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International Journal of Molecular... Sep 2022Autologous hematopoietic stem cell transplantation (aHSCT) is a highly efficient treatment of multiple sclerosis (MS), and hence it likely normalizes pathological and/or...
Autologous hematopoietic stem cell transplantation (aHSCT) is a highly efficient treatment of multiple sclerosis (MS), and hence it likely normalizes pathological and/or enhances beneficial processes in MS. The disease pathomechanisms include neuroinflammation, glial cell activation and neuronal damage. We studied biomarkers that in part reflect these, like markers for neuroinflammation (C-X-C motif chemokine ligand (CXCL) 9, CXCL10, CXCL13, and chitinase 3-like 1 (CHI3L1)), glial perturbations (glial fibrillary acidic protein (GFAP) and in part CHI3L1), and neurodegeneration (neurofilament light chain (NfL)) by enzyme-linked immunosorbent assays (ELISA) and single-molecule array assay (SIMOA) in the serum and cerebrospinal fluid (CSF) of 32 MS patients that underwent aHSCT. We sampled before and at 1, 3, 6, 12, 24 and 36 months after aHSCT for serum, as well as before and 24 months after aHSCT for CSF. We found a strong increase of serum CXCL10, NfL and GFAP one month after the transplantation, which normalized one and two years post-aHSCT. CXCL10 was particularly increased in patients that experienced reactivation of cytomegalovirus (CMV) infection, but not those with Epstein-Barr virus (EBV) reactivation. Furthermore, patients with CMV reactivation showed increased Th1 phenotype in effector memory CD4+ T cells. Changes of the other serum markers were more subtle with a trend for an increase in serum CXCL9 early post-aHSCT. In CSF, GFAP levels were increased 24 months after aHSCT, which may indicate sustained astroglia activation 24 months post-aHSCT. Other CSF markers remained largely stable. We conclude that MS-related biomarkers indicate neurotoxicity early after aHSCT that normalizes after one year while astrocyte activation appears increased beyond that, and increased serum CXCL10 likely does not reflect inflammation within the central nervous system (CNS) but rather occurs in the context of CMV reactivation or other infections post-aHSCT.
Topics: Biomarkers; Chitinases; Cytomegalovirus Infections; Epstein-Barr Virus Infections; Glial Fibrillary Acidic Protein; Hematopoietic Stem Cell Transplantation; Herpesvirus 4, Human; Humans; Ligands; Multiple Sclerosis; Transplantation, Autologous
PubMed: 36142860
DOI: 10.3390/ijms231810946 -
Neurotherapeutics : the Journal of the... Apr 2022In the past two decades, monoclonal antibodies (mAbs) have revolutionized the treatment of multiple sclerosis (MS). However, a remarkable number of mAbs failed due to... (Review)
Review
In the past two decades, monoclonal antibodies (mAbs) have revolutionized the treatment of multiple sclerosis (MS). However, a remarkable number of mAbs failed due to negative study results were withdrawn because of unexpected serious adverse events (SAEs) or due to studies being halted for other reasons. While trials with positive outcomes are usually published in prestigious journals, negative trials are merely published as abstracts or not at all. This review summarizes MS mAbs that have either failed in phase II-III trials, have been interrupted for various reasons, or withdrawn from the market since 2015. The main conclusions that can be drawn from these 'negative' experiences are as follows. mAbs that have been proven to be safe in other autoimmune conditions, will not have the same safety profile in MS due to immunopathogenetic differences in these diseases (e.g., daclizumab). Identification of SAEs in clinical trials is difficult highlighting the importance of phase IV studies. Memory B cells are central players in MS immunopathogenesis (e.g., tabalumab). The pathophysiological mechanisms of disease progression are independent of leukocyte 'outside-in' traffic which drives relapses in MS. Therefore, therapies for progressive MS must be able to sufficiently cross the blood-brain barrier. Sufficiently long trial duration and multicomponent outcome measures are important for clinical studies in progressive MS. The success of trials on remyelination-promoting therapies mainly depends on the sufficient high dose of mAb, the optimal readout for 'proof of concept', time of treatment initiation, and appropriate selection of patients. Failed strategies are highly important to better understand assumed immunopathophysiological mechanisms and optimizing future trial designs.
