Immunological Predictors of Dimethyl Fumarate-Induced Lymphopenia.
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ABSTRACT:
SUBMITTER: Diebold M
PROVIDER: S-EPMC9314128 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveTo examine the mechanism underlying the preferential CD8+ vs CD4+ T-cell lymphopenia induced by dimethyl fumarate (DMF) treatment of MS.MethodsTotal lymphocyte counts and comprehensive T-cell subset analyses were performed in high-quality samples obtained from patients with MS prior to and serially following DMF treatment initiation. Random coefficient mixed-effects analysis was used to model the trajectory of T-cell subset losses in vivo. Survival and apoptosis of distinct T-cell subsets were assessed following in vitro exposure to DMF.ResultsBest-fit modeling indicated that the DMF-induced preferential reductions in CD8+ vs CD4+ T-cell counts nonetheless followed similar depletion kinetics, suggesting a similar rather than distinct mechanism involved in losses of both the CD8+ and CD4+ T cells. In vitro, DMF exposure resulted in dose-dependent reductions in T-cell survival, which were found to reflect apoptotic cell death. This DMF-induced apoptosis was greater for CD8+ vs CD4+, as well as for memory vs naive, and conventional vs regulatory T-cell subsets, a pattern which mirrored preferential T-cell subset losses that we observed during in vivo treatment of patients.ConclusionsDifferential apoptosis mediated by DMF may underlie the preferential lymphopenia of distinct T-cell subsets, including CD8+ and memory T-cell subsets, seen in treated patients with MS. This differential susceptibility of distinct T-cell subsets to DMF-induced apoptosis may contribute to both the safety and efficacy profiles of DMF in patients with MS.
| S-EPMC5365096 | biostudies-literature
Project description:BackgroundDimethyl fumarate (DMF) is licensed for treatment of relapsing-remitting multiple sclerosis (RRMS). DMF can induce lymphopenia, which is assumed to increase the risk for opportunistic infections like progressive multifocal leukoencephalopathy. Our goal for this work was to estimate the frequency of grade 3 lymphopenia in DMF-treated patients with RRMS and to characterize patient-sided factors influencing the time course of lymphocyte repopulation after DMF withdrawal.Material and methodsA single-center retrospective data analysis was performed at University Hospital Bern, Switzerland. Patients with DMF treatment were analyzed for lymphocyte counts. Demographic factors were statistically analyzed in grade 3 lymphopenic patients.ResultsWe estimated a grade 3 lymphopenia frequency of 11/246 (4.5%), corroborating previous studies. In all patients, lymphocytes recovered to values ⩾800/µl within 0.5 years. Multivariate linear regression analysis unmasked older age as being associated with a longer duration of repopulation.ConclusionConsidering the aging population, our findings warrant further investigations of DMF-induced lymphopenia.
| S-EPMC6506915 | biostudies-literature
Project description:In delayed-release dimethyl fumarate (DMF)-treated patients, absolute lymphocyte count (ALC) often declines in the first year and stabilizes thereafter; early declines have been associated with development of severe prolonged lymphopenia (SPL). Prolonged moderate or severe lymphopenia is a known risk factor for progressive multifocal leukoencephalopathy (PML); DMF-associated PML is very rare. It is unknown whether genetic predictors of SPL secondary to DMF treatment exist. We aimed to identify genetic predictors of reduced white blood cell (WBC) counts in DMF-treated multiple sclerosis (MS) patients. Genotyping (N = 1,258) and blood transcriptional profiling (N = 1,133) were performed on MS patients from DEFINE/CONFIRM. ALCs were categorized as: SPL, < 500 cells/µL for ≥6 months; moderate prolonged lymphopenia (MPL), < 800 cells/µL for ≥6 months, excluding SPL; mildly reduced lymphocytes, < 910 cells/µL at any point, excluding SPL and MPL; no lymphopenia, ≥910 cells/µL. Genome-wide association, HLA, and cross-sectional gene expression studies were performed. No common variants, HLA alleles, or expression profiles clinically useful for predicting SPL or MPL were identified. There was no overlap between genetic peaks and genetic loci known to be associated with WBC. Gene expression profiles were not associated with lymphopenia status. A classification model including gene expression features was not more predictive of lymphopenia status than standard covariates. There were no genetic predictors of SPL (or MPL) secondary to DMF treatment. Our results support ALC monitoring during DMF treatment as the most effective way to identify patients at risk of SPL.
| S-EPMC6844186 | biostudies-literature
Project description:Gut microbiota composition as a candidate risk factor for dimethyl fumarate-induced lymphopenia in multiple sclerosis
| PRJEB55040 | ENA
Project description: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.
