Bart Van Wijmeersch

Ablation of Proliferating Microglia Does Not Affect Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis Caused by Mutant Superoxide Dismutase

Microglial activation is a hallmark of all neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Here, a detailed characterization of the microglial cell population within the spinal cord of a mouse model of familial ALS was performed. Using flow cytometry, we detected three distinct microglial populations within the spinal cord of mice overexpressing mutant superoxide dismutase (SOD1): mature microglial cells (CD11b+, CD45low), myeloid precursor cells (CD11b+, CD45int), and macrophages (CD11b+, CD45high). Characterization of cell proliferation within the CNS of SOD1G93A mice revealed that the expansion in microglial cell population is mainly attributable to the proliferation of myeloid precursor cells. To assess the contribution of proliferating microglia in motor neuron degeneration, we generated CD11b-TKmut-30; SOD1G93A doubly transgenic mice that allow the elimination of proliferating microglia on administration of ganciclovir. Surprisingly, a 50% reduction in reactive microglia specifically in the lumbar spinal cord of CD11b-TKmut-30; SOD1G93A doubly transgenic mice had no effect on motor neuron degeneration. This suggests that proliferating microglia-expressing mutant SOD1 are not central contributors of the neurodegenerative process in ALS caused by mutant SOD1.

Experimental and clinical approaches for optimization of the graft-versus-leukemia effect

The goal of allogeneic (allo)-hematopoietic stem-cell transplantation (HSCT) in the treatment of hematologic malignancies is to harness the graft-versus-leukemia (GVL) effect, while minimizing the risk of graft-versus-host disease (GVHD). Allo-HSCT research has focused on the GVL target antigens and effector mechanisms, and on potential approaches to exploit GVL independently of GVHD. Donor lymphocyte infusion (DLI) achieves the most powerful anti-leukemic responses, and this approach is often used in combination with nonmyeloablative transplant regimens to optimize GVL and reduce GVHD. Serial, dose-escalating, and CD8+ T-cell-depleted DLI have been introduced into clinical practice, while other variants of DLI have so far been explored only in animal models. The role of naturally occurring regulatory T cells in transplantation tolerance is being increasingly acknowledged, and murine studies indicate the potential ability of T cells to regulate GVHD while maintaining GVL. Experimental and clinical studies have demonstrated the importance of host-type chimerism, particularly for antigen-presenting cells, in determining the occurrence of DLI-induced GVL. Murine studies could assist in the development of clinical strategies targeted at antigen-presenting cells. Clinical studies exploiting natural killer-cell-mediated antitumor reactivity in the context of killer inhibitory receptor-ligand-mismatched allo-HSCT have provided promising results.

Optimizing therapy early in multiple sclerosis: An evidence-based view

Therapies that target the underlying pathology of multiple sclerosis (MS), including focal and diffuse damage, may improve long-term disease control. Focal damage (inflammatory lesions) manifests clinically mainly as relapses, whereas diffuse damage (neurodegeneration and brain volume loss) has been more closely associated with disability progression and cognitive decline. Given that first-line therapies such as beta-interferon and glatiramer acetate, which are primarily directed against inflammation, might fail to adequately control disease activity in some patients, it has been recommended to switch these patients early to a therapy of higher efficacy, possibly targeting both components of MS pathology more rigorously. This review provides an overview of the efficacy of EU-approved disease-modifying therapies on conventional MS outcome measures (relapses, disability progression and paraclinical magnetic resonance imaging endpoints) in addition to brain volume loss, a measure of diffuse damage in the brain. In addition, the evidence supporting early treatment optimization in patients with high disease activity despite first-line therapy will be reviewed and an algorithm for optimal disease control will be presented.

Compositional Changes of B and T Cell Subtypes during Fingolimod Treatment in Multiple Sclerosis Patients: A 12-Month Follow-Up Study