Topics: Antibodies, Monoclonal; Autoimmune Diseases; Daclizumab; Humans; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive
PubMed: 35794296
DOI: 10.1007/s13311-022-01246-3 -
Multiple Sclerosis (Houndmills,... Sep 2022Siponimod significantly reduced the risk of confirmed disability progression (CDP), worsening in cognitive processing speed (CPS), relapses, and magnetic resonance...
BACKGROUND
Siponimod significantly reduced the risk of confirmed disability progression (CDP), worsening in cognitive processing speed (CPS), relapses, and magnetic resonance imaging (MRI) measures of brain atrophy and inflammation versus placebo in secondary progressive multiple sclerosis (SPMS) patients in the Phase 3 EXPAND study.
OBJECTIVE
The aim of this study was to assess long-term efficacy and safety of siponimod 2 mg/day from the EXPAND study including the extension part, up to > 5 years.
METHODS
In the open-label extension part, participants receiving placebo during the core part were switched to siponimod (placebo-siponimod group) and those on siponimod continued the same treatment (continuous siponimod group).
RESULTS
Continuous siponimod reduced the risk of 6-month CDP by 22% (hazard ratio (HR) (95% confidence interval (CI)): 0.78 (0.66-0.92) = 0.0026) and 6-month confirmed worsening in CPS by 23% (HR (95% CI): 0.77 (0.65-0.92) = 0.0047) versus the placebo-siponimod group. Sustained efficacy on annualized relapse rate, total and regional brain atrophy, and inflammatory disease activity was also observed. No new, unexpected safety signals for siponimod were identified over the long term.
CONCLUSION
The sustained efficacy and consistent long-term safety profile of siponimod up to > 5 years support its clinical utility for long-term treatment of SPMS. Benefits in the continuous siponimod versus placebo-siponimod group highlight the significance of earlier treatment initiation.
TRIAL REGISTRATION NUMBER
NCT01665144.
Topics: Humans; Atrophy; Azetidines; Benzyl Compounds; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Recurrence
PubMed: 35380078
DOI: 10.1177/13524585221083194 -
Frontiers in Immunology 2022This study aimed to explore the shared mechanism and candidate drugs of multiple sclerosis (MS) and Sjögren's syndrome (SS).
OBJECTIVE
This study aimed to explore the shared mechanism and candidate drugs of multiple sclerosis (MS) and Sjögren's syndrome (SS).
METHODS
MS- and SS-related susceptibility genes and differentially expressed genes (DEGs) were identified by bioinformatics analysis based on genome-wide association studies (GWAS) and transcriptome data from GWAS catalog and Gene Expression Omnibus (GEO) database. Pathway enrichment, Gene Ontology (GO) analysis, and protein-protein interaction analysis for susceptibility genes and DEGs were performed. The drugs targeting common pathways/genes were obtained through Comparative Toxicogenomics Database (CTD), DrugBank database, and Drug-Gene Interaction (DGI) Database. The target genes of approved/investigational drugs for MS and SS were obtained through DrugBank and compared with the common susceptibility genes.
RESULTS
Based on GWAS data, we found 14 hub common susceptibility genes (, , , , , , , , , , , , , and ), with 8 drugs targeting two or more than two genes, and 28 common susceptibility pathways, with 15 drugs targeting three or more than three pathways. Based on transcriptome data, we found 3 hub common DEGs (, , ) with 3 drugs and 10 common risk pathways with 435 drugs. "JAK-STAT signaling pathway" was included in common susceptibility pathways and common risk pathways at the same time. There were 133 overlaps including JAK-STAT inhibitors between agents from GWAS and transcriptome data. Besides, we found that and , identified as hub common susceptibility genes, were the targets of daclizumab and glatiramer that were used for MS, indicating that daclizumab and glatiramer may be therapeutic for SS.
CONCLUSION
We observed the shared mechanism of MS and SS, in which JAK-STAT signaling pathway played a vital role, which may be the genetic and molecular bases of comorbidity of MS with SS. Moreover, JAK-STAT inhibitors were potential therapies for MS and SS, especially for their comorbidity.
Topics: Computational Biology; Daclizumab; Genome-Wide Association Study; Glatiramer Acetate; HLA-DRB1 Chains; Humans; Multiple Sclerosis; Sjogren's Syndrome; Transcriptome
PubMed: 35356004
DOI: 10.3389/fimmu.2022.857014 -
Diagnostics (Basel, Switzerland) Mar 2022Free light chains kappa (FLCκ) in cerebrospinal fluid (CSF) are a part of the intrathecal immune response. This observational study was conducted to investigate the...
