Immunomodulatory potential of anti-IFN-beta antibodies on monocyte-derived macrophages.

Multiple sclerosis (MS) is a disabling neurological disease with an unknown etiology, where the recombinant interferon beta (rIFNβ) is the most established treatment. However, the development of anti-IFNβ antibodies has posed a significant therapeutic drawback. In this study, the interaction between anti-IFNβ antibodies and macrophages was investigated to assess the effects on the immune system.

The Benefits and Risks of Switching from Fingolimod to Siponimod for the Treatment of Relapsing-Remitting and Secondary Progressive Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic neurodegenerative disease that affects the central nervous system (CNS). Currently, MS treatment is limited to several Food and Drug Administration (FDA)- and European Medicines Agency (EMA)-approved medications that slow disease progression by immunomodulatory action. Fingolimod and siponimod have similar mechanisms of action, and consequently, their therapeutic effects may be comparable.

The agenda of the global patient reported outcomes for multiple sclerosis (PROMS) initiative: Progresses and open questions.

On 12 September 2019, the global Patient Reported Outcome for Multiple Sclerosis (PROMS) Initiative was launched at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The multi-stakeholder PROMS Initiative is jointly led by the European Charcot Foundation (ECF) and the Multiple Sclerosis International Federation (MSIF), with the Italian Multiple Sclerosis Society (AISM) acting as the lead agency for and on behalf of the global MSIF movement. The initiative has the ambitious mission to (i) maximize the impact of science with and of patient input on the life of people affected by MS, and (ii) to represent a unified view on Patient-Reported Outcomes for MS to people affected by MS, healthcare providers, regulatory agencies and Health Technologies Assessments agencies.

Ozanimod in relapsing multiple sclerosis: Pooled safety results from the clinical development program.

Background: Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for the treatment of relapsing multiple sclerosis (RMS). In phase 3 trials, ozanimod was well tolerated and superior to interferon beta-1a 30 µg once-weekly in reducing clinical and radiologic disease activity. The objective of this integrated safety analysis was to evaluate the safety of extended ozanimod exposure in participants with RMS from all clinical trials and compare it with phase 3 trial data.

Secretome Analysis of Mesenchymal Stem Cell Factors Fostering Oligodendroglial Differentiation of Neural Stem Cells In Vivo.

Mesenchymal stem cell (MSC)-secreted factors have been shown to significantly promote oligodendrogenesis from cultured primary adult neural stem cells (aNSCs) and oligodendroglial precursor cells (OPCs). Revealing underlying mechanisms of how aNSCs can be fostered to differentiate into a specific cell lineage could provide important insights for the establishment of novel neuroregenerative treatment approaches aiming at myelin repair. However, the nature of MSC-derived differentiation and maturation factors acting on the oligodendroglial lineage has not been identified thus far.

Rescuing the negative impact of human endogenous retrovirus envelope protein on oligodendroglial differentiation and myelination.

Remyelination in the adult CNS depends on activation, differentiation, and functional integration of resident oligodendroglial precursor cells (OPCs) and constitutes the only spontaneous neuroregenerative process able to compensate for functional deficits upon loss of oligodendrocytes and myelin sheaths as it is observed in multiple sclerosis. The proteins encoded by p57kip2- and by human endogenous retrovirus type W (pHERV-W) envelope genes were previously identified as negative regulators of OPC maturation. We here focused on the activity of the ENV protein and investigated how it can be neutralized for an improved myelin repair.

ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis.

Background: Multiple sclerosis (MS) is a complex disease with new drugs becoming available in the past years. There is a need for a reference tool compiling current data to aid professionals in treatment decisions.

Objectives: To develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS.

Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria.

The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions.

The Role of Peripheral Myelin Protein 2 in Remyelination.

The protein component of the myelin layer is essential for all aspects of peripheral nerves, and its deficiency can lead to structural and functional impairment. The presence of peripheral myelin protein 2 (P2, PMP2, FABP8, M-FABP) in Schwann cells has been known for decades and shown recently to be involved in the lipid homeostasis in the peripheral neural system. However, its precise role during de- and remyelination has yet to be elucidated.

A placebo randomized controlled study to test the efficacy and safety of GNbAC1, a monoclonal antibody for the treatment of multiple sclerosis - Rationale and design.

Background: GNbAC1, a humanized monoclonal antibody, is an innovative treatment currently in development for multiple sclerosis (MS) which, contrary to the immunomodulation/immunosuppressive mechanism of action of most of the MS drugs, targets specifically a protein of endogenous retroviral origin supposed to be critical in MS pathogenesis.

Methods: This trial is a randomized placebo controlled 4-arm study with the objective of demonstrating the efficacy of repeated doses of GNbAC1 on the cumulative number of T1 Gd-enhancing lesions measured from Week 12 to 24 in patients with relapsing remitting MS (RRMS). Two hundred sixty patients with RRMS are planned to be included.

Alteration of the cytokine signature by various TLR ligands in different T cell populations in MOG37-50 and MOG35-55-induced EAE in C57BL/6 mice.

Interleukin 17 (IL-17), produced by T cells, plays an important role in Multiple Sclerosis (MS) and its animal model, Experimental Autoimmune Encephalomyelitis (EAE). In contrast to IL-17-producing CD4+ T cells, the contribution of IL-17-producing CD8+ T cells (Tc17) in CNS autoimmunity has been investigated less intensively. Here we investigate the role of TC17 in EAE.

Isoniazid-induced polyneuropathy in a tuberculosis patient - implication for individual risk stratification with genotyping?