Background and objective The long term effects of fingolimod, an oral treatment for relapsing-remitting (RR) multiple sclerosis (MS), on blood circulating B and T cell subtypes in MS patients are not completely understood. This study describes for the first time the longitudinal effects of fingolimod treatment on B and T cell subtypes. Furthermore, expression of surface molecules involved in antigen presentation and costimulation during fingolimod treatment are assessed in MS patients in a 12 month follow-up study. Methods Using flow cytometry, B and T cell subtypes, and their expression of antigen presentation, costimulation and migration markers were measured during a 12 month follow-up in the peripheral blood of MS patients. Data of fingolimod-treated MS patients (n = 49) were compared to those from treatment-naive (n = 47) and interferon-treated (n = 27) MS patients. Results In the B cell population, we observed a decrease in the proportion of non class-switched and class-switched memory B cells (p<0.001), both implicated in MS pathogenesis, while the proportion of naive B cells was increased during fingolimod treatment in the peripheral blood (PB) of MS patients (p<0.05). The remaining T cell population, in contrast, showed elevated proportions of memory conventional and regulatory T cells (p<0.01) and declined proportions of naive conventional and regulatory cells (p<0.05). These naive T cell subtypes are main drivers of MS pathogenesis. B cell expression of CD80 and CD86 and programmed death (PD) -1 expression on circulating follicular helper T cells was increased during fingolimod follow-up (p<0.05) pointing to a potentially compensatory mechanism of the remaining circulating lymphocyte subtypes that could provide additional help during normal immune responses. Conclusions MS patients treated with fingolimod showed a change in PB lymphocyte subtype proportions and expression of functional molecules on T and B cells, suggesting an association with the therapeutic efficacy of fingolimod.

Perceived and actual arm performance in multiple sclerosis: relationship with clinical tests according to hand dominance

Background: The real-life relevance of frequently applied clinical arm tests is not well known in multiple sclerosis (MS). Objective: This study aimed to determine the relation between real-life arm performance and clinical tests in MS. Methods: Thirty wheelchair-bound MS patients and 30 healthy controls were included. Actual and perceived real-life arm performance was measured by using accelerometry and a self-reported measure (Motor Activity Log). Clinical tests on ‘body functions & structures’ (JAMAR handgrip strength, Motricity Index (MI), Fugl Meyer (FM)) and ‘activity’ level (Nine Hole Peg Test (NHPT), Action Research Arm test) of the International Classification of Functioning were conducted. Statistical analyses were performed separately for current dominant and non-dominant arm. Results: For all outcome measures, MS patients scored with both arms significantly lower than the control group. Higher correlations between actual arm performance and clinical tests were found for the non-dominant arm (0.63–0.80). The FM (55%) was a good predictor of actual arm performance, while the MI (46%) and NHPT (55%) were good predictors of perceived arm performance. Conclusions: Real-life arm performance is decreased in wheelchair-bound MS patients and can be best predicted by measures on ‘body functions & structures’ level and fine motor control. Hand dominance influenced the magnitude of relationships.

Anodal tDCS increases corticospinal output and projection strength in multiple sclerosis.

The application of anodal transcranial direct current stimulation (atDCS) to the human brain has been shown to elicit corticospinal (CS) excitability changes. This study evaluated the effect of a single session of atDCS on CS excitability in patients with multiple sclerosis (MS). atDCS and sham tDCS (stDCS) were applied to the primary motor cortex (M1) contralateral to the more severely impaired hand for 20min in a double-blinded crossover design. Changes in CS excitability were assessed using transcranial magnetic stimulation (TMS). The area under the recruitment curves increased significantly after application of atDCS (+56.58%, p=0.023) but not after stDCS. A sigmoidal curve-analysis revealed a higher plateau of the curve after atDCS (+22.2%, p<0.001). Our results showed that atDCS over M1 has the ability to increase CS output and projection strength in MS-patients, suggesting that atDCS can be considered during neural rehabilitation to facilitate motor recovery in MS.

Circulating Follicular Regulatory T Cells Are Defective in Multiple Sclerosis.

Follicular regulatory T cells (TFR) have been extensively characterized in mice and participate in germinal center responses by regulating the maturation of B cells and production of (auto)antibodies. We report that circulating TFR are phenotypically distinct from tonsil-derived TFR in humans. They have a lower expression of follicular markers, and display a memory phenotype and lack of high expression of B cell lymphoma 6 and ICOS. However, the suppressive function, expression of regulatory markers, and FOXP3 methylation status of blood TFR is comparable with tonsil-derived TFR. Moreover, we show that circulating TFR frequencies increase after influenza vaccination and correlate with anti-flu Ab responses, indicating a fully functional population. Multiple sclerosis (MS) was used as a model for autoimmune disease to investigate alterations in circulating TFR. MS patients had a significantly lower frequency of circulating TFR compared with healthy control subjects. Furthermore, the circulating TFR compartment of MS patients displayed an increased proportion of Th17-like TFR. Finally, TFR of MS patients had a strongly reduced suppressive function compared with healthy control subjects. We conclude that circulating TFR are a circulating memory population derived from lymphoid resident TFR, making them a valid alternative to investigate alterations in germinal center responses in the context of autoimmune diseases, and TFR impairment is prominent in MS.

