Strategies For Multiple Sclerosis Research Articles

Association of innate immune activation with latent Epstein-Barr virus in active MS lesions

To determine whether the activation of innate immune responses, which can be elicited by pathogenic and endogenous triggers, is associated with the presence of Epstein-Barr virus (EBV) infection in the multiple sclerosis (MS) brain. White matter postmortem MS (n = 10) and control tissue (n = 11) was analyzed for the expression of the proinflammatory cytokine interferon α (IFNα) by immunohistochemistry and for EBV by using the highly sensitive method of EBV-encoded RNA (EBER) in situ hybridization. We detected overexpression of IFNα in active areas of white matter MS lesions but not in inactive MS lesions, normal-appearing white matter, or normal brains. The presence of IFNα in macrophages and microglia (expressing human leukocyte antigen class II) is suggestive of local production as part of an acute inflammatory process. Interestingly, EBERs were also specifically detected in areas where IFNα was overexpressed in these preselected active MS lesions. EBER+ cells were also found in CNS lymphoma and stroke cases, but were absent in other control brains. We next addressed a potential mechanism, e.g., the role of EBERs in eliciting IFNα production, and transfected EBERs into human embryonic kidney (HEK) cells. We used HEK cells that stably expressed Toll-like receptor-3, which recognizes double-stranded RNAs, associated with many viral infections. EBERs elicited IFNα production in vitro. These findings suggest that latent EBV infection may contribute to the inflammatory milieu in active MS lesions by activating innate immune responses, e.g., IFNα production. Unraveling the underlying mechanisms may help in uncovering causal pathways and developing better treatment strategies for MS and other neuroinflammatory diseases.

Clinical and pathological effects of intrathecal injection of mesenchymal stem cell-derived neural progenitors in an experimental model of multiple sclerosis

Multiple sclerosis (MS) is associated with irreversible disability in a significant proportion of patients. At present, there is no treatment to halt or reverse the progression of established disability. In an effort to develop cell therapy-based strategies for progressive MS, we investigated the pre-clinical efficacy of bone marrow mesenchymal stem cell-derived neural progenitors (MSC-NPs) as an autologous source of stem cells. MSC-NPs consist of a subpopulation of bone marrow MSCs with neural progenitor and immunoregulatory properties, and a reduced capacity for mesodermal differentiation, suggesting that this cell population may be appropriate for clinical application in the CNS. We investigated whether MSC-NPs could promote repair and recovery after intrathecal injection into mice with EAE. Multiple injections of MSC-NPs starting at the onset of the chronic phase of disease improved neurological function compared to controls, whereas a single injection had no effect on disease scores. Intrathecal injection of MSC-NPs correlated with reduced immune cell infiltration, reduced area of demyelination, and increased number of endogenous nestin-positive progenitor cells in EAE mice. These observations suggest that MSC-NPs may influence the rate of repair through effects on endogenous progenitors in the spinal cord. This study supports the use of autologous MSC-NPs in MS patients as a means of promoting CNS repair.

Novel Agents and Emerging Treatment Strategies in Multiple Sclerosis

In the past decade, the treatment of multiple sclerosis has undergone a significant paradigm shift. Weekly to daily self-injections of moderate benefit are making way for more effective therapies with improved relapse and disability impact with more appealing routes and frequencies of administration. Some such therapies, like natalizumab, belong to the monoclonal antibody family, while others offer novel immunomodulatory mechanisms and the much sought after oral route of administration. While novel and more powerful immune mechanisms present new issues with respect to adverse effects, these new therapies offer significant advances in the quality of patient care.

Immune mechanisms of new therapeutic strategies in multiple sclerosis—A focus on alemtuzumab

Alemtuzumab is a humanized monoclonal antibody targeting CD52, a broadly expressed cell surface molecule on immune cells. Application results in a rapid and long-lasting removal of lymphocyte populations from the circulation. Alemtuzumab-treatment of MS patients with relapsing-remitting forms of the disease significantly reduced the risk of relapse and accumulation of disability compared to interferon β-1a treatment in a phase II trial. Interestingly, further analysis together with parallel experimental studies suggested that alemtuzumab not only reduces disease activity due to its immune cell-depleting effect, but also confers neuroprotective effects, presumably by inducing production of neurotrophic factors in autoreactive T cells. However, alemtuzumab-treated MS patients experienced increased rates of novel autoimmunity and a slight increase in infections, demonstrating that alemtuzumab-mediated skewing of the immune cell compartment has a broad influence on immune functions. This review discusses the current concepts about the underlying mechanisms causing these altered immune responses in alemtuzumab-treated MS patients.

