The role of alpha-4 integrin in the aetiology of multiple sclerosis: Current knowledge and therapeutic implications

William Sheremata, Alireza Minagar, J. Steven Alexander, Timothy Vollmer

Research output: Contribution to journalArticle

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Abstract

Multiple sclerosis (MS) has been recognised as a disease since the mid-19th century. The delineation of its CNS pathology, revealing the presence of inflammatory demyelination and relative sparing of axons, was originally interpreted as evidence of infection. Despite many studies, a primary infectious aetiology of MS has not been found. However, the occurrence of acute demyelinating disease following a variety of infections and vaccinations, leading to MS in about a third of cases, provides evidence for the existence of an auto-allergic pathogenesis for the disease. Improved understanding of the role of the blood-brain barrier in protecting the CNS, and the mechanisms by which cells gain entry into the brain and spinal cord has advanced the understanding of MS. Evidence of the central role of the adhesion molecule α4β1-integrin (very late activation antigen-4 [VLA-4]) for lymphocytes in endothelial transmigration into the CNS specifically, has provided a major insight into the pathogenesis of human demyelinating disease and its experimental model, experimental autoimmune encephalomyelitis (EAE). This finding has led to a new window of therapeutic opportunity in MS. Monoclonal antibodies to VLA-4 abrogate the development of EAE in sensitised animals and may actually reverse its clinical and pathological findings in manifest disease. Natalizumab, one such monoclonal antibody, which is administered intravenously, has been found to be a promising agent in the treatment of MS. Although single doses produced no improvement in the speed or quality of recovery from acute exacerbations of MS in a phase II trial, long-term administration (in phase II and phase III trials) have produced significant benefits with results showing both a marked reduction in the risk of new magnetic resonance imaging lesions and a significant reduction in the risk of exacerbations within 2 months of the initiation of therapy. Phase III double-blinded controlled trials have provided additional evidence of safety and a favourable impact on exacerbation rates over the 1 year of administration. Unfortunately, the success of natalizumab has been curtailed by three cases of progressive multifocal leukoencephalopathy, which have prompted the manufacturer to voluntary withdraw the drug from the market. An independent review board is currently investigating the safety of the drug to determine whether it should return to the market. The demonstration that selective modulation (blocking) of the adhesion molecule VLA-4 by natalizumab in MS, resembling that observed in experimental disease, represents a major advance in rational therapy.

Original languageEnglish
Pages (from-to)909-922
Number of pages14
JournalCNS Drugs
Volume19
Issue number11
DOIs
StatePublished - Nov 15 2005

Fingerprint

Integrin alpha Chains
Multiple Sclerosis
Integrin alpha4beta1
Demyelinating Diseases
Autoimmune Experimental Encephalomyelitis
Risk Reduction Behavior
Therapeutics
Monoclonal Antibodies
Progressive Multifocal Leukoencephalopathy
Transendothelial and Transepithelial Migration
Safety
Acute Disease
Infection
Blood-Brain Barrier
Integrins
Pharmaceutical Preparations
Axons
Spinal Cord
Vaccination
Theoretical Models

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Neuropsychology and Physiological Psychology
  • Pharmacology

Cite this

The role of alpha-4 integrin in the aetiology of multiple sclerosis : Current knowledge and therapeutic implications. / Sheremata, William; Minagar, Alireza; Alexander, J. Steven; Vollmer, Timothy.

In: CNS Drugs, Vol. 19, No. 11, 15.11.2005, p. 909-922.

Research output: Contribution to journalArticle

Sheremata, William ; Minagar, Alireza ; Alexander, J. Steven ; Vollmer, Timothy. / The role of alpha-4 integrin in the aetiology of multiple sclerosis : Current knowledge and therapeutic implications. In: CNS Drugs. 2005 ; Vol. 19, No. 11. pp. 909-922.
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