Fatal PML associated with efalizumab therapy

Schwab, Nicholas; Ulzheimer, Jochen C.; Fox, Robert J.; Schneider‐Hohendorf, Tilman; Kieseier, Bernd C.; Monoranu, Camelia; Staugaitis, Susan M.; Welch, William R.; Jilek, Samantha; Pasquier, Renaud Du; Brück, Wolfgang; Toyka, Klaus V.; Ransohoff, R. M.; Wiendl, Heinz

doi:10.1212/wnl.0b013e3182478d4b

Cited by 107 publications

(87 citation statements)

References 36 publications

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“…PBMCs were isolated by density gradient centrifugation using lymphocyte separation medium (PAA Laboratories) as previously described . Flow cytometry analysis of CSF was performed as described previously (Schwab et al, 2012a). Ex vivo isolated or cultured cells were washed with PBS supplemented with 0.1% BSA and stained with fluorescence-labeled mAbs together with blocking mouse IgG interactions even in the case of low P-selectin expression.…”

Section: Methodsmentioning

confidence: 99%

“…The fact that both VLA-4 and PSGL-1 are important for early steps of extravasation (Kerfoot et al, 2006) might suggest the PSGL-1 up-regulation is a compensatory mechanism of T cells during the treatment with natalizumab. We used two models of cell interaction under shear-flow conditions to assess the functional relevance of our observations: coated glass capillaries were used to answer questions of specific molecular interactions (Zarbock et al, 2007), whereas primary HBMECs were used to more closely mimic the in vivo setting (Schwab et al, 2012a; adapted to shear-flow conditions). We could show that fact that inflammation is necessary even though there is expression of VCAM-1 on resting endothelium is consistent with murine findings that the endothelium needs to secrete and interfere with rolling, proving that this step in the migration cascade does not involve VLA-4, which has previously only been shown in the murine system (Coisne et al, 2009).…”

Section: In Situ Detection Of Mcam + T Cells In Ms Lesions Suggests Amentioning

confidence: 99%

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VLA-4 blockade promotes differential routes into human CNS involving PSGL-1 rolling of T cells and MCAM-adhesion of TH17 cells

Schneider‐Hohendorf

Rossaint

Mohan

et al. 2014

Journal of Neuroimmunology

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Section: Methodsmentioning

confidence: 99%

Section: In Situ Detection Of Mcam + T Cells In Ms Lesions Suggests Amentioning

confidence: 99%

VLA-4 blockade promotes differential routes into human CNS involving PSGL-1 rolling of T cells and MCAM-adhesion of TH17 cells

Schneider‐Hohendorf

Rossaint

Mohan

et al. 2014

Journal of Neuroimmunology

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“…This demonstrates that some mechanisms regulating cell migration over the BBB seem to be redundant and that novel target molecules need to be chosen carefully. In this context, previous experiences using the LFA-1 neutralizing antibody efalizumab should be kept in mind [109]. This antibody was approved for the treatment of psoriasis until its withdrawal because of 2 cases of fatal PML.…”

Section: Therapies Aiming At T-lymphocyte Migration [Anti-α4β Integrimentioning

confidence: 99%

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

Bittner

Wiendl

2016

Neurotherapeutics

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Therapeutic options for multiple sclerosis (MS) have significantly increased over the last few years. T lymphocytes are considered to play a central role in initiating and perpetuating the pathological immune response. Currently approved therapies for MS target T lymphocytes, either in an unspecific manner or directly by interference with specific Tcell pathways. While the concept of BT-cell-specific therapyî mplies specificity and selectivity, currently approved approaches come from a general shaping of the immune system towards anti-inflammatory immune responses by non-T-cellselective immune suppression or immune modulation (e.g., interferons-immune modulation approach) to a depletion of immune cell populations involving T cells (e.g., anti-CD52, alemtuzumab-immune selective depletion approach), or a selective inhibition of distinct molecular pathways in order to sequester leucocytes (e.g., natalizumab-leukocyte sequestration approach). This review will highlight the rationale and results of different T-cell-directed therapeutic approaches coming from basic animal experiments to clinical trials. We will first discuss the pathophysiological rationale for targeting T lymphocytes in MS leading to currently approved treatments acting on T lymphocytes. Furthermore, we will disuss previous promising concepts that have failed to show efficacy in clinical trials or were halted as a result of unexpected adverse events. Learning from the discrepancies between expectations and failures in practical outcomes helps to optimize future research approaches and clinical study designs. As our current view of MS pathogenesis and patient needs is rapidly evolving, novel therapeutic approaches targeting T lymphocytes will also be discussed, including specific molecular interventions such as cytokine-directed treatments or strategies enhancing immunoregulatory mechanisms. Based on clinical experience and novel pathophysiological approaches, T-cell-based strategies will remain a pillarstone of MS therapy.

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“…In the last few years there has been a surge of cases of and clinical interest in PML. This is owing to the association of PML with monoclonal and other newer immunosuppressive agents, including natalizumab, efalizumab, rituximab, mycophenolate mofetil, etanercept, and leflunomide [176][177][178][179][180][181].…”

Section: Progressive Multifocal Leukoencephalopathymentioning

confidence: 99%

Immunotherapies for Neurological Manifestations in the Context of Systemic Autoimmunity

et al. 2016

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Neurological involvement is relatively common in the majority of systemic autoimmune diseases and may lead to severe morbidity and mortality, if not promptly treated. Treatment options vary greatly, depending on the underlying systemic pathophysiology and the associated neurological symptoms. Selecting the appropriate therapeutic scheme is further complicated by the lack of definite therapeutic guidelines, the necessity to differentiate primary neurological syndromes from those related to the underlying systemic disease, and to sort out adverse neurological manifestations caused by immunosuppressants or the biological agents used to treat the primary disease. Immunotherapy is a sine qua non for treating most, if not all, neurological conditions presenting in the context of systemic autoimmunity. Specific agents include classical immune modulators such as corticosteroids, cyclophosphamide, intravenous immunoglobulin, and plasma exchange, as well as numerous biological therapies, for example antitumor necrosis factor agents and monoclonal antibodies that target various immune pathways such as B cells, cytokines, and co-stimulatory molecules. However, experience regarding the use of these agents in neurological complications of systemic diseases is mainly empirical or based on small uncontrolled studies and case series. The aim of this review is to present the state-of-the-art therapies applied in various neurological manifestations encountered in the context of systemic autoimmune diseases; evaluate all treatment options on the basis of existing guidelines; and compliment these data with our personal experience derived from a large number of patients.

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Fatal PML associated with efalizumab therapy

Abstract: 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.

Cited by 107 publications

References 36 publications

VLA-4 blockade promotes differential routes into human CNS involving PSGL-1 rolling of T cells and MCAM-adhesion of TH17 cells

VLA-4 blockade promotes differential routes into human CNS involving PSGL-1 rolling of T cells and MCAM-adhesion of TH17 cells

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

Immunotherapies for Neurological Manifestations in the Context of Systemic Autoimmunity

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