Cell-Based Therapeutic Strategies in Multiple Sclerosis

2014 ◽  
Vol 9 (1) ◽  
pp. 37
Author(s):  
Ian Rossman ◽  
Jeffrey A Cohen ◽  
◽  
Keyword(s):  
Multiple Sclerosis ◽  
Neurological Deficits ◽  
Perivascular Spaces ◽  
Cns Injury ◽  
Surface Receptors ◽  
Immune Mediated ◽  
Relapsing Remitting ◽  
Disease Stages ◽  
Ongoing Phase

Multiple sclerosis (MS) is an immune-mediated disease in which acute inflammatory demyelination leads to axonal injury and neurodegeneration, and is manifested clinically by relapsing–remitting neurological deficits superimposed on chronic accumulation of disability. MS treatments are largely immunomodulatory with little, if any, effect on neurodegeneration. Mesenchymal stem cells MSCs) are pluripotent cells derived from adult tissues with intrinsic anti-inflammatory and repair-promoting properties. They cross the blood–brain barrier and target perivascular spaces, which are the sites of inflammatory cell infiltration in MS.In vitro, MSCs can be purified and expanded, labelled for post-transplant tracking and be manipulated to express surface receptors or neurotrophic factors for central nervous system (CNS) targeting or neuroprotection, respectively. Animal models of MS, traumatic CNS injury and neurodegenerative diseases demonstrate clinical and pathological benefits following MSC transplantation. Potentially, MSCs can be used to treat MS patients at various disease stages, which is the current focus of ongoing phase I/II clinical trials at multiple centres.

scholarly journals Increased Expression of Ephrins on Immune Cells of Patients with Relapsing Remitting Multiple Sclerosis Affects Oligodendrocyte Differentiation

2021 ◽  
Vol 22 (4) ◽  
pp. 2182
Author(s):  
Maya Golan ◽  
Avivit Krivitsky ◽  
Karin Mausner-Fainberg ◽  
Moshe Benhamou ◽  
Ifat Vigiser ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Cells ◽  
Inhibitory Effect ◽  
Autoimmune Response ◽  
Immune Mediated ◽  
Relapsing Remitting ◽  
The Central Nervous System ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

The effect of the inflammatory response on regenerative processes in the brain is complex. This complexity is even greater when the cause of the tissue damage is an autoimmune response. Multiple sclerosis (MS) is an immune-mediated disease in which demyelination foci are formed in the central nervous system. The degree of repair through oligodendrocyte regeneration and remyelination is insufficient. Ephrins are membrane-bound ligands activating tyrosine kinase signaling proteins that are known to have an inhibitory effect on oligodendrocyte regeneration. In this study, we examined the expression of ephrins on immune cells of 43 patients with relapsing-remitting (RR) MS compared to 27 matched healthy controls (HC). We found an increased expression of ephrin-A2, -A3 and -B3, especially on T cell subpopulations. We also showed overexpression of ephrins on immune cells of patients with RR-MS that increases the forward signaling pathway and that expression of ephrins on immune cells has an inhibitory effect on the differentiation of oligodendrocyte precursor cells (OPCs) in vitro. Our study findings support the concept that the immune activity of T cells in patients with RR-MS has an inhibitory effect on the differentiation capacity of OPCs through the expression and forward signaling of ephrins.

Case Report: Delayed Alemtuzumab-Induced Concurrent Neutropenia and Thrombocytopenia in Relapsing-Remitting Multiple Sclerosis

2021 ◽  
pp. 089719002110212
Author(s):  
Akaansha Ganju ◽  
James C. Stock ◽  
Kim Jordan
Keyword(s):  
Multiple Sclerosis ◽  
Case Reports ◽  
Severe Neutropenia ◽  
Cell Counts ◽  
Immune Mediated ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Study Participants ◽  
Relapsing Remitting Multiple Sclerosis