Novel Agents and Emerging Treatment Strategies in Multiple Sclerosis. What Role for Cladribine?

Multiple sclerosis (MS), a chronic inflammatory-degenerative illness of the central nervous system (CNS), remains at the moment a treatable but incurable disease. Currently available disease-modifying agents (DMA-s), the majority of which are being injected, mainly relieve the inflammatory phase of MS with little beneficial effect, if any, in halting neurodegeneration. Cladribine is an immunosuppressive agent that can be administered orally and by cycles of short-course dosing as opposed to continuous administration. Cladribine has been shown to be effective in reducing inflammatory activity of MS but much remains unknown regarding its potential beyond the control of CNS inflammation. In addition, knowledge on the safety profile of cladribine in MS is limited. Data from on going clinical studies and registries on its safety profile will shed more light on the actual benefit/risk ratio of cladribine.

Approaches to neuroprotective strategies in multiple sclerosis

Importance of the field: Multiple sclerosis (MS) is a neurologic disease that is the most common nontraumatic cause of serious disability in young adults.Areas covered in this review: We discuss the natural history of the disease, methods of measuring disease activity and burden, and cellular and molecular mechanisms of damage, in particular recent advances. These imply new therapeutic targets, which are beginning to be tested in animal models of MS as well as in patients.What the reader will gain: The reader will learn about some recent advances in understanding MS, especially the evolution from an inflammatory phase to a neurodegenerative phase, which have different therapeutic approaches.Take home message: MS has a long-term course of accumulating deficit in which neuroinflammation evolves into neurodegeneration, which require different treatment strategies – immune modulation and neuroprotection. Neuroprotective strategies are still under development.

Relapse management strategies in multiple sclerosis: Theories and practice

Relapses are experienced by 85–90% of people at and following onset of multiple sclerosis, as a feature of their disease (Lublin and Reingold, 1996). There is a great deal of uncertainty and variation with regards to presentation, duration and frequency of recurrence of relapses which varies for each individual. Guidance from the National Institute for Health and Clinical Excellence (2003) recommend treating a relapse with high doses of methylprednisolone over a 3-5-day period. The evidence underpinning these recommendations as well as some of the theory and practice behind this will be reviewed in this article.

A Novel Probiotic Mixture Exerts a Therapeutic Effect on Experimental Autoimmune Encephalomyelitis Mediated by IL-10 Producing Regulatory T Cells

BackgroundMultiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS). One potential therapeutic strategy for MS is to induce regulatory cells that mediate immunological tolerance. Probiotics, including lactobacilli, are known to induce immunomodulatory activity with promising effects in inflammatory diseases. We tested the potential of various strains of lactobacilli for suppression of experimental autoimmune encephalomyelitis (EAE), an animal model of MS.Methodology/Principal FindingsThe preventive effects of five daily-administered strains of lactobacilli were investigated in mice developing EAE. After a primary screening, three Lactobacillus strains, L. paracasei DSM 13434, L. plantarum DSM 15312 and DSM 15313 that reduced inflammation in CNS and autoreactive T cell responses were chosen. L. paracasei and L. plantarum DSM 15312 induced CD4+CD25+Foxp3+ regulatory T cells (Tregs) in mesenteric lymph nodes (MLNs) and enhanced production of serum TGF-β1, while L. plantarum DSM 15313 increased serum IL-27 levels. Further screening of the chosen strains showed that each monostrain probiotic failed to be therapeutic in diseased mice, while a mixture of the three lactobacilli strains suppressed the progression and reversed the clinical and histological signs of EAE. The suppressive activity correlated with attenuation of pro-inflammatory Th1 and Th17 cytokines followed by IL-10 induction in MLNs, spleen and blood. Additional adoptive transfer studies demonstrated that IL-10 producing CD4+CD25+ Tregs are involved in the suppressive effect induced by the lactobacilli mixture.Conclusions/SignificanceOur data provide evidence showing that the therapeutic effect of the chosen mixture of probiotic lactobacilli was associated with induction of transferable tolerogenic Tregs in MLNs, but also in the periphery and the CNS, mediated through an IL-10-dependent mechanism. Our findings indicate a therapeutic potential of oral administration of a combination of probiotics and provide a more complete understanding of the host-commensal interactions that contribute to beneficial effects in autoimmune diseases.

