Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02789670 |
| Other study ID # |
2013_35 |
| Secondary ID |
2014-A00248-39 |
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
July 2014 |
| Est. completion date |
April 2021 |
Study information
| Verified date |
September 2020 |
| Source |
University Hospital, Lille |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial 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.
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.
