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Analysis of the Distribution of Regulatory B Cells in Blood of Multiple Sclerosis Patients (B-MS)

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ClinicalTrials.gov Identifier: NCT02789670
Recruitment Status : Recruiting
First Posted : June 3, 2016
Last Update Posted : July 10, 2019
Sponsor:
Information provided by (Responsible Party):
University Hospital, Lille

Brief Summary:
New therapeutic approaches of MS are emerging, targeting different actors of the immune system. Some of them target a specific population of white blood cells: B lymphocytes composed of different subpopulations. The subsets of B cells express different functional properties that control the immune response, but these regulation mechanisms have yet to be clearly described. Some subpopulations could amplify inflammation through IL-6 production for example, whereas some ones contribute to its regulation through the production of IL-10. Using samples collected in a large cohort of individuals with risk of MS and treatment-naive patients in the early onset of the disease, the investigators aim to develop a 2 year follow-up study of the different blood B cells subset distribution and their functional properties in terms of pro- and anti-inflammatory cytokine production in MS. This approach can identify new biomarkers for monitoring of MS patients and lead to better define the indication use of depletive B cell drugs and not to counteract the regulatory action of these cells.

Condition or disease Intervention/treatment
Multiple Sclerosis Systemic Sclerosis Other: Blood sample collection

Detailed Description:

Multiple sclerosis (MS) is a progressive immuno-inflammatory and degenerative disease of the central nervous system (CNS) and represents the second most common cause of disability in young people. The pathophysiologic mechanisms involved are complex and effective therapeutic strategies have yet to be defined. Moreover it's today evident that treatment approaches have to be performed in a personalized point of view. In this context, biomarkers evaluating the course of the disease but also predicting efficacy of therapy are particularly needed in MS.

Recent data underlines the direct role of B-cells in MS. Such comprehensive data have led to new therapeutic strategies using biotherapies in order to deplete, or modulate, the functions of peripheral B cells. Such approaches have led to contradictory results of efficacy. Today, it remains unclear whether B-cells exert diminished regulatory effects or instead potentiate the pathogenic response of T-cells. Such dual properties may depend on the release of inhibitory (e.g. interleukin-10) or pro-inflammatory cytokines (e.g. interleukin-6) and/or direct interactions with other cells, especially T cells.

The investigators aim to longitudinally evaluate quantitative and functional changes in peripheral blood B-cell subsets (1) at the initiation phases of MS, i.e. radiological isolated syndrome (RIS) and clinically isolated syndrome (CIS) (2) during progression of MS and (3) between the two clinical forms of MS in naïve treatment patient: Relapsing-Remittent MS (RRMS) and Primary Progressive MS (PPMS). B-cell subsets are defined by a combination of membrane markers and enumerated at different time points (inclusion (before treatment) and at 3, 6, 12, 24 months of treatment initiation) in a whole blood flow cytometric (FCM) analysis. The absolute counts and relative proportions of transitional, naïve, memory, and marginal zone-like B-cell subsets are being followed up prospectively in patients with a radiologically isolated syndrome (RIS, n= 20), with clinically isolated syndrome (CIS, n= 20), in MS patients with relapsing remitting form (RRMS, n = 20) and in MS patients with primary progressive evolution of the disease (PPMS, n = 20). Control samples are being collected from patients affected by other inflammatory diseases with neurological symptoms (Devic syndrome, Neurobehcet, neurosarcoidosis n = 20) or without neurological symptoms (systemic sclerosis, SSc, n= 20) and from blood donors (n = 40). In order to evaluate functional properties of B cells, peripheral blood mononuclear cells (PBMC) from each group of patients are activated with CD40 ligand and CpG Oligodeoxynucleotides (CpG ODNs), and IL-10-producing B-cells are enumerated by FCM after a brief incubation with phorbol myristate acetate, ionomycin, and brefeldin A as a protein transport inhibitor agent. In selected CIS and MS patients whose changes in B-cell subpopulations associated with onset or progression of the disease are representative, the B-cell subpopulations will be purified and activated with CD40 ligand and CpG ODNs to be co cultured with anti-CD3-activated autologous T-cells to evaluate inhibitory or potentiating effects on T-cell production of pro-inflammatory cytokines (e.g. IFN-gamma, IL-17).

All phenotypic analyses and cell cultures are performed using previously validated protocols. Our ultimate goal is to correlate quantitative and functional changes of subsets composing the systemic B-cell population with the grading and evolution of MS. Such a strategy could lead to identify which MS patients should receive treatment targeting B cells and when. Further, it may offer a rationale for alternative forms of cell therapy that could introduce for example autologous purified B regulator cells after depletive strategies.