Update on the treatment options for multiple sclerosis

Recent progress in the treatment of multiple sclerosis (MS) is remarkable, and the introduction of new therapies is yielding improvements in the management of MS. Furthermore, clinical trials with many different types of agents, especially selected monoclonal antibodies, have been undertaken or are ongoing, and some of the agents involved will probably be available as treatments for MS in the near future. Although these new and promising agents include targeted immunotherapies, some of them have limitations such as associated severe adverse events and the development of neutralizing antibodies. With regard to risk–benefit ratios, pharmacogenetics could shed light on inherited differences in drug metabolism and response, which would make individualized therapy possible in MS. Here, we review the recent progress in current therapeutic strategies for MS, and the potential options for future MS treatment.

Impact of cognitive impairment on coping strategies in multiple sclerosis

Objectives: To assess the impact of cognitive impairment (CI) on coping strategies in multiple sclerosis (MS). Materials and methods: Sixty-three patients (40 women, 55 relapsing-remitting and 8 secondary progressive, age 42.6 ± 10.1 years, Expanded Disability Status Scale 2.2 ± 1.7) were assessed using the Coping Orientation for Problem Experiences-New Italian version Inventory, the Beck Depression Inventory and the Rao's Brief Repeatable Battery. Results: MS patients were less likely to use positive and problem-focused strategies, whereas avoiding strategies were adopted more frequently. Twenty-three (36.5%) cases were CI. We found no differences in the type of coping between CI and cognitively preserved patients. Scores on the Stroop test (beta = −0.91, p = 0.04) and on the Word List Generation (beta = 1.15, p = 0.04) were associated with poorer coping strategies. Conclusions: Our study suggests that cognitive functioning (in particular on sustained attention and aspects of executive function) must be considered in a comprehensive account of the factors contributing to successful coping in MS patients.

FP36-WE-01 Adaptive seamless trial designs in neurology: a case study in secondary progressive multiple sclerosis

Purpose: Adaptive seamless Phase II/III designs are attractive, and have been proposed for neurological settings such as: stroke, amyotrophic lateral sclerosis and pain control. In essence, they commence with a multi-arm stage, stopping treatments or treatment doses, for futility in an interim analysis (eg based on early biological markers), whilst taking the promising compound(s)/ dose(s) through to the final stage. Despite the advent of a raft of novel drug strategies in multiple sclerosis (MS) which reduce relapse rate, the problem of trying to slow or stop disease progression remains intractable. We explored the feasibility of implementing an adaptive seamless design (ASD) in the context of secondary progressive multiple sclerosis (SPMS).

Antigen-Based Therapy for the Treatment of Type 1 Diabetes

Antigen-based therapies (ABTs) seek to prevent or inhibit autoimmune diseases by inducing regulatory T-cell responses (active tolerance) or anergizing/deleting pathogenic T-cells (passive tolerance). The theoretical appeal of this therapeutic approach is that it may promote tolerance with little debilitation of the immune system. The clinical application of ABTs for autoimmune disease is still in its infancy. Although initial attempts to apply this therapeutic strategy in multiple sclerosis, rheumatoid arthritis, and type 1 diabetes met with failure, recent results from clinical studies hold promise that this approach may be able to delay the onset of type 1 diabetes as well as preserve β-cell function in latent autoimmune diabetes in adults (LADA) patients and in children newly diagnosed with type 1 diabetes. If verified, it would be an important translation of NOD mouse findings to clinical applications. NOD mouse studies, however, indicate that the immunological impact of ABTs is much more dynamic and complex than previously appreciated. The differences in type 1 diabetes pathogenesis between rodents and humans, as well as other immunotherapeutic approaches, have been extensively reviewed elsewhere (e.g., [1–3]). Here, we will focus on ABTs and discuss what has been learned about their immunological impact, the theoretical factors affecting their efficacy and safety, as well as potential markers of their therapeutic efficacy. ### Inflammatory T-cell responses spread among β-cell antigens during the development of murine and human type 1 diabetes. Type 1 diabetes is mediated by autoreactive T-cells recognizing β-cell autoantigens (β-CAAs). In NOD mice, autoreactive CD4+ T-cells are generally Th1 type (interferonγ secreting), and autoimmunity progressively spreads intra- and intermolecularly among β-CAAs such as insulin, GAD, heat shock protein (HSP), and IGRP during the disease process (4,5). Similarly, spontaneous CD8+ T-cell responses develop to β-CAAs such as insulin, GAD, IGRP, and others (6). Paralleling observations in NOD mice, autoreactive Th1-biased CD4+ and CD8+ T-cells arise in human …

