Optimal response to dimethyl fumarate associates in MS with a shift from an inflammatory to a tolerogenic blood cell profile

Medina, Silvia; Villarrubia, Noelia; Cantero, Susana; Lifante, José; Costa‐Frossard, Lucienne; Roldán, Ernesto; Picón, Carmen; Álvarez‐Cermeño, José C.; Villar, Luisa María

doi:10.1177/1352458517717088

Cited by 48 publications

(67 citation statements)

References 29 publications

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“…In line with other publications, DMF therapy was associated with reduced CD8 + T cell and B cell counts among total PBMC (Fig. K and L) …”

Section: Resultssupporting

confidence: 93%

“…Furthermore, mDC from DMF‐treated MS patients exhibit a rather immature phenotype with reduced expression of costimulatory molecules and impaired T‐cell activation capacity . Lower numbers of circulating mDC, CD8 + cytotoxic T cells and B lymphocytes but enhanced CD56 bright NK cell frequencies in the blood of DMF‐treated MS patients further support the concept of an anti‐inflammatory shift in the peripheral immune cell compartment probably mediated by NRF2 activation . Close associations between a reduction in B lymphocytes, respectively, an increase in regulatory CD56 bright NK cells and a good response to treatment were previously described for other immunomodulatory drugs .…”

Section: Discussionsupporting

confidence: 72%

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The NRF2 pathway as potential biomarker for dimethyl fumarate treatment in multiple sclerosis

Hammer

Waschbisch

Kuhbandner

et al. 2018

Ann Clin Transl Neurol

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ObjectiveImmunological studies have demonstrated a plethora of beneficial effects of dimethyl fumarate (DMF) on various cell types. However, the cellular and molecular targets are incompletely understood and response markers are scarce. Here, we focus on the relation between nuclear factor (erythroid‐derived 2)‐like 2 (NRF2) pathway induction under DMF therapy and the composition of the blood immune cell compartment and clinical efficacy in relapsing‐remitting multiple sclerosis (MS) patients.MethodsWe explored effects of DMF on peripheral immune cell subsets by flow cytometric and transcriptional analysis of serial blood samples obtained from 43 MS patients during the first year of therapy.ResultsGene expression analysis proved activation of NRF2 signaling under DMF therapy that was paralleled by a temporal expansion of FoxP3+ regulatory T cells, CD56bright natural killer cells, plasmacytoid dendritic cells, and a decrease in CD8+ T cells, B cells, and type 1 myeloid dendritic cells. In a subgroup of 28 patients with completely available clinical data, individuals with higher levels of the NRF2 target gene NAD(P)H quinone dehydrogenase 1 (NQO1) 4–6 weeks after DMF therapy initiation were more likely to achieve no evidence of disease activity status 1 year later. The degree of NQO1 induction further correlated with patient age.InterpretationWe demonstrate that positive effects of DMF on the clinical outcome are paralleled by induction of the antioxidant NRF2 transcriptional pathway and a shift toward regulatory immune cell subsets in the periphery. Our data identify a role of the NRF2 pathway as potential biomarker for DMF treatment in MS.

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“…In line with other publications, DMF therapy was associated with reduced CD8 + T cell and B cell counts among total PBMC (Fig. K and L) …”

Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 72%

The NRF2 pathway as potential biomarker for dimethyl fumarate treatment in multiple sclerosis

Hammer

Waschbisch

Kuhbandner

et al. 2018

Ann Clin Transl Neurol

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show abstract

“…Although not addressed in this work, it would be interesting to analyze the expression of CXCR3 and CCR6 in the Treg population to know whether this reduction is related to a decrease of pro‐inflammatory Th1 and/or Th17 Treg . Regarding discrepancies with other studies reporting a reduction on Th1 and Th17 cells and no alteration or even expansion of Treg, they might be caused by the use in those studies of isolated, cryopreserved, and stimulated PBMC (since it has been reported that these procedures can modify the expression of chemokine receptors) . We consider that the direct analysis of whole blood leukocytes subpopulations can reflect better the effects caused by DMF treatment, avoiding variability caused by cell manipulation.…”

Section: Discussionmentioning

confidence: 92%

“…Studies focused on the mechanism of action of DMF demonstrated that the treatment induces lymphopenia, selectively depleting memory T and B cells and promoting a shift toward a tolerogenic immune profile . Specifically, Medina and colleagues reported that DMF induces a change in the ratio between regulatory CD56 bright NK cells and effector TNF‐α‐producing CD8 + T cells, which is required for the efficacy of the treatment.…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, Medina and colleagues reported that DMF induces a change in the ratio between regulatory CD56 bright NK cells and effector TNF‐α‐producing CD8 + T cells, which is required for the efficacy of the treatment. The authors also suggested that monitorization of leukocyte subpopulations could be a useful tool for early identification of responder and nonresponder patients …”

Section: Introductionmentioning

confidence: 99%

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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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Dimethyl fumarate treatment induces lipid metabolism alterations that are linked to immunological changes

Bhargava

Fitzgerald

Venkata

et al. 2018

Ann Clin Transl Neurol

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ObjectiveIdentify metabolic changes produced by dimethyl fumarate (DMF) treatment and link them to immunological effects.MethodsWe enrolled 18 MS patients and obtained blood prior to DMF and 6 months postinitiation. We also enrolled 18 healthy controls for comparison. We performed global metabolomics on plasma and used weighted correlation network analysis (WGCNA) to identify modules of correlated metabolites. We identified modules that changed with treatment, followed by targeted metabolomics to corroborate changes identified in global analyses. We correlated changes in metabolite modules and individual metabolites with changes in immunological parameters.ResultsWe identified alterations in lipid metabolism after DMF treatment – increases in two modules (phospholipids, lysophospholipids and plasmalogens) and reduction in one module (saturated and poly‐unsaturated fatty acids) eigen‐metabolite values (all P < 0.05). Change in the fatty acid module was greater in participants who developed lymphopenia and was strongly associated with both reduction in absolute lymphocyte counts (r = 0.65; P = 0.005) and change in CD8+ T cell subsets. We also noted significant correlation of change in lymphocyte counts with multiple fatty acid levels (measured by targeted or untargeted methods).InterpretationThis study demonstrates that DMF treatment alters lipid metabolism and that changes in fatty acid levels are related to DMF‐induced immunological changes.

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Optimal response to dimethyl fumarate associates in MS with a shift from an inflammatory to a tolerogenic blood cell profile

Abstract: A pro-tolerogenic shift in the blood leukocyte profile associates with an optimal response to DMF in MS.

Cited by 48 publications

References 29 publications

The NRF2 pathway as potential biomarker for dimethyl fumarate treatment in multiple sclerosis

The NRF2 pathway as potential biomarker for dimethyl fumarate treatment in multiple sclerosis

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

Dimethyl fumarate treatment induces lipid metabolism alterations that are linked to immunological changes

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