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  • Review Article
  • Published:

Novel therapeutic strategies for multiple sclerosis — a multifaceted adversary

Key Points

  • Our understanding of the pathogenesis of multiple sclerosis (MS) has widened beyond the traditional view of a chronic autoinflammatory disease of the CNS white matter, which is mediated by self-reactive T cells. It is now clear that MS is a constitutive diffuse syndrome, affecting both grey and white matter, with ongoing autoinflammation and neurodegeneration even from early stages, and involving immune dysfunction at many levels.

  • Abnormalities in B cells, natural killer cells, dendritic cells and microglia also appear to be key players in the initiation and natural course of MS. In particular, dendritic cell (innate immunity) dysregulation may relate to disease progression. Attempting to establish potential relationships between specific dysfunctional immunonophenotypes and the clinical course, and response to therapy in each patient with MS is a provocative, yet logical, approach.

  • Therapeutic strategies for MS have radically changed in the past years. The importance of early treatment in MS has become evident. Furthermore, as we unravel the complex immunopathogenesis of this disease, new targets for potential therapeutic intervention arise and the notion of combination therapy, individually tailored to the particular immunophenotype in each patient and/or disease stage is taking centre stage.

  • Humanized monoclonal antibodies including natalizumab, rituximab, alemtuzumab and the novel sphingosine-1-phosphate receptor modulator FTY720 have shown a robust effect on the reduction of MS relapse rate and magnetic resonance imaging measures of disease activity. The use in MS of effective antigen-specific therapies and stem-cell transplantation are also being actively investigated. In addition, a number of other new promising drugs are also in the clinical trial pipeline and are discussed in this Review.

  • For the most part, the efficacy of these agents has been mainly tested in relapsing–remitting MS, while prevention of functional disability and MS progression still remain a major challenge.

Abstract

Therapeutic strategies for multiple sclerosis have radically changed in the past 15 years. Five regulatory-approved immunomodulatory agents are reasonably effective in the treatment of relapsing–remitting multiple sclerosis, and appear to delay the time to progression to disabling stages. Inhibiting disease progression remains the central challenge for the development of improved therapies. As understanding of the immunopathogenesis of multiple sclerosis has advanced, a number of novel potential therapeutics have been identified, and are discussed here. It has also become apparent that traditional views of multiple sclerosis simply as a CD4+ T-cell-mediated disease of the central nervous system are incomplete. The pathogenic role of other immune components such as the innate immune system, regulatory T cells, T helper 17 cells and B cells is reaching centre stage, opening up exciting avenues and novel potential targets to affect the natural course of multiple sclerosis.

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Figure 1: The immune response dichotomy in multiple sclerosis.
Figure 2: Multiple sclerosis immunopathogenesis and therapeutic targets.
Figure 3: Rituximab: potential mechanisms of action in multiple sclerosis.

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Correspondence to Howard L. Weiner.

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H.L.W. has received consulting fees from Autoimmune, VBL, Genentech, Teva and Enzo Biochem. He has also received lecture fees from Biogen, EMD Serono and Teva.

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DATABASES

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Glossary

T2 lesion

Focal hyperintensity on T2-weighted MRI images. These lesions are non-specific, representing various brain parenchyma damage aetiologies. The appearance of new T2 lesions with temporospatial dissemination is part of the current the diagnostic criteria of multiple sclerosis (MS). Typical MS T2 lesions are small, oval or rounded, located around the ventricles, corpus callosum and/or subcortical white matter.

Demyelination

Damage to the myelin sheath surrounding nerves in the brain and spinal cord, which affects the function of the nerves involved. Demyelination occurs in multiple sclerosis, a chronic disease of the nervous system affecting young and middle-aged adults, and in experimental autoimmune encephalomyelitis, which is a mouse model of multiple sclerosis.

Experimental autoimmune encephalomyelitis

(EAE). An animal model of the human autoimmune disease multiple sclerosis. EAE is induced in experimental animals by immunization with myelin or peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.

Progressive multifocal leukoencephalopathy

A rapidly progressive, often fatal, human brain infection by the Jacob–Creutzfeldt (JC) virus, with tropism for oligodendrocytes. Common initial manifestations include cognitive, visual, motor and coordination dysfunction.

JC virus

A common human polyoma virus. Infection is usually subclinical in immunocompetent hosts, but it is associated with progressive multifocal leukoencephalopathy in immunocompromised individuals.

Tolerance

A term that denotes lymphocyte non-responsiveness to antigen, but implies an active process, not simply a passive lack of response.

CD4+CD25+ regulatory T (TReg) cell

A specialized type of CD4+ T cell that can suppress the responses of other T cells. These cells provide a crucial mechanism for the maintenance of peripheral self-tolerance and are characterized by expression of CD25 (also known as the α-chain of the interleukin 2 receptor) and the transcription factor forkhead box P3 (FOXP3).

γδ T cell

A T cell that expresses a T-cell receptor consisting of a γ-chain and a δ-chain. These T cells are present mainly in the intestinal epithelium as intraepithelial lymphocytes (IELs). Although the exact function of γδ T cells (or IELs) is still unknown, it has been suggested that mucosal γδ T cells are involved in innate immune responses by the mucosal immune system.

Vγ2 T cells

This is a γδ T-cell subset expressing the variable γ2 chain in the surface T-cell receptor. The specific function of these cells remains unknown.

CD56bright natural killer cell

This innate immune cell is characterized by lack of expression of CD3 and T-cell receptors and high expression of surface CD56 (also termed neural cell adhesion molecule; NCAM). This natural killer cell subset appears to have immunoregulatory function primarily, whereas CD56dim natural killer cells function as potent cytolytic effectors.

Bystander suppression

The extension of tolerogen-induced suppression of immune responses that are directed against antigens not structurally related to the tolerogen but expressed by the same target cell or organ.

Anergy

A state of unresponsiveness to antigen. Anergic T cells or B cells cannot respond to their cognate antigens under optimal conditions of stimulation.

Altered peptide ligands

(APLs). APLs are peptide analogues that are derived from the original antigenic peptide. They commonly have amino-acid substitutions at T-cell receptor (TCR)-contact residues. TCR engagement by these APLs usually leads to partial or incomplete T-cell activation. Antagonistic APLs can specifically antagonize and inhibit T-cell activation that is induced by the wild-type antigenic peptide.

Plasmapheresis

The extracorporeal removal of blood plasma proteins from the circulation. Removal of circulating autoantibodies is used as therapy in several autoimmune disorders.

TH3 cell

A regulatory T-cell subset that was originally described in oral tolerance, and that primarily secretes transforming growth factor-β (TGF-β). TGF-β produced by TH3 cells provides help for IgA class switching and has suppressive properties for both TH1 and TH2 cells. The expression of CD25 and forkhead box P3 (FOXP3) is induced in T cells under experimental TH3-cell differentiation conditions.

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Lopez-Diego, R., Weiner, H. Novel therapeutic strategies for multiple sclerosis — a multifaceted adversary. Nat Rev Drug Discov 7, 909–925 (2008). https://doi.org/10.1038/nrd2358

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