Imaging outcomes for neuroprotection and repair in multiple sclerosis trials

Multiple sclerosis (MS) is commonly regarded as an inflammatory disease, but it also has a neurodegenerative component, which represents an additional target for treatment. The use of MRI to evaluate the inflammatory disease component in 'proof-of concept' clinical trials is well established, but no systematic assessment of imaging outcomes to evaluate neuroprotection or repair in MS has been performed. In this Review, we examine the potential of traditional and novel imaging parameters to serve as primary outcomes in phase II clinical trials of neuroprotective and reparative strategies in MS. We present the conclusions of an international meeting of imaging, clinical and statistical experts, as well as a review of relevant literature. The available imaging techniques are appraised in five categories of performance: pathological specificity, reproducibility, sensitivity to change, clinical relevance, and response to treatment. At present, the three most promising primary outcomes in phase II trials of neuroprotective and/or reparative strategies in MS are: changes in whole-brain volume to gauge general cerebral atrophy; T1 hypointensity and magnetization transfer ratio to monitor the evolution of lesion damage; and optical coherence tomography findings to evaluate the anterior visual pathway. Power calculations show that these outcome measures can be applied with attainable sample sizes.

Coping strategies, psychological variables and their relationship with quality of life in multiple sclerosis

The aim of this study was to assess the impact of psychological features in the choice of coping strategies in multiple sclerosis (MS) patients, and their influence on quality of life (QoL). One hundred four patients (72 women, age 45.3 +/- 10.9 years, disease duration 17.9 +/- 13.2 years, Expanded Disability Status Scale 2.8 +/- 2.0) were assessed through the Beck Depression Inventory, the State-Trait Anxiety Inventory, the Eysenck Personality Questionnaire, the Coping Orientation for Problem Experiences-New Italian version and the MSQoL-54. MS patients were less likely to use problem-focused strategies, whereas avoiding strategies were adopted more frequently. The use of positive strategies positively influenced both mental and overall QoL. Depression had a negative impact on all QoL domains and anxiety on mental domains. These data point out the importance of a comprehensive assessment of MS patients. Orienting therapeutic interventions, to oppose depression and anxiety and to favour more appropriate coping strategies can improve the patients' QoL.

Immunomodulatory treatment strategies in multiple sclerosis

Multiple sclerosis (MS) represents the prototypic inflammatory autoimmune disorder of the central nervous system and the most common cause of neurological disability in young adults. The mainstays in the immunomodulatory therapy of MS are currently interferon beta and glatiramer acetate, both of which have proven to be clinically and paraclinically effective. Current clinical evidence indicates that treatment should be initiated as early as possible. In this review we summarize available data from clinical studies on clinical efficacy of immunomodulatory drugs for treating patients with multiple sclerosis.

Magnetic resonance imaging in clinical trials

The aim of this article is to review the latest clinical trials in neurological diseases where magnetic resonance imaging was used to assess treatment outcome. The unique sensitivity of magnetic resonance imaging for detecting disorders in the brain has made it an attractive noninvasive tool for assessing treatment efficacy in several diseases. Volumetric and functional magnetic resonance imaging have proved to represent robust biomarkers for the evaluation of anti-Alzheimer treatments, and have demonstrated a significant impact of cholinesterase inhibitors. The optimization of thrombolytic therapy in acute ischemic stroke has concentrated on the quantification of the ischemic penumbra, using perfusion-weighted and diffusion-weighted imaging. Standard assessment of T2 or fluid-attenuated inversion recovery lesion load remains the method of choice to evaluate new therapeutic strategy in multiple sclerosis. Other nonconventional quantitative magnetic resonance imaging techniques such as magnetic resonance volumetry, magnetization transfer imaging, diffusion-weighted imaging, or magnetic resonance spectroscopy are increasingly used in the field. Magnetic resonance imaging has become a major surrogate marker of treatment response in clinical trials of neurological disorders, offering the possibility to reduce the required sample size or to shorten the duration of the trial.

