Dimethyl fumarate therapy suppresses B cell responses and follicular helper T cells in relapsing-remitting multiple sclerosis

Hansen, Rasmus Hvass; Chow, Helene Højsgaard; Sellebjerg, Finn; Essen, Marina Rode von

doi:10.1177/1352458518790417

Cited by 22 publications

(25 citation statements)

References 28 publications

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“…It was not addressed whether this increase was due to an increase of transitional B cells or to a suppression of their differentiation to naïve mature B cells. This finding is in accordance with previous studies also showing an increase of transitional B cells following 12 months of treatment, although our work is the first reporting this effect after only 3 months of DMF therapy.…”

Section: Discussionsupporting

confidence: 94%

“…On the other hand, we also observed a selective decrease on circulating memory B cells (both switched and preswitched), in parallel with an increase of naïve B lymphocytes, in accordance with previous publications . B cells can produce pro‐inflammatory cytokines, and treatments depleting the B‐cell compartment such as rituximab (anti‐CD20 monoclonal antibody) have demonstrated beneficial effects on MS patients.…”

Section: Discussionsupporting

confidence: 91%

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Optimal response to dimethyl fumarate is mediated by a reduction of Th1‐like Th17 cells after 3 months of treatment

et al. 2019

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Aim Dimethyl fumarate (DMF) is one of the most promising therapies for relapsing‐remitting multiple sclerosis (RRMS) patients since it has shown immunomodulatory and neuroprotective effects. However, a percentage of RRMS patients do not exhibit an optimal response to DMF. The objective of this study was to identify early biomarkers of treatment response by analyzing changes in peripheral leukocyte subpopulations directly in whole blood samples. Methods A longitudinal and prospective study analyzing peripheral blood leukocyte subpopulations in 22 RRMS patients before initiating DMF treatment (baseline) and at 1, 3, 6, and 12 months of follow‐up was performed. Differences between no evidence of disease activity (NEDA) and ongoing disease activity (ODA) patients were analyzed. Results The beneficial effect of DMF was associated with a specific depletion of memory CD4+ and CD8+ T lymphocytes and B cells. Importantly, only NEDA patients showed (a) a shift from a pro‐ to an antiinflammatory profile, with an increase of Th2 cells and a decrease of Th1‐like Th17 lymphocytes; and (b) an increase of regulatory CD56bright NK cells. Conclusion The optimal response to DMF is mediated by a shift to antiinflammatory and immunoregulatory profile, which puts forward Th1‐like Th17 lymphocytes as a potential early biomarker of treatment response.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 91%

Optimal response to dimethyl fumarate is mediated by a reduction of Th1‐like Th17 cells after 3 months of treatment

et al. 2019

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“…Such reductions affect mostly cytotoxic T cells, effector/central memory T cells, Th1 cells, Th17 cells, mucosa-associated lymphoid tissue (MALT) cells follicular T cells with a Tfh1/17 phenotype, antigen experienced and memory B cells, and B cells producing TNF. Immunoregulatory CD56 bright NK-cells, naïve T and B cells, Th2 cells, FoxP3 + Tregs, and follicular T cells with a Tfh2 phenotype are increased (151, 153–155, 157–162). Such a pro-tolerogenic shift is associated with NEDA in MS patients (158); higher levels of the NRF2 target gene NAD(P)H quinone dehydrogenase 1 (NQO1) was also associated with NEDA status after 1 year of DMF treatment (151).…”

Section: Dimethyl Fumarate (Dmf)mentioning

confidence: 99%

Immunological Aspects of Approved MS Therapeutics

et al. 2019

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Multiple sclerosis (MS) is the most common neurological immune-mediated disease leading to disability in young adults. The outcome of the disease is unpredictable, and over time, neurological disabilities accumulate. Interferon beta-1b was the first drug to be approved in the 1990s for relapsing-remitting MS to modulate the course of the disease. Over the past two decades, the treatment landscape has changed tremendously. Currently, more than a dozen drugs representing 1 substances with different mechanisms of action have been approved (interferon beta preparations, glatiramer acetate, fingolimod, siponimod, mitoxantrone, teriflunomide, dimethyl fumarate, cladribine, alemtuzumab, ocrelizumab, and natalizumab). Ocrelizumab was the first medication to be approved for primary progressive MS. The objective of this review is to present the modes of action of these drugs and their effects on the immunopathogenesis of MS. Each agent's clinical development and potential side effects are discussed.

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“…Moreover, several studies confirmed that the orally given agent increases the proportion of transitional B cells while reducing memory and antigen-activated B cells with a disproportionate decrease of plasmablasts [ 128 , 131 , 132 ]. In this line, B cells of treated patients produce less interleukin-6 and tumor necrosis factor, resulting in a more anti-inflammatory cytokine profile and reduced levels of serum interleukin-6 [ 133 , 134 ]. In addition, the expression of molecules involved in antigen presentation (CD40, CD80 and CD86) was found to be decreased in patients treated with dimethyl fumarate [ 128 , 131 ].…”

Section: Effects Of Ms Medications On Peripheral B Cells In Humansmentioning

confidence: 99%

Differential Effects of MS Therapeutics on B Cells—Implications for Their Use and Failure in AQP4-Positive NMOSD Patients

Traub

Häusser‐Kinzel

Weber

2020

IJMS

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B cells are considered major contributors to multiple sclerosis (MS) pathophysiology. While lately approved disease-modifying drugs like ocrelizumab deplete B cells directly, most MS medications were not primarily designed to target B cells. Here, we review the current understanding how approved MS medications affect peripheral B lymphocytes in humans. These highly contrasting effects are of substantial importance when considering these drugs as therapy for neuromyelitis optica spectrum disorders (NMOSD), a frequent differential diagnosis to MS, which is considered being a primarily B cell- and antibody-driven diseases. Data indicates that MS medications, which deplete B cells or induce an anti-inflammatory phenotype of the remaining ones, were effective and safe in aquaporin-4 antibody positive NMOSD. In contrast, drugs such as natalizumab and interferon-β, which lead to activation and accumulation of B cells in the peripheral blood, lack efficacy or even induce catastrophic disease activity in NMOSD. Hence, we conclude that the differential effect of MS drugs on B cells is one potential parameter determining the therapeutic efficacy or failure in antibody-dependent diseases like seropositive NMOSD.

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Dimethyl fumarate therapy suppresses B cell responses and follicular helper T cells in relapsing-remitting multiple sclerosis

Abstract: In summary, these data suggest an anti-inflammatory role of DMF and its metabolite MMF on the B cell compartment.

Cited by 22 publications

References 28 publications

Optimal response to dimethyl fumarate is mediated by a reduction of Th1‐like Th17 cells after 3 months of treatment

Optimal response to dimethyl fumarate is mediated by a reduction of Th1‐like Th17 cells after 3 months of treatment

Immunological Aspects of Approved MS Therapeutics

Differential Effects of MS Therapeutics on B Cells—Implications for Their Use and Failure in AQP4-Positive NMOSD Patients

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