Alemtuzumab is an anti-CD52 monoclonal antibody used to treat relapsing-remitting multiple sclerosis following failure of second-line medications. It is administered intravenously in 2 treatment sequences 1 year apart. This drug is frequently associated with mild infusion reactions within days of administration, increased infection risk, and long term adverse events from secondary autoimmunity. Alemtuzumab-induced serious immune-mediated thrombocytopenia (ITP) is well-reported and occurred in 1.0-2.2% of participants in initial phase 2 and 3 trials for multiple sclerosis. Significant neutropenia, however, is rare and was only observed in 0.1% of study participants. Delayed neutropenia and/or ITP is thought to occur from secondary autoimmunity. Few case reports have described severe neutropenia occurring beyond 2 months of last alemtuzumab dose. We present an unusual case of delayed combined neutropenia and thrombocytopenia that occurred 15 months after the second infusion of alemtuzumab. The patient was asymptomatic and presented following discovery of neutropenia and thrombocytopenia during routine laboratory studies. The patient responded to steroids initially and was discharged, although outpatient cell counts subsequently revealed recurrent neutropenia and ITP. The adverse drug reaction probability (Naranjo) scale was completed and showed probable likelihood that the adverse event was alemtuzumab-related. Long term screening for delayed hematologic abnormalities, at least 4 years after initial dose, is necessary when using alemtuzumab. Greater research is needed to understand the mechanism of drug-associated neutropenia.

Cognition in Early Relapsing-Remitting Multiple Sclerosis: Consequences May Be Relative to Working Memory

2013 ◽  
Vol 19 (8) ◽  
pp. 938-949 ◽  
Author(s):  
Lindsay I. Berrigan ◽  
Jo-Anne LeFevre ◽  
Laura M. Rees ◽  
Jason Berard ◽  
Mark S. Freedman ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Working Memory ◽  
Processing Speed ◽  
Cognitive Functions ◽  
Group Membership ◽  
Equation Modeling ◽  
Mediating Role ◽  
Relapsing Remitting ◽  
Disease Stages

AbstractThe Relative Consequence Model proposes multiple sclerosis (MS) patients have a fundamental deficit in processing speed that compromises other cognitive functions. The present study examined the mediating role of processing speed, as well as working memory, in the MS-related effects on other cognitive functions for early relapsing-remitting patients. Seventy relapsing-remitting MS patients with disease duration not greater than 10 years and 72 controls completed tasks assessing processing speed, working memory, learning, and executive functioning. The possible mediating roles of speed and working memory in the MS-related effects on other cognitive functions were evaluated using structural equation modeling. Processing speed was not significantly related to group membership and could not have a mediating role. Working memory was related to group membership and functioned as a mediating/intervening factor. The results do not support the Relative Consequence Model in this sample and they challenge the notion that working memory impairment only emerges at later disease stages. The results do support a mediating/intervening role of working memory. These results were obtained for early relapsing-remitting MS patients and should not be generalized to the broader MS population. Instead, future research should examine the relations that exist at other disease stages. (JINS, 2013, 19, 1–12)

CRYAB modulates the activation of CD4+ T cells from relapsing–remitting multiple sclerosis patients

2013 ◽  
Vol 19 (14) ◽  
pp. 1867-1877 ◽  
Author(s):  
Que Lan Quach ◽  
Luanne M Metz ◽  
Jenna C Thomas ◽  
Jonathan B Rothbard ◽  
Lawrence Steinman ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Cytokine Production ◽  
Clinical Signs ◽  
Healthy Controls ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Multiple Sclerosis Patients ◽  
Relapsing Remitting Multiple Sclerosis