Background: Development of polyneuropathy (PNP) under treatment for tuberculosis (TB), including isoniazid (INH), is a highly relevant adverse drug effect. The NAT2 acetylation status is a predictor of potential toxic effects of INH. The question as to whether individual risk stratification by genotyping is useful to avoid suffering of patients and to lower costs for the health care system is of considerable clinical importance.

Dimethyl fumarate in relapsing-remitting multiple sclerosis: rationale, mechanisms of action, pharmacokinetics, efficacy and safety.

Dimethyl fumarate (DMF), a fumaric acid ester, is a new orally available disease-modifying agent that was recently approved by the US FDA and the EMA for the management of relapsing forms of multiple sclerosis (MS). Fumaric acid has been used for the management of psoriasis, for more than 50 years. Because of the known anti-inflammatory properties of fumaric acid ester, DMF was brought into clinical development in MS.

Clinical management of multiple sclerosis and neuromyelitis optica with therapeutic monoclonal antibodies: approved therapies and emerging candidates.

Therapeutic monoclonal antibodies (mAbs) are a relatively novel class of drugs that has substantially advanced immunotherapy for patients with multiple sclerosis. The advantage of these agents is that they bind specifically and exclusively to predetermined proteins or cells. Natalizumab was the first mAb in neurology to obtain approval.

Molecular mechanism underlying the impact of vitamin D on disease activity of MS.

Objective: Some previous studies suggest modest to strong effects of 25-hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic rationale that may explain potential clinical effects of 25(OH)D.

Methods: This study measured serum 25(OH)D levels and global gene expression profiles over a course of up to 2 years in patients starting treatment with interferon beta-1b (IFNB-1b) after a clinically isolated syndrome.

Bacterial flagellin and diphtheria toxin co-stimulate IL-17-producing thymocytes.

IL-17-producing thymocytes have been recently described and are believed to play a role as an immune cell population which is able to react against microbial components rapidly. For this reason, we here investigated the ability of two microbial stimulants, bacterial flagellin (a ligand for TLR5) and diphtheria toxin from Corynebacterium diphtheriae, to activate or co-activate (together with α-CD3 stimulation) thymocyte cytokine production. We find that both bacterial molecules do not induce cytokine-production by themselves, but co-activate IL-17-producing thymocytes together with α-CD3.

Citalopram suppresses thymocyte cytokine production.

Antidepressant drugs, in particular those targeting the serotonin (5-HT)-reuptake system via the serotonin transporter (5-HTT), are known to exhibit antiinflammatory properties and have demonstrated therapeutic efficacy in rodent models of autoimmune disease like experimental autoimmune encephalomyelitis or experimental rheumatoid arthritis. A crucial difference between animal models and the actual human autoimmune disease is the fact that in animals predominantly induced T cells are studied after sensitization with autoantigen. In humans, however, naturally occurring cytokine-producing T cells might play a significant role as well.

Induction of pro-inflammatory cytokine production in thymocytes by the immune response modifiers Imiquimod and Gardiquimod™.

An emerging role is postulated for IL-17-producing thymocytes, which in their majority consist of IL-17-producing CD4(+) cells. For these, a specific role in the immediate defense against infectious pathogens is suggested, independent from the development of an adaptive immune response in the immune periphery. Immune response modifiers, like the TLR7 ligands Imiquimod and Gardiquimod™ are effective pharmacological therapeutics applied topically against dermal tumors and virus infections and have been demonstrated to activate immune cells.

Efficacy and safety of interferon beta-1b sc in older RRMS patients--a posthoc analysis of the BEYOND study.

Evidence of a significant improvement of IFNB-1b in clinical severity in the older population with RRMS has not been established so far. The aim of this exploratory post hoc analysis of the 250 mcg IFNB-1b group of the BEYOND study is to compare the efficacy and safety of older versus younger patients using a cut-off at the age of 50 and at the age of 40, respectively. There was no difference between age groups in adjusted relapse risk (age 50 cut-off: P = 0.

Recovery of the T-cell repertoire in CIDP by IV immunoglobulins.

Objective: To investigate changes in the T-cell repertoire in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) without and with treatment of IV immunoglobulins (IVIg).

Methods: The T-cell receptor (TCR) repertoire of CD4+ and CD8+ T cells in the peripheral blood was analyzed using CDR3 spectratyping. Patients with CIDP were included without (n = 14) and with IVIg treatment (n = 11) cross-sectionally and longitudinally (n = 2).

Clinical improvement precedes lesion size regression in a severe case of acute disseminated encephalomyelitis.

Here, we present a case of a severe acute disseminated encephalomyelitis (ADEM) of a 42-year-old male patient. The diagnosis was established after brain biopsy and due to acutely evolving encephalopathy occurring in the context of atypical Mycoplasma pneumoniae (MP). We analysed the prominent MRI white matter lesions using a three-dimensional algorithm as cutting-edge technique to study morphological abnormalities and correlated them to the clinical condition of the patient.

Ex vivo activation of naturally occurring IL-17-producing T cells does not require IL-6.

Interleukin (IL-)17 is a potent proinflammatory cytokine for which an important role in the immune response against infections and in autoimmune diseases has been demonstrated. Recently, it has been shown that - in addition to mature T cells which are primed in the immune periphery - this cytokine can also be produced by T cells in the thymus, so-called naturally occurring IL-17-producing T cells (nT17 cells). In this study we demonstrate that the generation and activation of nT17 cells in the thymus do not depend on the cytokine IL-6.

Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients.

Background: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity.

Objective: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus.