Fatal PML associated with efalizumab therapy
Insights into integrin αLβ2 in JC virus control
- N. Schwab, PhD,
- J.C. Ulzheimer, MD,
- R.J. Fox, MD,
- T. Schneider-Hohendorf, MSc,
- B.C. Kieseier, MD,
- C.M. Monoranu, MD,
- S.M. Staugaitis, MD, PhD,
- W. Welch, MD,
- S. Jilek, PhD,
- R.A. Du Pasquier, MD,
- W. Brück, MD,
- K.V. Toyka, MD,
- R.M. Ransohoff, MD* and
- H. Wiendl, MD*
- From the Department of Neurology–Department of Inflammatory Diseases of the Nervous System and Neurooncology (N.S., T.S.-H., H.W.), University of Münster, Germany; Department of Neurology (N.S., J.C.U., T.S.-H., K.V.T., H.W.) and Department of Pathology, Division of Neuropathology (C.M.M.), University of Würzburg, Germany; Neurological Clinic (J.C.U.), Bad Mergentheim, Germany; Mellen Center for Multiple Sclerosis, Neurological Institute (R.J.F., R.M.R.), Departments of Neurosciences and Anatomic Pathology (S.M.S.), and Neuroinflammation Research Center, Lerner Research Institute (R.M.R.), Cleveland Clinic Foundation, Cleveland, OH; Department of Neurology (B.C.K.), University of Düsseldorf, Germany; Topeka Neurology Associates (W.W.), Topeka, KS; Divisions of Immunology and Allergy and of Neurology (S.J., R.A.D.), Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; and Institute of Neuropathology (W.B.), University of Göttingen, Germany.
- Correspondence & reprint requests to Prof. Wiendl: heinz.wiendl{at}ukmuenster.de
-
↵* These authors contributed equally to this work.
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
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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.
