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Dimethyl fumarate treatment restrains the antioxidative capacity of T cells to control autoimmunity.

ABSTRACT: Dimethyl fumarate, an approved treatment for relapsing-remitting multiple sclerosis, exerts pleiotropic effects on immune cells as well as CNS resident cells. Here, we show that dimethyl fumarate exerts a profound alteration of the metabolic profile of human CD4+ as well as CD8+ T cells and restricts their antioxidative capacities by decreasing intracellular levels of the reactive oxygen species scavenger glutathione. This causes an increase in mitochondrial reactive oxygen species levels accompanied by an enhanced mitochondrial stress response, ultimately leading to impaired mitochondrial function. Enhanced mitochondrial reactive oxygen species levels not only result in enhanced T-cell apoptosis in vitro as well as in dimethyl fumarate-treated patients, but are key for the well-known immunomodulatory effects of dimethyl fumarate both in vitro and in an animal model of multiple sclerosis, i.e. experimental autoimmune encephalomyelitis. Indeed, dimethyl fumarate immune-modulatory effects on T cells were completely abrogated by pharmacological interference of mitochondrial reactive oxygen species production. These data shed new light on dimethyl fumarate as bona fide immune-metabolic drug that targets the intracellular stress response in activated T cells, thereby restricting mitochondrial function and energetic capacity, providing novel insight into the role of oxidative stress in modulating cellular immune responses and T cell-mediated autoimmunity.

SUBMITTER: Liebmann M

PROVIDER: S-EPMC8634070 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionLimited comparative effectiveness data for rituximab (RTX) versus natalizumab (NTZ), fingolimod (FTY), and dimethyl fumarate (DMF) for the treatment of multiple sclerosis (MS) exist.MethodsClinician-reported data on patients prescribed RTX, NTZ, FTY, or DMF for the treatment of MS at the Rocky Mountain MS Center at the University of Colorado were retrospectively collected. Outcomes included a composite effectiveness measure consisting of clinical relapse, contrast-enhancing lesions, and/or new T2 lesions, individual effectiveness outcomes, and discontinuation. Logistic regression was used on patients matched by propensity scores and using average treatment effect on treated doubly robust weighting estimator.ResultsA total of 182, 451, 271, and 342 patients initiated RTX, NTZ, FTY, and DMF and were followed for 2 years. Before and after adjustment, the odds of experiencing disease activity was significantly higher for FTY [adjusted OR (aOR) = 3.17 (95% CI: 1.81-5.55), P < 0.001].and DMF [aOR = 2.68 (95% CI:1.67-4.29), P < 0.001], and similar for NTZ [aOR = 1.36 (95% CI:0.83-2.23), P = 0.216] versus RTX. When examining months 6-24, NTZ demonstrated higher odds of disease activity compared to RTX [aOR = 2.21 (95% CI: 1.20-4.06), P = 0.007]. Similar odds of discontinuation were seen between NTZ and RTX [aOR = 1.39 (95% CI: 0.88-2.20), P = 0.157]; however, FTY [aOR = 2.02 (95% CI: 1.24-3.30), P = 0.005] and DMF [aOR = 3.27 (95% CI: 2.15-4.97), P < 0.001] had greater odds of discontinuation than RTX.InterpretationRTX demonstrated superior effectiveness and discontinuation outcomes compared to FTY and DMF. Although RTX demonstrated similar effectiveness and discontinuation compared to NTZ, RTX had superior effectiveness during months 6-24 and fewer discontinuations when excluding discontinuations due to insurance issues. Results suggest superiority of RTX in reducing disease activity and maintaining long-term treatment in a real-world MS cohort.

Project description:Multiple sclerosis (MS) shares an immune-mediated origin with psoriasis. Long-term safety and efficacy data generated in Europe from usage of fumaric acid formulations in the latter disease constituted grounds to investigate their effects in MS patients. Dimethyl fumarate (DMF) was found to be the active principle in those formulations and in vitro studies have demonstrated that DMF has immune-modulatory properties exerted through abilities to divert cytokine production toward a Th2 profile, both on lymphocytes and microglial cells. More importantly, DMF was discovered to impact the anti-oxidative stress cell machinery promoting the transcription of genes downstream to the activation of the nuclear factor (erythroid derived 2)-like2 (NRF2). DMF exposure increases the cytosol concentrations of NRF2, which besides immune regulatory effects, has the potential for cytoprotection on glial cells, oligodendrocytes and neurons. Extensive and rigorous clinical trials have assessed the efficacy and safety of DMF at the dose of 240 mg twice and three times a day in relapsing-remitting MS patients during one phase IIb and two phase III trials. Robust, positive results were obtained across a number of clinical and paraclinical parameters. In one study (DEFINE), the relative reductions of the adjusted annualized relapse rate of the low and high dose regimens in comparison with placebo were 53% and 48%, respectively (p < 0.001 for both comparisons). In the other trial (CONFIRM), DMF decreased the annualized relapse rate in comparison with placebo by 44% in the lower and by 51% in higher dosage group (also p < 0.001). The number and size of lesions as detected by magnetic resonance imaging were also significantly decreased in comparison with the patients receiving DMF at every dosage. Multiple post hoc and subgroup analyses corroborated the clinical data, rendering DMF an appealing medication whose potential for impacting the degenerative aspects of MS remains to be explored.

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Dimethyl fumarate treatment restrains the antioxidative capacity of T cells to control autoimmunity.

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