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Study Type : Observational
Estimated Enrollment : 160 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Analysis of the Distribution of Regulatory B Cells in Blood of Multiple Sclerosis Patients
Actual Study Start Date : July 2014
Estimated Primary Completion Date : July 2020
Estimated Study Completion Date : December 2020


Group/Cohort Intervention/treatment
MS patients
MS patient group is composed by 20 Individuals with inflammatory brain lesions seen in MRI (Radiologically Isolated syndrome) 20 patients with only one clinically isolated syndrome (CIS) 20 patients with relapsed remittent Multiple sclerosis (RRMS) 20 patients with primary progressive Multiple Sclerosis (PPMS)
Other: Blood sample collection
Peripheral blood will be collected in patients at the different time of the study to analyze phenotypic and functional properties of B cells in MS patients and control group

Control group patients

Control patient cohort is composed by 20 patients suffering from inflammatory neurological disease other than MS Devic syndrome, Neurosarcoidosis, Neurobehcet... (autoimmune disease control group with neurological disease) 20 patients with systemic sclerosis (autoimmune disease control group) without neurological disease)

40 healthy subjects

Other: Blood sample collection
Peripheral blood will be collected in patients at the different time of the study to analyze phenotypic and functional properties of B cells in MS patients and control group




Primary Outcome Measures :
  1. Comparison of the production of IL-10 and IL-6 by B cells in MS patients and the control group at inclusion time point [ Time Frame: inclusion ]
    Percentage of B cells expressing intracellular IL-6 and/or IL-10 will be analyzed in MS patients versus controls at inclusion


Secondary Outcome Measures :
  1. Comparison of the production of IL-10 and IL-6 by B cells in MS patients and the control group at the different time points of the study [ Time Frame: 3, 6, 12, 24 months ]
    Percentage of B cells expressing intracellular IL-6 and/or IL-10 will be analyzed in MS patients versus controls at the different time points

  2. Comparison of the production of IL-10 and IL-6 by B cells in the MS patient subgroups at the inclusion time point [ Time Frame: inclusion ]
    Percentage of B cells expressing intracellular IL-6 and/or IL-10 will be analyzed in the different MS patient subgroups at the inclusion time point

  3. Comparison of the production of IL-10 and IL-6 by B cells in the MS patient subgroups at the different time points of the study [ Time Frame: 3, 6, 12, 24 months ]
    Percentage of B cells expressing intracellular IL-6 and/or IL-10 will be analyzed in the different MS patient subgroups at the different time points

  4. Comparison B cell subset distribution in MS patients and the control group [ Time Frame: at inclusion ]
    Distribution of B cell subsets (expressed in percentages) analyzed by flow cytometry in MS and the control group at inclusion time point

  5. Comparison B cell subset distribution [ Time Frame: at inclusion ]
    Distribution of B cell subsets (expressed in absolute values) analyzed by flow cytometry in MS and the control group at inclusion time point

  6. Comparison B cell subset distribution in MS patients versus the control group at the different time points of the study [ Time Frame: 3, 6, 12, 24 months ]
    Distribution of B cell subsets (expressed in percentages) analyzed by flow cytometry in MS and the control group at the different time points of the study

  7. Comparison B cell subset distribution in MS patients versus the control group at the different time points of the study [ Time Frame: 3, 6, 12, 24 months ]
    Distribution of B cell subsets (absolute values) analyzed by flow cytometry in MS and the control group at the different time points of the study


Biospecimen Retention:   Samples Without DNA
Blood samples to collect peripheral blood mononuclear cells Phenotypic and functional studies using flow cytometric approaches


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Primary care clinic
Criteria

Inclusion Criteria:

  • Patients with MS criteria (McDonald et al. 2001) or with Clinically isolated syndrome (CIS) or radiologically isolated syndrome(RIS) or
  • Patients patients with other neurological inflammatory disease (OIND) or with autoimmune disease without neurological disease Leroy Metsger' criteria of systemic sclerosis) (OID)

Exclusion Criteria:

  • Women without reliable contraception
  • Nursing women
  • Patients having immunosuppressive treatment in the last month ( beta interféron, glatiramer acetate, natalizumab, fingolimod, glucocorticoid)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02789670


Contacts
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Contact: Sylvain DUBUCQUOI, MD PhD (3)20445572 ext +33 sylvain.dubucquoi@chru-lille.fr
Contact: Hélène ZEPHIR, MD PhD helene.zephir@chru-lille.fr

Locations
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France
CHRU de Lille Recruiting
Lille, France, 59037
Sponsors and Collaborators
University Hospital, Lille
Investigators
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Principal Investigator: Sylvain DUBUCQUOI, MD PhD CHRU de LILLE

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Responsible Party: University Hospital, Lille
ClinicalTrials.gov Identifier: NCT02789670     History of Changes
Other Study ID Numbers: 2013_35
2014-A00248-39 ( Other Identifier: ID-RCB number, ANSM )
First Posted: June 3, 2016    Key Record Dates
Last Update Posted: July 10, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Multiple Sclerosis
Scleroderma, Systemic
Scleroderma, Diffuse
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Connective Tissue Diseases
Skin Diseases