Upper Limb Rehabilitation in People With Multiple Sclerosis A Systematic Review

Background. There has been an increasing research interest in upper limb rehabilitation in multiple sclerosis (MS). The current changes in the research field inquire a new literature review. Objective. This systematic review aimed to provide an overview of the upper limb rehabilitation strategies in people with MS (PwMS). Methods. Articles published in PubMed and Web of Knowledge were selected when written in English, published in the past 25 years, peer reviewed, that included at least 5 PwMS, and described the effects of an intervention study including rehabilitation strategies targeting the upper limbs. Included articles were screened based on title/abstract and full text by 2 independent reviewers. Results. Thirty articles met the criteria and were included for data extraction. Only half of the included studies investigated the effects of a training program specially targeted toward the upper limbs, while in the other studies, a general whole body therapy was used. The therapy content and dosage varied greatly between the different included studies. Multidisciplinary and robot-based rehabilitation were the most investigated rehabilitation strategies and showed to improve upper limb capacity. Strength and endurance training improved the upper limb body functions and structures but did not influence the upper limb capacity and performance. Conclusions. The results of this systematic review indicated that different types of upper limb rehabilitation strategies can improve upper limb function in PwMS. Further research is necessary to compare directly the effects of different rehabilitation strategies and to investigate the optimal therapy dosage according to the upper limb disability level.

IL-15 Amplifies the Pathogenic Properties of CD4+CD28− T Cells in Multiple Sclerosis

CD4+CD28− T cells arise through repeated antigenic stimulation and are present in diseased tissues of patients with various autoimmune disorders, including multiple sclerosis (MS). These cells are believed to have cytotoxic properties that contribute to the pathogenic damaging of the target organ. Endogenous cues that are increased in the diseased tissue may amplify the activity of CD4+CD28− T cells. In this study, we focused on IL-15, a cytotoxicity-promoting cytokine that is increased in the serum and cerebrospinal fluid of MS patients. Using immunohistochemistry, we demonstrate that IL-15 is mainly produced by astrocytes and infiltrating macrophages in inflammatory lesions of MS patients. Moreover, in vitro transmigration studies reveal that IL-15 selectively attracts CD4+CD28− T cells of MS patients, but not of healthy individuals. IL-15 further induces the expression of chemokine receptors and adhesion molecules on CD4+CD28− T cells, as investigated using flow cytometry, resulting in enhanced migration over a monolayer of human brain endothelial cells. Finally, flow cytometric analyses revealed that IL-15 increases the proliferation and production of GM-CSF, expression of cytotoxic molecules (NKG2D, perforin, and granzyme B), and degranulation capacity of CD4+CD28− T cells. Taken together, these findings indicate that increased peripheral and local levels of IL-15 amplify the pathogenic potential of CD4+CD28− T cells, thus contributing to tissue damage in MS brain lesions.

Documenting outdoor activity and travel behaviour in persons with neurological conditions using travel diaries and GPS tracking technology: a pilot study in multiple sclerosis

Abstract Objective: Persons with multiple sclerosis (PwMS) experience several physical and cognitive problems which can influence their travel behaviour. This study aimed to document the number of activities, the activity type and the transport mode of the related trips that are daily made by PwMS. Their outdoor activity and travel behaviour was studied in relation to disease-related disability. Methods: Thirty six PwMS (Expanded Disability Status Scale, EDSS, 1.5–8.0, age 27–63) and 24 healthy controls (age 25–62) were studied, using activity-related travel diaries and GPS tracking devices. Information about overall disability characteristics was gained by standard clinical tests and questionnaires. PwMS were further divided in three subgroups based on EDSS cut-off scores 4.5 and 6.5. Results: Persons with mild ambulatory dysfunction (EDSS 1.5–4.0, n = 17) showed similar travel characteristics to healthy controls, with few restrictions during travelling. Statistically significant changes in activity and travel behaviour were detected in the moderate (EDSS 4.5–6.5, n = 8) and severe MS subgroups (EDSS > 6.5–8.0, n = 11) compared with healthy controls: driving independently became less frequent, significant more trips were made with company and the duration of performed activities had increased. Conclusion: The combination of self-reported travel diaries and objective GPS loggers offered detailed information about the actual outdoor travel behaviour of PwMS, which was significantly changed in PwMS with EDSS greater than 4. Implications for Rehabilitation Activity and travel behaviour changes significantly in persons with multiple sclerosis (MS) with moderate to severe disability (EDSS greater than 4). Behavioural therapy could help to develop better coping and problem-solving skills to overcome anxiety in the making of trips by persons with MS with a mild severity. Enhancing community environments could serve as a promising approach to increase the outdoor participation of persons with (more severe) impairments.