Wakiro Sato

Multiple sclerosis (MS) therapies primarily rely on lymphocyte depletion or trafficking blockade, carrying risks of systemic immunosuppression; however, such treatments have limited efficacy in secondary progressive multiple sclerosis (SPMS). Thus, drugs that target stage-specific inflammation without broad immunosuppression are an unmet clinical need. In this double-blind, placebo-controlled phase II trial, 30 patients with relapsing MS received weekly oral OCH or placebo for 24 weeks. In the pre-specified SPMS subgroup (n=12), OCH achieved complete relapse prevention (p=0.0003), prolonged relapse-free survival (p=0.0079), no new lesions (0/6), with no evidence of disease activity (NEDA-3) in 5/6 patients. In comparison, for the placebo-treated group, 5/6 patients suffered relapses, 2/6 patients developed new lesions, and no placebo-treated SPMS achieved NEDA-3. Invariant natural killer T (iNKT) cells, a regulatory lymphocyte population that is numerically and functionally impaired in MS, are a potential target for MS therapy. Glycolipid OCH is a selective iNKT cell stimulator, skewing the cytokine environment towards Th2. OCH treatment resulted in increased IL-4-producing Th cells in patient peripheral blood while decreasing pathogenic GM-CSF-producing Th cells. Parallel studies in mouse models of MS (EAE) corroborated this mechanism and further revealed that OCH activated gut iNKT cells. Disease amelioration by OCH depended on IL-4 and its efficacy was further enhanced by depletion of B cells. These data revealed the gut-brain axis mediation of progressive-stage pathology distinct from relapsing-remitting MS. Findings from this bidirectional translational study uncover mechanistic differences between SPMS and other types of MS and highlight divergent roles for B cells and Th cells. Furthermore, OCH exerts its therapeutic benefit via targeting mechanisms that are distinct from currently available drugs; exploiting iNKT cell regulatory potential to reprogram pathogenic T helper responses without lymphocyte depletion. The unique yet effective nature of OCH treatment positions it as an attractive future oral therapy for SPMS. One Sentence Summary: The iNKT cell activating ligand OCH suppresses disease activity selectively in secondary progressive MS in a phase II clinical trial, revealing stage-specific IL-4-mediated immune cell interactions in MS pathology.

Age‐associated B cells (ABCs), initially identified in aged mice, are a distinct B cell subset that plays crucial roles in autoimmune diseases through the production of autoantibodies, proinflammatory cytokines, and antigen presentation. Although a definitive set of markers for identifying ABCs has not yet been established, they are commonly characterized by the expression of CD11c, CD11b, and the transcription factor T‐bet, along with reduced levels of CD21, either alone or in combination. ABC differentiation is driven by Toll‐like receptor 7 (TLR7) signaling in conjunction with cytokines such as interleukin‐21 (IL‐21) and interferon‐gamma (IFNγ). Importantly, ABCs expand in the blood or inflamed tissues and exhibit pathogenic functions in various autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, Crohn's disease, axial spondyloarthritis, Grave's disease, and multiple sclerosis. Recently, ABCs have been implicated in neuromyelitis optica spectrum disorder (NMOSD), a chronic inflammatory astrocytopathy mediated by anti‐AQP4 antibody‐producing B cells characterized by relapses and remissions. In the acute phase, CD21^lo B cells can differentiate into anti‐AQP4 antibody‐producing cells and expand in both cerebrospinal fluid and blood. In the chronic phase, an increased frequency of CD11c^hi B cells in the blood correlates with chronic neurological damage or brain injury. T peripheral helper type 1 cells, which produce IFNγ and IL‐21, may support ABC differentiation in both phases. This review explores the role of ABCs in NMOSD, highlighting key studies that link ABC subsets to disease pathology. Understanding ABC‐mediated mechanisms in NMOSD may open avenues for novel therapeutic strategies.

1. Multiple sclerosis (MS) is an autoimmune demyelinating disease of the CNS, of which pathogenesis would involve a wide variety of innate and acquired immune cells, including self-reactive T cells...

Neuromyelitis optica (NMO) is an autoimmune astrocytopathy mediated by anti-AQP4 antibody-producing B cells. Recently, a B-cell subset highly expressing CD11c and T-bet, originally identified as age-associated B cells, has been shown to be involved in the pathogenesis of various autoimmune diseases. The objective of this study was to determine the relationship between the frequency of CD11c^high B cells per CD19⁺ B cells in the peripheral blood of patients with NMO and the clinical profiles including the brain volume. In this observational study, 45 patients with anti-AQP4 antibody-positive NMO in remission and 30 healthy control subjects (HCs) were enrolled. Freshly isolated peripheral blood mononuclear cells were analyzed for immune cell phenotypes. The frequency of CD11c^high B cells per CD19⁺ B cells was assessed by flow cytometry and was evaluated in association with the clinical profiles of patients. Brain MRI data from 26 patients were included in the study for the analysis on the correlation between CD11c^high B-cell frequency and brain atrophy. We found that the frequency of CD11c^high B cells in CD19⁺ B cells was significantly increased in patients with NMO compared with HCs. The expansion of CD11c^high B cells significantly correlated with EDSS, past relapse numbers, and disease duration. In addition, a higher frequency of CD11c^high B cells negatively correlated with total brain, white matter, and gray matter volumes and positively correlated with T2/FLAIR high lesion volumes. When the past clinical relapse episodes of patients with or without the expansion of CD11c^high B cells were compared, relapses in the brain occurred more frequently in patients with CD11c^high B-cell expansion. CD11c^high B cells had distinct features including expression of chemokine receptors associated with migration into peripheral inflammatory tissues and antigen presentation. CD11c^high B-cell frequency was positively correlated with T peripheral helper-1 (Tph-1) cell frequency. Even during the relapse-free period, CD11c^high B cells could expand in the long disease context, possibly through the interaction with Tph-1 cells. The increased frequency of CD11c^high B cells associated with brain atrophy and disease severity, indicating that this cell population could be involved in chronic neuroinflammation in NMO.