Background: Suppression of activation of pathogenic CD4+ T cells is a potential therapeutic intervention in multiple sclerosis (MS). We previously showed that a small heat shock protein, CRYAB, reduced T cell proliferation, pro-inflammatory cytokine production and clinical signs of experimental allergic encephalomyelitis, a model of MS. Objective: We assessed whether the ability of CRYAB to reduce the activation of T cells translated to the human disease. Methods: CD4+ T cells from healthy controls and volunteers with MS were activated in vitro in the presence or absence of a CRYAB peptide (residues 73–92). Parameters of activation (proliferation rate, cytokine secretion) and tolerance (anergy, activation-induced cell death, microRNAs) were evaluated. Results: The secretion of pro-inflammatory cytokines by CD4+ T cells was decreased in the presence of CRYAB in a subset of relapsing–remitting multiple sclerosis (RRMS) participants with mild disease severity while no changes were observed in healthy controls. Further, there was a correlation for higher levels of miR181a microRNA, a marker upregulated in tolerant CD8+ T cells, in CD4+ T cells of MS patients that displayed suppressed cytokine production (responders). Conclusion: CRYAB may be capable of suppressing the activation of CD4+ T cells from a subset of RRMS patients who appear to have less disability but similar age and disease duration.

scholarly journals Unraveling Natalizumab Effects on Deregulated miR-17 Expression in CD4+T Cells of Patients with Relapsing-Remitting Multiple Sclerosis

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Maria Meira ◽  
Claudia Sievers ◽  
Francine Hoffmann ◽  
Maria Rasenack ◽  
Jens Kuhle ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell Activation ◽  
Posttranscriptional Regulation ◽  
Cell Activation ◽  
Target Genes ◽  
Regulation Of Gene Expression ◽  
Expression Of Genes ◽  
Relapsing Remitting

MicroRNAs (miRNAs) are a family of noncoding RNAs that play critical roles in the posttranscriptional regulation of gene expression. Accumulating evidence supports their involvement in the pathogenesis of multiple sclerosis (MS). Here, we compare miR-17 expressions in CD4+T cells from relapsing-remitting (RR) MS patients treated with natalizumab versus untreated patients. miR-17 was downregulated under natalizumab treatment and upregulated during relapse, therefore supporting a possible role of miR-17 in MS immunopathogenesis. Downregulation of miR-17 was associated with upregulation of PTEN, BIM, E2F1, and p21 target genes.In vitromiR-17 inhibition was associated with upregulation of the same targets and resulted in impaired CD4+T cell activation and proliferation. We further describe deregulated TGFBR2 expression in untreated patients versus healthy volunteers (HVs) and confirmin vitrothe link between miR-17 and TGFBR2 expressions. These findings support an effect of natalizumab on expression of specific miRNA and subsequent expression of genes involved in proliferation and control of the cell cycle.

Alemtuzumab—A New Efficacy Benchmark in Relapsing–Remitting Multiple Sclerosis?

US Neurology ◽  
2010 ◽  
Vol 06 (02) ◽  
pp. 82
Author(s):  
Omar A Khan ◽  
Keyword(s):  
Multiple Sclerosis ◽  
Phase Iii ◽  
Mri Findings ◽  
Disability Score ◽  
Disease Modifying Drugs ◽  
Relapsing Remitting ◽  
Phase Iii Trials ◽  
Magnetic Resonance Imaging Mri ◽  
Relapsing Remitting Multiple Sclerosis ◽  
Ongoing Phase

The disease-modifying drugs (DMDs) available for the treatment of multiple sclerosis (MS) have been used effectively for nearly two decades. These treatments delay the neurorodegenerative process, but do not restore lost neurological function. New oral DMDs are becoming available that offer improved convenience over existing injectable DMDs. Recently, several monoclonal antibody treatments have been developed for MS; the furthest developed is alemtuzumab (Campath-1H). In a landmark phase II clinical trial (CAMMS223) on patients with relapsing–remitting MS (RRMS), short cycles of alemtuzumab given at baseline, at 12 months, and optionally at 24 months, demonstrated superior and sustained efficacy in terms of relapse rates and magnetic resonance imaging (MRI) findings over the comparator compound, interferon beta-1a (IFNβ-1a), which was given subcutaneously and continuously. Most notably, the mean disability score for patients receiving alemtuzumab showed an unprecedented improvement, whereas for IFNβ-1a it deteriorated. Alemtuzumab in treating RRMS is the subject of two ongoing phase III trials, the results of which have the potential to change future treatments and prognoses for many patients.

