Journal
NEUROLOGY
Volume 78, Issue 7, Pages 458-467Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0b013e3182478d4b
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Funding
- German Competence Network of MS (KKNMS)
- University of Wurzburg
- Merck Serono
- Bayer Schering Pharma
- Biogen Idec
- National Multiple Sclerosis Society [RG 4091A3/1, RG 4103A4/2, RC 1004-A-5]
- Novartis
- Roche
- sanofi-aventis
- Talecris Biotherapeutics
- Teva Pharmaceutical Industries Ltd.
- Swiss National Foundation
- Swiss Society for Multiple Sclerosis
- Biaggi Foundation
- Lundbeck, Inc.
- DFG (German Research Foundation)
- BMBF (German Federal Ministry of Education and Science)
- Binational German-Polish Grant for MS Dendritic Cell Research
- State of Bavaria Research Funds and University Research Funds
- Gemneinnutzige Hertie Foundation (GHS)
- German MS Society
- NIH
- National MS Society
- Dana Foundation
- Nancy Davis Center Without Walls
- Biogen Idec/Elan Corporation
- Novo Nordisk
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Objectives: Progressive multifocal leukoencephalopathy (PML) has become much more common with monoclonal antibody treatment for multiple sclerosis and other immune-mediated disorders. Methods: We report 2 patients with severe psoriasis and fatal PML treated for >= 3 years with efalizumab, a neutralizing antibody to alpha L beta 2-leukointegrin (LFA-1). In one patient, we conducted serial studies of peripheral blood and CSF including analyses of leukocyte phenotypes, migration ex vivo, and CDR3 spectratypes with controls coming from HIV-infected patients with PML. Extensive pathologic and histologic analysis was done on autopsy CNS tissue of both patients. Results: Both patients developed progressive cognitive and motor deficits, and JC virus was identified in CSF. Despite treatment including plasma exchange (PE) and signs of immune reconstitution, both died of PML 2 and 6 months after disease onset. Neuropathologic examination confirmed PML. Efalizumab treatment was associated with reduced transendothelial migration by peripheral T cells in vitro. As expression levels of LFA-1 on peripheral T cells gradually rose after PE, in vitro migration increased. Peripheral and CSF T-cell spectratyping showed CD8+ T-cell clonal expansion but blunted activation, which was restored after PE. Conclusions: From these data we propose that inhibition of peripheral and intrathecal T-cell activation and suppression of CNS effector-phase migration both characterize efalizumab-associated PML. LFA-1 may be a crucial factor in homeostatic JC virus control. Neurology (R) 2012;78:458-467
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