Primary objective: * Increases treatment with DMF the ability of Tregs to inhibit in relapsing-remitting MS patients? Proliferation of conventional T cells * Provides treatment with DMF to an increase in the number of nTreg (Foxp3 expression) or…
ID
Source
Brief title
Condition
- Demyelinating disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
-Effect of DMF treatment on Treg function as assessed in an in vitro,
carboxyfluorescein succinimidyl ester (CFSE)-based proliferation suppression
assay: to assess suppressive capacity of Tregs (CD4+CD25+CD127- T lymphocytes)
we will use a proliferation suppression assay, in which responder T cells are
cultured with varying amounts of T regs (Treg/Tresp ratio*s).(18;42) Treg
normally suppress the proliferation of activated Tresps, but this pathway is
defective in MS patients and might be restored by DMF.
-Effect of DMF treatment on Treg numbers as assessed by flow cytometry. After
isolation, PBMC will be directly incubated with fluorescently labeled
monoclonal antibodies which are directed against cell-subset-specific CD
markers (CD4+CD25+CD127-FoxP3+)
-Effect of DMF treatment on Breg differentiation, i.e. IL-10 producing B cells
after CpG stimulation: phenotypical analysis will be performed by intracellular
flow cytometry, measuring frequencies of IL-10 producing B cells upon in vitro
culture in the presence of CpG, a TLR-9 agonist.(23) The Breg frequency in MS
patients is strongly reduced and may be restored by DMF treatment.
Secondary outcome
-T cell subset analysis based on intracellular cytokine expression as evaluated
by flow cytometry (IL-10, IL-4, IL-17, IFN-*, TNF-* and GM-CSF); changes in the
cytokine profiles will be associated with changes in Treg and Breg.
-Clinical outcome parameters such as the Kurtzke Expanded Disability Status
Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), relapse rate and
Fatigue Scale for Motor and Cognitive Functions (FSMC) will be associated with
changes in Treg and Breg.
Background summary
Although the exact pathophysiology of MS is uncertain, it is clear that the T
cell compartment in here plays an important role. Autoreactive Th1 and Th17
cells in the central nervous system provide for inflammation. Regulatory T
cells (Treg), which normally maintain the balance between pro-and
anti-inflammatory T cells, are less effective in MS. Furthermore, it is now
thought that B cells are important in the disease process. Clinical studies
found that IL-10-producing B cells (Breg) also have regulatory properties. In
our previous studies we found that MS patients have a decreased proportion Breg
relative healthy subjects. Restore or stimulate both the Treg and Breg function
seems a target in the treatment of MS.
Of different therapies for MS is indeed shown to exert their effects on Treg
and / or Breg. However, DMF is a new therapy, whose mechanism of action is not
well known. Through this study we investigate the mechanism of action of DMF is
also based on effects on Treg and / or Breg.
Study objective
Primary objective:
* Increases treatment with DMF the ability of Tregs to inhibit in
relapsing-remitting MS patients? Proliferation of conventional T cells
* Provides treatment with DMF to an increase in the number of nTreg (Foxp3
expression) or iTreg (IL-10 production) in relapsing remitting MS patients?
* Resulting treatment with DMF in an increase in Bregs, producing (more) of
IL-10 in relapsing-remitting MS patients?
Secondary objective:
, Treatment with DMFals result in a shift of CD4 + T-cell cytokines to a less
pro-and anti-inflammatory profile in relapsing-remitting MS patients?
* To assess the clinical outcome measures (EDSS, MSFC, relapse rate and FSMC)
are associated with changes in patients treated with DMF. In Treg and Breg in
relapsing-remitting MS
Study design
An observational study of 20 patients with RRMS who start Dimethylfumaratre.
Patients will be treated with DMF as a regular patient. Ex vivo studies will
be performed at 3 time points: prior to the start of the treatment with DMF,
after 12 weeks and after 48 weeks of treatment with DMF.
Study burden and risks
Participating patients will have to participate in neurological examination and
are asked to cooperate with neuropsychological tests. Besides that the
assessments can be more or less fatiguing to the patients, there are no risks
of these assessments. Finally, patients will donate blood. The risks of a blood
donation are a temporary vasovagal reaction or a local haematoma at the
puncture spot.
Dr. H van der Hoffplein 1
Sittard-Geleen 6162 BG
NL
Dr. H van der Hoffplein 1
Sittard-Geleen 6162 BG
NL
Listed location countries
Age
Inclusion criteria
Relapsing Remitting Multiple Sclerose according to 2010 revised McDonald criteria
Age > 18 years
Disease duration < 5 years
Exclusion criteria
Relapse < 6 weeks prior to inclusion
Use of glucocorticosteriods < 6 weeks prior to inclusion
Use of disease modifying therapies in the past.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL50071.096.14 |