cells, macrophages) within the central nervous system (CNS) and with concomitant degradation of myelin, oligodendrocytes and axons, along with reactive astrogliosis and activated microglia [1]. Available disease modifying therapies for MS aim to reduce the immune response by targeting immunological pathways: β-interferons, IFNβ-1α (Avonex, Rebif) and IFNβ-1β (Betaseron); the synthetic peptide glatiramer acetate (Copaxone); the antineoplastic agent mitoxantrone (Novantrone), and; a very late antigen-4 (VLA-4) blocker natulizumab (Tysabri) [7], but all are only partially effective. All of these drugs are administered by injection and many MS patients prefer oral treatment [7]. The frontier aims to delay disease progression and recover lost neurological function via MS therapeutics and eventually develop agents that directly affect myelin repair
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