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Brain. 2010 Aug;133(Pt 8):2232-47. doi: 10.1093/brain/awq176. Epub 2010 Jul 21.

Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity.

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  • 1Department of Clinical Neuroscience, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK. jls53@medschl.cam.ac.uk

Abstract

Treatment of early relapsing-remitting multiple sclerosis with the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath [registered trade mark]) significantly reduced the risk of relapse and accumulation of disability compared with interferon β-1a in a phase 2 trial [Coles et al., (Alemtuzumab vs. interferon β-1a in early multiple sclerosis. N Engl J Med 2008; 359: 1786-801)]. Patients treated with alemtuzumab experienced an improvement in disability at 6 months that was sustained for at least 3 years. In contrast, those treated with interferon β-1a steadily accumulated disability. Here, by post hoc subgroup analyses of the CAMMS223 trial, we show that among participants with no clinical disease activity immediately before treatment, or any clinical or radiological disease activity on-trial, disability improved after alemtuzumab but not following interferon β-1a. This suggests that disability improvement after alemtuzumab is not solely attributable to its anti-inflammatory effect. So we hypothesized that lymphocytes, reconstituting after alemtuzumab, permit or promote brain repair. Here we show that after alemtuzumab, and only when specifically stimulated with myelin basic protein, peripheral blood mononuclear cell cultures produced increased concentrations of brain-derived neurotrophic factor, platelet-derived growth factor and ciliary neurotrophic factor. Analysis by reverse transcriptase polymerase chain reaction of cell separations showed that the increased production of ciliary neurotrophic factor and brain-derived neurotrophic factor after alemtuzumab is attributable to increased production by T cells. Media from these post-alemtuzumab peripheral blood mononuclear cell cultures promoted survival of rat neurones and increased axonal length in vitro, effects that were partially reversed by neutralizing antibodies against brain-derived nerve growth factor and ciliary neurotrophic factor. This conditioned media also enhanced oligodendrocyte precursor cell survival, maturation and myelination. Taken together, the clinical analyses and laboratory findings support the interpretation that improvement in disability after alemtuzumab may result, in part, from neuroprotection associated with increased lymphocytic delivery of neurotrophins to the central nervous system.

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PMID:
20659956
[PubMed - indexed for MEDLINE]
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