Fatal PML associated with efalizumab therapy
Insights into integrin αLβ2 in JC virus control
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Abstract
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 αLβ2-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.
GLOSSARY
- BBB=
- blood-brain barrier;
- IRIS=
- immune reconstitution inflammatory syndrome;
- JCV=
- JC virus;
- PBMC=
- peripheral blood mononuclear cell;
- PE=
- plasma exchange;
- PML=
- progressive multifocal leukoencephalopathy;
- TCR=
- T-cell receptor;
- Tcm=
- central memory T cells;
- Tem=
- effector memory T cells.
Footnotes
Study funding: Supported by the “German Competence Network of MS” (KKNMS) (H.W.) and by intramural research funds of the University of Würzburg.
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Supplemental data at www.neurology.org
- Received January 19, 2011.
- Accepted July 6, 2011.
- Copyright © 2012 by AAN Enterprises, Inc.
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