| S-EPMC6331509 | biostudies-literature
Project description:IntroductionAdverse drug reactions (ADRs) are a global public health issue. The potential for pharmacogenomic biomarkers has been demonstrated in several therapeutical areas, including HIV infection and oncology. Dimethyl fumarate (DMF) is a licensed disease-modifying therapy for the treatment of multiple sclerosis (MS). The use of DMF in MS has been associated with a severe reduction in lymphocyte counts and reports of progressive multifocal leukoencephalopathy. Here, we outline the protocol for a case-control study designed to discover genomic variants associated with DMF-induced lymphopenia. The ultimate goal is to replicate these findings and create an efficient and adaptable approach towards the identification of genomic markers that could assist in mitigating adverse drug reactions in MS.Methods and analysisThe population sample will comprise DMF-exposed patients with MS, with cases representing those who developed lymphopenia and controls who did not. DNA genotyping will take place using a high-throughput genome-wide array. Fine mapping and imputation will be performed to focus in on the potentially causal variants associated with lymphopenia. Multivariable logistic regression will be used to compare genotype and allele frequencies between the cases and the controls, with consideration of potential confounders. The association threshold will be set at p<1.0×10-5 for the discovery of genomic association analyses to select variants for replication.Ethics and disseminationEthics approval has been obtained from the respective research ethics board, which includes written informed consent. Findings will be disseminated widely, including at scientific conferences, via podcasts (targeted at both healthcare professionals as well as patients and the wider community), through patient engagement and other outreach community events, written lay summaries for all participants and formal publication in peer-reviewed scientific journals.
| S-EPMC5623385 | biostudies-literature
Project description:BackgroundOxidative stress and inflammatory pathways are involved in migraine and endogenous antioxidant defense system has a role in the prevention of hyperalgesia in migraine. In this study, we aimed to evaluate the role of the most pharmacologically effective molecules among the fumaric acid esters (FAEs), dimethyl fumarate, nuclear factor E2-related factor 2/antioxidant response element (Nrf-2/ARE) pathway-mediated, in regulating the hypersensitivity in a mouse model of nitroglycerine (NTG)-induced migraine.MethodsMice were orally administered with DMF at the doses of 10, 30, and 100 mg/kg, 5 min after NTG intraperitoneal injections. We performed histological and molecular analysis on the whole brain and behavioral tests after 4 h by NTG-migraine induction. The expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кB) subunit p65, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα), inducible nitrite oxide synthase (iNOS), cyclooxygenase 2 (COX-2), Nrf-2, manganese superoxide dismutase (Mn-SOD), and heme-oxygenase-1 (HO-1) were detected by Western blot. Tail flick, hot plate, orofacial formalin, and photophobia tests were used to evaluate migraine-like pain and migraine-related light sensitivity. Moreover, we evaluate Nrf-2-dependent mechanism by the in vitro stimulation of cells extracted by trigeminal ganglia with diethylenetriamine/nitric oxide (DETA/NO), a nitric oxide (NO) donor. The cells were pre-treated with DMF and an antagonist of Nrf-2, trigonelline (TR) 2 h before DETA/NO stimulation.ResultsDMF treatment notably reduced histological damage as showed by cresyl violet staining; also, regulating both NF-κB and Nrf-2 pathway, DMF treatment decreased the severity of inflammation and increased the protective antioxidant action. Moreover, the headache was significantly reduced. The protective effect of DMF treatment, via Nrf-2, was confirmed in in vitro studies, through inhibition of Nrf-2 by trigonelline. Cytotoxicity, iNOS, and MnSOD expression were evaluated.ConclusionThese results provided the evidence that DMF, by Nrf-2 modulation, has a protective effect on central sensitization induced by NTG, suggesting a new insight into the potential application of DMF as novel candidates in drug development for migraine.
