Blocking MS

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Science  28 Feb 2003:
Vol. 299, Issue 5611, pp. 1283-1285
DOI: 10.1126/science.299.5611.1283d

In multiple sclerosis (MS), lymphocytes and monocytes gain access to the central nervous system by breaking through the blood-brain barrier at sites of inflammation. The transendothelial migration and activation of these immune cells depends on the cell surface integrin α4β1/VLA-4. Administration of antibodies against α4 integrins suppresses disease progression in a mouse model of MS. Miller et al. have extended this promising finding by treating patients suffering from relapsing MS with a humanized monoclonal antibody against α4 integrins, called natalizumab. In a small, placebo-controlled study, patients treated with this integrin antagonist for 6 months showed a 90% reduction in brain lesion formation and progression.

In an independent study, Cannella et al. tested a synthetic small-molecule antagonist of α4β1/VLA-4 called TBC 3486 in the mouse model of MS. Mice given this compound before disease onset showed delayed and reduced demyelination and production of proinflammatory cytokines. Even when treatment was terminated, disease severity was reduced for several weeks. However, the drug had little effect when given during the chronic phase of the disease, suggesting that once inflammation and lesions are established, other adhesion molecules may be involved in disease progression.

Thus, immune cells bearing the α4 integrins are likely to be important in MS pathogenesis, and selective inhibition of α4 integrins may be effective in the clinic. — LC

N. Engl. J. Med. 348,15 (2003); J. Neurosci. Res. 71, 407 (2003).

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