Multiple sclerosis: new treatment trials and emerging therapeutic targets

This review focuses on new therapeutic strategies in multiple sclerosis. The past decade has marked the advent of various new therapeutic strategies in multiple sclerosis. Whereas the current armamentarium of immunomodulatory medications has demonstrated beneficial effects on the disease, more effective and tolerable therapies are needed. Several novel therapeutic strategies in testing include oral therapies, monoclonal antibodies, symptomatic treatments as well as insights into neuroprotection and repair. Ways to build upon existing therapies are also under investigation, including early initiation of treatment and various combination regimens. New therapies, along with variations of currently available treatments, may prove more efficacious and tolerable than the available arsenal of treatments. Nevertheless, as the treatment horizon broadens, choosing first-line therapies will become more complicated, with greater influence of risk-to-benefit ratios in light of premature safety data. Patient's clinical, paraclinical and biomarker fingerprint profiles may help elucidate disease subtypes as well as response to therapy in an effort to individualize treatment choice. A complete discussion of all studies currently underway is beyond the scope of this review, which will highlight recent promising therapeutic strategies under investigation in the field of multiple sclerosis.

Prospective memory and the efficacy of a memory strategy in multiple sclerosis.

Prospective memory (PM), which is the ability to remember to carry out actions that are planned for the future, plays an important role in professional and social life as well as in activities of daily living. This study examined PM performance among adults with multiple sclerosis (MS) and evaluated the efficacy of a mnemonic strategy, implementation intentions. Compared to controls, adults with MS were impaired on PM, both in terms of acting when encountering the correct circumstances (prospective component) and in terms of remembering the correct action to perform (retrospective component). The prospective-component deficit was greater for tasks that depended on more resource-demanding cognitive processes and smaller on tasks that could be performed more automatically. Use of implementation intentions improved MS-group performance on the prospective component, particularly on the more resource-demanding tasks, consistent with the explanation that implementation intentions improved performance by allowing the use of more automatic processes to perform these PM tasks. Implications for providing environmental support to encourage the use of mnemonic strategies are discussed.

Proteomic strategies in multiple sclerosis and its animal models

The early and precise diagnosis, the prognosis, and the clinical management of multiple sclerosis, remain a considerable challenge. In recent years, the development of novel and powerful proteomic techniques prompted the use of these approaches for the search of unique biomarkers in the cerebrospinal fluid of multiple sclerosis patients. A few studies have also utilized proteomics to delineate the profile of differentially expressed proteins in animal models of the human disease in order to gain global insights into affected pathways. The identification of differentially expressed proteins may be an initial step in the discovery of novel targets and mechanisms that play critical roles in the pathology of multiple sclerosis. Based on these findings, future investigations may elucidate the events leading to demyelination, axonal damage, and neurodegeneration, providing better insights into mechanisms governing the onset and progression of the disease. Although these proteomic studies provide valuable information, they are also faced with a number of challenges. The present review discusses some of the strengths and limitations of proteomic investigations as applied to multiple sclerosis.

Multiple sclerosis therapy: an update on recently finished trials.

Six pharmacological agents are currently approved for the treatment of multiple sclerosis (MS).However, all established substances are only partially effective in reducing disease progression or relapse rates. In addition, they have potentially serious side effects. Thus, significant efforts are being made to develop new agents or to optimize current therapies. The latter includes modifications of dose, route of administration or the time point of treatment initiation. In this review, we provide an update on the most important clinical phase II/III trials on approved and novel immunotherapeutic strategies in MS reported during the last two years. Pharmacotherapies include agents that target chemoattraction, cell migration, chemotherapies, and antigen-based therapies.