Journal of Medical Internet Research - International Scientific Journal for Medical Research, Information and Communication on the Internet #Preprint #PeerReviewMe: Warning: This is a unreviewed preprint. Readers are warned that the document has not been peer-reviewed by expert/patient reviewers or an academic editor, may contain misleading claims, and is likely to undergo changes before final publication, if accepted, or may have been rejected/withdrawn. Readers with interest and expertise are encouraged to sign up as peer-reviewer, if the paper is within an open peer-review period. Please cite this preprint only for review purposes or for grant applications and CVs (if you are the author). Background: Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that causes myelin sheath damage and axonal degeneration. The glycolipid OCH-NCNP1 (OCH) exerts an immunoregulatory action that suppresses Th1 cell-mediated immune responses through natural killer T cell activation, selective interleukin-4 production, and Th2 bias induction in human CD4-positive natural killer T cells. Objective: This trial investigates the efficacy and safety of the immunomodulator OCH in patients with relapsing MS through 24-week repeated administration. The protocol was also designed to confirm exploratory biomarkers of T cells and natural killer cells that fluctuated in the Phase I trial, as well as efficacy-related clinical endpoints, including relapses, disability, magnetic resonance imaging changes, and their association with combined endpoints. Methods: This protocol describes a double-blind, multicenter, placebo-controlled, randomized, phase II clinical trial conducted in September 2019. The duration of the trial was 24 weeks. The participants were randomly assigned to either a placebo control group or an OCH-NCNP1 group for the 24-week duration. Outcome measures included the primary outcome of magnetic resonance imaging changes and secondary outcomes including annual relapse rate, relapse-free period, sustained reduction in disability occurrence rate, period until sustained reduction in disability, no evidence of disease activity, and exploratory biomarkers from phase I trials (such as gene expression, cell frequency, and intestinal and oral microbiome). Results: We plan to enroll 30 patients in the full analysis set. Enrollment was closed in June 2021, and the study analysis was planned to end in March 2023. Conclusions: This randomized controlled trial will determine whether OCH-NCNP1 is effective and safe in patients with MS as well as provide evidence for the potential of OCH-NCNP1 as a therapeutic agent for MS. Clinical Trial: ClinicalTrials.gov Trial registration ID#: NCT04211740

Early cognitive impairment (CI) detection is crucial in multiple sclerosis (MS). However, it can progress silently regardless of relapse activity and reach an advanced stage. We aimed to determine whether the corpus callosum area (CCA) is a sensitive and feasible marker for CI in MS compared to other neuroimaging markers. We assessed cognitive function in 77 MS patients using the Symbol Digit Modalities Test, Paced Auditory Serial Additions Task, Wechsler Adult Intelligence Scale-IV, and Wechsler Memory Scale-Revised. The neuroimaging markers included manually measured CCA, two diffusion tensor imaging markers, and nine volumetric measurements. Apart from volumes of the hippocampus and cerebellum, ten markers showed a significant correlation with all neuropsychological tests and significant differences between the groups. The normalized CCA demonstrated a moderate-to-strong correlation with all neuropsychological tests and successfully differentiated between the CI and cognitively normal groups with 80% sensitivity and 83% specificity. The marker had a large area under the curve and a high Youden index (0.82 and 0.63, respectively) and comparability with established cognitive markers. Therefore, the normalized CCA may serve as a reliable marker for CI in MS and can be easily implemented in clinical practice, providing a supportive diagnostic tool for CI in MS.