Free light chains kappa (FLCκ) in cerebrospinal fluid (CSF) are a part of the intrathecal immune response. This observational study was conducted to investigate the effects of different disease-modifying therapies (DMT) on the humoral intrathecal immune response in the CSF of patients with multiple sclerosis (MS). FLCκ were analyzed in CSF and serum samples from MS patients taking DMT (n = 60) and those in a control cohort of treatment-naïve MS patients (n = 90). DMT was classified as moderately effective (including INFß-1a, INFß-1b, glatiramer acetate, dimethyl fumarate, teriflunomide, triamcinolone); highly effective (including fingolimod, daclizumab) and very highly effective (alemtuzumab, natalizumab, rituximab/ocrelizumab, mitoxantrone). FLCκ were measured using a nephelometric FLCκ kit. Intrathecal FLCκ and IgG concentrations were assessed in relation to the hyperbolic reference range in quotient diagrams. Intrathecal FLCκ concentrations and IgG concentrations were significantly lower in samples from the cohort of MS patients taking very highly effective DMT than in samples from the cohort of MS patients taking highly effective DMT and in the treatment-naïve cohort (FLCκ: p = 0.004, p < 0.0001 respectively/IgG: p = 0.013; p = 0.021). The reduction in FLCκ could contribute to an anti-inflammatory effect in the CNS through this mechanism. There was no difference in the appearance of CSF-specific oligoclonal bands (p = 0.830). Longitudinal analyses are required to confirm these results.
PubMed: 35328273
DOI: 10.3390/diagnostics12030720 -
Pharmacoepidemiology and Drug Safety Apr 2022Multiple sclerosis (MS) is a chronic disease of the central nervous system that disproportionately affects women, with typical onset during reproductive age. Several...
PURPOSE
Multiple sclerosis (MS) is a chronic disease of the central nervous system that disproportionately affects women, with typical onset during reproductive age. Several disease-modifying therapies (DMTs) are FDA-approved to slow disease progression, but are not indicated for use during pregnancy. Our objective was to describe trends over time (2010-2019) in monthly point prevalence of DMT use among reproductive-age women, overall and by generic name.
METHODS
This study used administrative claims data from the US during 2009-2019 to identify women age 15-44 with MS and continuous insurance coverage for ≥12 months. DMTs were identified using prescription fills and procedural claims for alemtuzumab, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta, mitoxantrone, natalizumab, ocrelizumab, and teriflunomide. Monthly prevalent use was defined as ≥1 days' supply of a DMT in the month. Age- and region-standardized monthly prevalence was estimated nonparametrically.
RESULTS
Among 42 281 reproductive-aged women over 818 179 person-months, DMT use increased from a minimum monthly prevalence of 49.3% (February, 2011) to a maximum of 58.7% (April, 2019). In 2010, prevalence of injectable DMTs was 43.1% compared to 2.5% for oral DMTs; by 2014, however, oral DMTs (26.5%) surpassed injectable DMTs (23.7%) as the most common route of administration. In the most recent data available (December, 2019), the most common DMTs were dimethyl fumarate, glatiramer acetate, and fingolimod.
CONCLUSIONS
DMT use among reproductive-aged women has rapidly evolved during the past decade. Collaborative treatment decision making between women with MS and clinicians may help optimize MS care and improve DMT uptake during reproductive years.
Topics: Adolescent; Adult; Female; Fingolimod Hydrochloride; Glatiramer Acetate; Humans; Immunosuppressive Agents; Interferon-beta; Multiple Sclerosis; United States; Young Adult
PubMed: 35088492
DOI: 10.1002/pds.5411 -
Frontiers in Immunology 2021The induction of specific immunological tolerance represents an important therapeutic goal for multiple sclerosis and other autoimmune diseases. Sound knowledge of the... (Review)
Review
The induction of specific immunological tolerance represents an important therapeutic goal for multiple sclerosis and other autoimmune diseases. Sound knowledge of the target antigens, the underlying pathomechanisms of the disease and the presumed mechanisms of action of the respective tolerance-inducing approach are essential for successful translation. Furthermore, suitable tools and assays to evaluate the induction of immune tolerance are key aspects for the development of such treatments. However, investigation of the mechanisms of action underlying tolerance induction poses several challenges. The optimization of sensitive, robust methods which allow the assessment of low frequency autoreactive T cells and the long-term reduction or change of their responses, the detection of regulatory cell populations and their immune mediators, as well as the validation of specific biomarkers indicating reduction of inflammation and damage, are needed to develop tolerance-inducing approaches successfully to patients. This short review focuses on how to demonstrate mechanistic proof-of-concept in antigen-specific tolerance-inducing therapies in MS.