| S-EPMC7469611 | biostudies-literature
Project description:Doxorubicin (DOX) is limited in clinical application because of its cardiotoxicity. Oxidative stress and apoptosis are crucial in DOX-induced cardiac injury. Dimethyl fumarate (DMF) is an FDA-approved oral drug with powerful effects to reduce oxidative stress and apoptosis through the Nrf2 pathway. This study was aimed to determine whether DMF can protect against DOX-induced cardiac injury. We used both neonatal rat cardiomyocytes (NRCMs) in vitro and DOX-induced cardiac toxicity in vivo to explore the effects of DMF. The results showed that DMF significantly improved cell viability and morphology in NRCMs. In addition, DMF alleviated DOX-induced cardiac injury in rats, as evidenced by decreased CK-MB, LDH levels, improved survival rates, cardiac function, and pathological changes. Moreover, DMF significantly inhibited cardiac oxidative stress by reducing MDA levels and increasing GSH, SOD, and GSH-px levels. And DMF also inhibited DOX-induced cardiac apoptosis by modulating Bax, Bcl-2 and cleaved caspase-3 expression. Moreover, DMF exerted its protective effects against DOX by promoting Nrf2 nuclear translocation, which activated its downstream antioxidant gene Hmox1. Silencing of Nrf2 attenuated the protective effects of DMF in NRCMs as manifested by increased intracellular oxidative stress, elevated apoptosis levels, and decreased cell viability. In addition, DMF showed no protective effects on the viability of DOX-treated tumor cells, which suggested that DMF does not interfere with the antitumor effect of DOX in vitro. In conclusion, our data confirmed that DMF alleviated DOX-induced cardiotoxicity by regulating oxidative stress and apoptosis through the Nrf2 pathway. DMF may serve as a new candidate to alleviate DOX-related cardiotoxicity in the future.
| S-EPMC9089305 | biostudies-literature
Project description:BackgroundImmune thrombocytopenia (ITP) is an autoimmune disease characterized as a low platelet count resulting from immune-mediated platelet destruction. Dimethyl fumarate (DMF) is widely applied for the treatment of several autoimmune diseases with immunosuppressive effect. However, whether it ameliorates ITP is unclear. This study aims to evaluate whether DMF has a preventive effect on ITP in mice.MethodsDMF (30, 60 or 90 mg/kg body weight) was intraperitoneally injected into mice followed by injection of rat anti-mouse integrin GPIIb/CD41antibody to induce ITP. Peripheral blood was isolated to measure platelet count and spleen mononuclear cells were extracted to measure Th1 and Treg cells along with detecting the levels of IFN-γ, and TGFβ-1 in plasma and CD68 expression in spleen by immuohistochemical staining. Additionally, macrophage cell line RAW264.7 was cultured and treated with DMF followed by analysis of cell apoptosis and cycle, and the expression of FcγRI, FcγRIIb and FcγRIV mRNA.ResultsDMF significantly inhibited antiplatelet antibody-induced platelet destruction, decreased Th1 cells and the expression of T-bet and IFN-γ, upregulated Treg cells and the expression of Foxp3 and TGF-β1 as well as reduced CD68 expression in the spleen of ITP mouse. DMF-treated RAW264.7 cells showed S-phase arrest, increased apoptosis and downregulated expression of FcγRI and FcγRIV. Meanwhile, in vitro treatment of DMF also decreased the expression of cyclin D1 and E2, reduced Bcl-2 level and increased Bax expression and caspase-3 activation.ConclusionsIn conclusion, DMF prevents antibody-mediated platelet destruction in ITP mice possibly through promoting apoptosis, indicating that it might be used as a new approach for the treatment of ITP.
| S-EPMC8403390 | biostudies-literature
Project description:Background:Oxidative damage may contribute to post-stroke cognitive impairment (PSCI), but the underlying mechanisms are not fully elucidated. Dimethyl fumarate (DMF) has been used as an antioxidant in multiple sclerosis and psoriasis patients. We hypothesized that redox state was associated with PSCI, and DMF might exert neuroprotective effect against PSCI via anti-oxidative actions. Methods:To confirm this hypothesis, we first conducted a clinical study (NCT03519828) that enrolled patients diagnosed with acute ischemic stroke within 48 hours. Data were analyzed based on demographic characteristics, disease history, clinical data and redox state. Logistic regression was used to identify the factors associated with PSCI. Next, a middle cerebral artery occlusion (MCAO) rat model was used to explore the antioxidant capacity and neuroprotective effect of DMF. Furthermore, behavioural experiments, histology and immunostaining, and transmission electron microscopy were also performed. Results:Higher baseline NIHSS score, lower GSH/GSSG and T-AOC levels were found in the PSCI patients. Better performance in Morris water maze and shuttle box testing, more regular arranged neurons and Nissl bodies, less TUNEL-positive cells and autophagosomes, lower expression of 4-HNE, and higher expression of GCLM and NQO1 were found in the (DMF + MCAO) rats compared with the MCAO rats. Conclusions:These findings suggest that DMF may alleviate PSCI via neuroprotective actions, providing a new therapeutic strategy for PSCI.
| S-EPMC7186746 | biostudies-literature