Chitinase 3-like proteins as diagnostic and prognostic biomarkers of multiple sclerosis

2015 ◽  
Vol 21 (10) ◽  
pp. 1251-1261 ◽  
Author(s):  
G Hinsinger ◽  
N Galéotti ◽  
N Nabholz ◽  
S Urbach ◽  
V Rigau ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Prognostic Biomarkers ◽  
Disease Stage ◽  
Rank Test ◽  
Differential Analysis ◽  
Diagnostic Biomarkers ◽  
Relapsing Remitting ◽  
Optimized Treatment ◽  
Disease Stages ◽  
In Cis

Background: Despite sensitivity of MRI to diagnose multiple sclerosis (MS), prognostic biomarkers are still needed for optimized treatment. Objective: The objective of this paper is to identify cerebrospinal fluid (CSF) diagnostic biomarkers of MS using quantitative proteomics and to analyze their expression at different disease stages. Methods: We conducted differential analysis of the CSF proteome from control and relapsing–remitting MS (RRMS) patients followed by verification by ELISA of candidate biomarkers in CSF and serum in control, clinically isolated syndrome (CIS), RRMS and progressive MS (PMS) patients. Results: Twenty-two of the 527 quantified proteins exhibited different abundances in control and RRMS CSF. These include chitinase 3-like protein 1 (CHI3L1) and 2 (CHI3L2), which showed a strong expression in brain of MS patients, especially in astrocytes and microglial cells from white matter plaques. CSF and serum CHI3L1 levels increased with the disease stage and CIS patients with high CSF (>189 ng/ml) and serum (>33 ng/ml) CHI3L1 converted more rapidly to RRMS (log rank test, p < 0.05 and p < 0.001, respectively). In contrast, CSF CHI3L2 levels were lower in PMS than in RRMS patients. Accordingly, CSF CHI3L1/CHI3L2 ratio accurately discriminated PMS from RRMS. Conclusions: CSF CHI3L1 and CHI3L2 and serum CHI3L1 might help to define MS disease stage and have a prognostic value in CIS.

A case of immune-mediated encephalitis related to daclizumab therapy

2018 ◽  
Vol 25 (5) ◽  
pp. 750-753 ◽  
Author(s):  
Michael Devlin ◽  
Andrew Swayne ◽  
Martin Newman ◽  
Cullen O’Gorman ◽  
Helen Brown ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Adverse Reactions ◽  
Brain Biopsy ◽  
Disease Modifying Therapy ◽  
Immune Mediated ◽  
Relapsing Remitting ◽  
The Central Nervous System ◽  
Disease Modifying ◽  
Relapsing Remitting Multiple Sclerosis ◽  
Csf Examination

This report will detail a case of immune-mediated encephalitis in the context of daclizumab therapy. Daclizumab is a humanised monoclonal antibody which, prior to its recent worldwide withdrawal due to safety concerns, was utilised as a disease-modifying therapy in relapsing-remitting multiple sclerosis. The withdrawal of this therapy was prompted by concerns over 12 cases of serious immune-mediated adverse reactions in the central nervous system. We report an additional case, including clinical data and results of neuroimaging, cerebrospinal fluid (CSF) examination and brain biopsy.

scholarly journals CCN3 is dynamically regulated by treatment and disease state in multiple sclerosis

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Michelle Naughton ◽  
Jill Moffat ◽  
George Eleftheriadis ◽  
Nira de la Vega Gallardo ◽  
Andrew Young ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease State ◽  
Immune Mediated ◽  
Relapsing Remitting ◽  
The Central Nervous System ◽  
Patient Groups ◽  
Ccn3 Expression ◽  
Disease Modifying Treatment ◽  
And Control