Topics: Biomarkers; Humans; Immune Tolerance; Immunotherapy; Multiple Sclerosis; T-Lymphocytes, Regulatory
PubMed: 35069562
DOI: 10.3389/fimmu.2021.787498 -
Frontiers in Immunology 2021Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, in which autoreactive T and B cells play important roles. Other lymphocytes such as NK...
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, in which autoreactive T and B cells play important roles. Other lymphocytes such as NK cells and innate-like T cells appear to be involved as well. To name a few examples, CD56 NK cells were described as an immunoregulatory NK cell subset in MS while innate-like T cells in MS were described in brain lesions and with proinflammatory signatures. Autologous hematopoietic stem cell transplantation (aHSCT) is a procedure used to treat MS. This procedure includes hematopoietic stem/progenitor cell (HSPC) mobilization, then high-dose chemotherapy combined with anti-thymocyte globulin (ATG) and subsequent infusion of the patients own HSPCs to reconstitute a functional immune system. aHSCT inhibits MS disease activity very effectively and for long time, presumably due to elimination of autoreactive T cells. Here, we performed multidimensional flow cytometry experiments in peripheral blood lymphocytes of 27 MS patients before and after aHSCT to address its potential influence on NK and innate-like T cells. After aHSCT, the relative frequency and absolute numbers of CD56 NK cells rise above pre-aHSCT levels while all studied innate-like T cell populations decrease. Hence, our data support an enhanced immune regulation by CD56 NK cells and the efficient reduction of proinflammatory innate-like T cells by aHSCT in MS. These observations contribute to our current understanding of the immunological effects of aHSCT in MS.
Topics: Adult; CD56 Antigen; Case-Control Studies; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunity, Innate; Killer Cells, Natural; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Phenotype; T-Lymphocytes; Transplantation, Autologous; Treatment Outcome
PubMed: 34975899
DOI: 10.3389/fimmu.2021.794077 -
Scientific Reports Nov 2021Small antibody mimetics that contain high-affinity target-binding peptides can be lower cost alternatives to monoclonal antibodies (mAbs). We have recently developed a...
Small antibody mimetics that contain high-affinity target-binding peptides can be lower cost alternatives to monoclonal antibodies (mAbs). We have recently developed a method to create small antibody mimetics called FLuctuation-regulated Affinity Proteins (FLAPs), which consist of a small protein scaffold with a structurally immobilized target-binding peptide. In this study, to further develop this method, we established a novel screening system for FLAPs called monoclonal antibody-guided peptide identification and engineering (MAGPIE), in which a mAb guides selection in two manners. First, antibody-guided design allows construction of a peptide library that is relatively small in size, but sufficient to identify high-affinity binders in a single selection round. Second, in antibody-guided screening, the fluorescently labeled mAb is used to select mammalian cells that display FLAP candidates with high affinity for the target using fluorescence-activated cell sorting. We demonstrate the reliability and efficacy of MAGPIE using daclizumab, a mAb against human interleukin-2 receptor alpha chain (CD25). Three FLAPs identified by MAGPIE bound CD25 with dissociation constants of approximately 30 nM as measured by biolayer interferometry without undergoing affinity maturation. MAGPIE can be broadly adapted to any mAb to develop small antibody mimetics.
Topics: Amino Acid Sequence; Animals; Antibodies, Monoclonal; Antibody Affinity; Cell Line; Cell Line, Tumor; Cell Surface Display Techniques; Flow Cytometry; HEK293 Cells; HeLa Cells; Humans; Interleukin-2 Receptor alpha Subunit; K562 Cells; Mammals; Peptide Library; Protein Binding
PubMed: 34764369
DOI: 10.1038/s41598-021-01603-w