BACKGROUND Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that causes myelin sheath damage and axonal degeneration. The glycolipid (2S, 3S, 4R)-1-O-(α-d-galactosyl)-2-tetracosanoylamino-1,3,4-nonaetriol (OCH-NCNP1 or OCH) exerts an immunoregulatory action that suppresses T helper (Th)1 cell–mediated immune responses through natural killer T cell activation, selective interleukin-4 production, and Th2 bias induction in human CD4-positive natural killer T cells. OBJECTIVE This trial aims to investigate the efficacy and safety of the immunomodulator OCH in patients with relapsing MS through 24-week repeated administration. METHODS This protocol describes a double-blind, multicenter, placebo-controlled, randomized phase II clinical trial that was initiated in September 2019. The participants were randomly assigned to either a placebo control group or an OCH-NCNP1 group and the investigational drug (3.0 mg) was orally administered once weekly for the 24-week duration. Major inclusion criteria are as follows: patients had been diagnosed with relapsing MS (relapsing-remitting and/or secondary progressive MS) based on the revised McDonald criteria or were diagnosed with MS by an attending physician as noted in their medical records; patients with at least two medically confirmed clinical exacerbations within 24 months prior to consent or one exacerbation within 12 months prior to consent; patients with at least one lesion suspected to be MS on screening magnetic resonance imaging (MRI); and patients with 7 points or less in the Expanded Disability Status Scale during screening. Major exclusion criteria are as follows: diagnosis of neuromyelitis optica and one of optic neuritis, acute myelitis, and satisfying at least two of the following three items: (1) spinal cord MRI lesion extending across at least three vertebral bodies, (2) no brain MRI lesions during onset (at least four cerebral white matter lesions or three lesions, one of which is around the lateral ventricle), and (3) neuromyelitis optica–immunoglobulin G or antiaquaporin-4 antibody-positive. Outcome measures include the primary outcome of MRI changes (the percentage of subjects with new or newly expanded lesions at 24 weeks on T2-weighted MRI) and the secondary outcomes annual relapse rate (number of recurrences per year), relapse-free period (time to recurrence), sustained reduction in disability (SRD) occurrence rate, period until SRD (time to SRD occurrence), no evidence of disease activity, and exploratory biomarkers from phase I trials (such as gene expression, cell frequency, and intestinal and oral microbiome). RESULTS We plan to enroll 30 patients in the full analysis set. Enrollment was closed in June 2021 and the study analysis was completed in March 2023. CONCLUSIONS This randomized controlled trial will determine whether OCH-NCNP1 is effective and safe in patients with MS as well as provide evidence for the potential of OCH-NCNP1 as a therapeutic agent for MS. CLINICALTRIAL ClinicalTrials.gov NCT04211740; https://clinicaltrials.gov/study/NCT04211740 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/46709

Pathogenic T helper cells (Th cells) that respond to self‐antigen cannot be easily distinguished from beneficial Th cells. These cells can generate systemic autoimmune disease in response to widely expressed self‐antigens. In this study, we have identified neuropilin‐1 (NRP1) as a cell surface marker of self‐reactive Th cells. NRP1⁺ Th cells, absent in non‐regulatory T cell subsets in normal mice, appeared in models of systemic autoimmune disease and strongly correlated with disease symptoms. NRP1⁺ Th cells were greatly reduced in Nr4a2 cKO mice, which have reduced self‐reactive responses but showed normal responses against exogenous antigens. Transfer of NRP1⁺ Th cells was sufficient to initiate or accelerate systemic autoimmune disease, and targeting NRP1‐expressing Th cells therapeutically ameliorated SLE‐like autoimmune symptoms in BXSB‐Yaa mice. Peripheral NRP1⁺ Th cells were significantly increased in human SLE patients. Our data suggest that self‐reactive Th cells can be phenotypically distinguished within the Th cell pool. These findings offer a novel approach to identify self‐reactive Th cells and target them to treat systemic autoimmune disease.

Background: Several magnetic resonance imaging markers of cognitive impairment have been reported in multiple sclerosis. Nonetheless, measurement often requires volumetry, a time-consuming technique that has problems with respect to accuracy in the segmentation of brain structures. The corpus callosum area is a marker of cognitive impairment that requires no volumetric technique; however, the usefulness of this marker has not been fully examined. This study aimed to determine whether the normalized corpus callosum area is a feasible and sensitive magnetic resonance imaging marker of cognitive impairment in multiple sclerosis. Methods: A total of 136 patients with multiple sclerosis who underwent the Montreal cognitive assessment and magnetic resonance imaging examination of the head were retrospectively reviewed. The normalized corpus callosum area was manually measured on a sagittal midline T1-weighted sequence using a picture archiving communication system. The normalized volumes of the brain parenchyma, cortex, thalamus, hippocampus, putamen, globus pallidus, caudate, and cerebellum were measured using FreeSurfer software. The normalized lesion volume was measured using the SPM software. Receiver operating characteristic curves were drawn for 10 MRI markers, along with the optimal cutoff value, sensitivity, specificity, and area under the curve. The Youden index was calculated for all parameters. Results: The normalized corpus callosum area was moderately associated with the Montreal cognitive assessment score after adjusting for age, sex, disease duration, and type of magnetic resonance imaging scanner (ρ = 0.56; p < 0.001). This indicator showed the strongest correlation among all the magnetic resonance imaging markers. Among all MRI markers, the normalized corpus callosum area showed the largest area under the curve (0.782) and had the second highest Youden index (0.463), following the normalized lesion volume. Conclusions: The normalized corpus callosum area, which is easily measured without volumetry, showed the strongest correlation with cognitive function. Therefore, this indicator may be a reliable and feasible marker of cognitive impairment in patients with multiple sclerosis.