Abstract Background Multiple sclerosis (MS) is an immune-mediated disease that damages myelin in the central nervous system (CNS). We investigated the profile of CCN3, a known regulator of immune function and a potential mediator of myelin regeneration, in multiple sclerosis in the context of disease state and disease-modifying treatment. Methods CCN3 expression was analysed in plasma, immune cells, CSF and brain tissue of MS patient groups and control subjects by ELISA, western blot, qPCR, histology and in situ hybridization. Results Plasma CCN3 levels were comparable between collective MS cohorts and controls but were significantly higher in progressive versus relapsing-remitting MS and between patients on interferon-β versus natalizumab. Higher body mass index was associated with higher CCN3 levels in controls as reported previously, but this correlation was absent in MS patients. A significant positive correlation was found between CCN3 levels in matched plasma and CSF of MS patients which was absent in a comparator group of idiopathic intracranial hypertension patients. PBMCs and CD4+ T cells significantly upregulated CCN3 mRNA in MS patients versus controls. In the CNS, CCN3 was detected in neurons, astrocytes and blood vessels. Although overall levels of area immunoreactivity were comparable between non-affected, demyelinated and remyelinated tissue, the profile of expression varied dramatically. Conclusions This investigation provides the first comprehensive profile of CCN3 expression in MS and provides rationale to determine if CCN3 contributes to neuroimmunological functions in the CNS.

scholarly journals Signatures of immune reprogramming in anti-CD52 therapy of MS: markers for risk stratification and treatment response

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Laura Bierhansl ◽  
Tobias Ruck ◽  
Steffen Pfeuffer ◽  
Catharina C. Gross ◽  
Heinz Wiendl ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Adverse Events ◽  
Treatment Response ◽  
De Novo ◽  
Ex Vivo ◽  
Phase Iii ◽  
Serum Samples ◽  
Two Phase ◽  
Relapsing Remitting

Abstract Background Multiple sclerosis is one of the most prevalent neurological diseases in young adults affecting over 2 million people worldwide. Alemtuzumab is a highly effective therapy in relapsing remitting MS. Alemtuzumab is a monoclonal CD52 antibody that proved its efficacy against an active comparator (interferon [IFN]-β1a) in a phase II trial and two phase III trials regarding clinical and MRI outcomes. Nevertheless, the exact mode of action is still unknown. Alemtuzumab is commonly associated with secondary autoimmune disorders significantly affecting the risk-benefit ratio. Therefore, new biomarkers predicting treatment response and adverse events are urgently needed. This study aims to further elucidate the mechanism of action of the neuroprotective potential of alemtuzumab in relapsing-remitting multiple sclerosis (RRMS). Methods/Design This is a 3-year multicentre, explorative study including overall 150 patients comprising three different groups: (i) de novo patients prior and after alemtuzumab treatment initiation, (ii) patients under alemtuzumab treatment and (iii) patients requiring more than two alemtuzumab infusions. Peripheral blood and serum samples will be collected semi-annually for several in vitro/ex vivo assays to detect and characterize immune cells including their functional activity. Furthermore, data of MRI scans and disease-related impairment (using EDSS and MSFC), as well as the number and time of relapses, will be assessed. The clinical study is registered at clinicaltrials.gov (NCT04082260). Perspective Our study will provide deep insights into the underlying immunological changes in a longitudinal analysis of alemtuzumab treated RRMS patients. By combining clinical, radiological and functional immune-phenotype data, we will be able to identify biomarkers and/or immune signatures predicting treatment response and adverse events. Thereby, the understanding of the mechanisms of action of alemtuzumab will improve its efficacy and safety for present and future patients.

Sign in / Sign up

Export Citation Format

Share Document