PT  - JOURNAL ARTICLE
AU  - N. Schwab
AU  - J.C. Ulzheimer
AU  - R.J. Fox
AU  - T. Schneider-Hohendorf
AU  - B.C. Kieseier
AU  - C.M. Monoranu
AU  - S.M. Staugaitis
AU  - W. Welch
AU  - S. Jilek
AU  - R.A. Du Pasquier
AU  - W. Brück
AU  - K.V. Toyka
AU  - R.M. Ransohoff
AU  - H. Wiendl
TI  - Fatal PML associated with efalizumab therapy
AID  - 10.1212/WNL.0b013e3182478d4b
DP  - 2012 Feb 14
TA  - Neurology
PG  - 458--467
VI  - 78
IP  - 7
4099  - http://n.neurology.org/content/78/7/458.short
4100  - http://n.neurology.org/content/78/7/458.full
SO  - Neurology2012 Feb 14; 78
AB  - 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. 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.