Cytotoxic CD8+ T cell-neuron interactions: perforin-dependent electrical silencing precedes but is not causally linked to neuronal cell death

Cytotoxic CD8(+) T cells are considered important effector cells contributing to neuronal damage in inflammatory and degenerative CNS disorders. Using time-lapse video microscopy and two-photon imaging in combination with whole-cell patch-clamp recordings, we here show that major histocompatibility class I (MHC I)-restricted neuronal antigen presentation and T cell receptor specificity determine CD8(+) T-cell locomotion and neuronal damage in culture and hippocampal brain slices. Two separate functional consequences result from a direct cell-cell contact between antigen-presenting neurons and antigen-specific CD8(+) T cells. (1) An immediate impairment of electrical signaling in single neurons and neuronal networks occurs as a result of massive shunting of the membrane capacitance after insertion of channel-forming perforin (and probably activation of other transmembrane conductances), which is paralleled by an increase of intracellular Ca(2+) levels (within <10 min). (2) Antigen-dependent neuronal apoptosis may occur independently of perforin and members of the granzyme B cluster (within approximately 1 h), suggesting that extracellular effects can substitute for intracellular delivery of granzymes by perforin. Thus, electrical silencing is an immediate consequence of MHC I-restricted interaction of CD8(+) T cells with neurons. This mechanism is clearly perforin-dependent and precedes, but is not causally linked, to neuronal cell death

Acute immunoinflammatory neuropathy: update on Guillain-Barré syndrome

This review provides an update on the current understanding of the pathogenesis of Guillain-Barré syndrome (GBS). Progress has been made in elucidating relevant pathomechanisms, especially in the axonal variants of the disease. However, the precise target autoantigens still need to be determined. Future therapeutic approaches and currently available strategies are critically discussed

Chemotherapeutics in the treatment of multiple sclerosis

The likely pathogenic mechanisms of multiple sclerosis (MS) provide a sound rationale for investigating the efficacy of drugs possessing immunosuppressive or immunomodulatory properties. With proven efficacy, safety and tolerability, interferon beta formulations and glatiramer acetate have become the mainstay of initial treatment for patients with relapsing forms of MS. More recently, natalizumab, a humanized monoclonal antibody (mAb) against the cellular adhesion molecule α4-integrin, has been employed for patients with an inadequate response or lack of tolerability to an alternate MS therapy, or as initial therapy for patients with severe disease. Various agents initially developed for oncological indications, either as chemotherapeutics or mAbs, may also have current or future uses in MS treatment. Mitoxantrone is currently the only chemotherapeutic agent approved for treatment of MS in the United States, while in parts of Europe azathioprine is approved and widely used for MS treatment. Other chemotherapeutics that have been tested in MS to date include cyclophosphamide, methotrexate, cladribine, and the mAbs alemtuzumab and rituximab. While there has been varying evidence of efficacy for these compounds, each appears to be associated with serious risks that require careful consideration and management. Given the risks that have been demonstrated for available chemotherapeutic agents and while long-term postmarketing safety data are still not available for those agents in development, it seems prudent to carefully assess the possible use of chemotherapeutics in the treatment of MS. A thorough risk–benefit analysis is becoming increasingly important in the assessment of therapeutic options for this disabling disease

Safety and clinical outcomes of rituximab treatment in patients with multiple sclerosis and neuromyelitis optica: experience from a national online registry (GRAID)

INTRODUCTION: Multiple sclerosis (MS) is an immune-mediated disease. Over the last decades therapeutic options have broadened tremendously. Nevertheless, various therapeutic agents, e.g., rituximab, are currently used in the treatment of MS off label. Disease or health registries are useful methods to collect information about off-label treatments. The German registry for autoimmune disease (GRAID) is a multicenter, retrospective, non-interventional database of patients with various autoimmune diseases. AIM/METHODS: The aim of this observational analysis is to present safety data of rituximab in the treatment of MS and neuromyelitis optica (NMO) in a real life clinical setting based on the available registry data. RESULTS: Data were collected nationwide in patients who received rituximab. 56 patients were treated with rituximab for MS or NMO. Average observation period was 9.6 months (SD 7.6, ranging from 6 to 29.7 months). Interval between treatments cycles differed tremendously (ranging from 0 to 21 months, median 10 months). Number of infusions ranged from 1 up to more than 8. The analysis provides experience on almost 50 patient years. Infusion related reactions were most common and reported in four patients; infections were seen in three patients (two of them were hospitalized for urinary tract infection and urosepsis). All patients recovered from infection. Full treatment response was attested in a quarter of the patients; two thirds benefited partially from treatment. DISCUSSION: Safety data of almost 50 patient years of treatment with rituximab show that rituximab is tolerated well in MS/NMO patients. Infections and infusion reactions are the most common adverse events. Our data may help the individual physician to balance efficacy of rituximab against the risk. * Data on rituximab in MS and NMO are provided for almost 50 patientyears * Rituximab was tolerated well * No unexpected side effects were seen * Almost 80 % of the patients benefited at least partially from treatment

Fatal PML associated with efalizumab therapy: Insights into integrin αLβ2 in JC virus control.

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