Contributions
Abstract: P1912
Type: Poster
Abstract Category: Late breaking news
Background: Dimethylfumarate (DMF) is metabolized to monomethylfumarate (MMF) by esterases in the intestine and absorbed in the blood, where it is rapidly metabolized to fumarate and citric acid via the tricarboxylic acid (TCA) cycle. Intracellular accumulations of fumarate, however, have been shown to hypermethylate DNA by inhibiting multiple α-ketoglutarate (α-KG)-dependent dioxygenases, including DNA demethylases, in certain cancer cells. Here we investigated whether fumaric acid esters could also modulate DNA methylation levels in CD4 T cells.
Methods: PBMCs were collected from 57 Naive and 49 DMF treated MS patients for immunophenotyping and CD4 T cells were isolated from 36 Naïve and 44 DMF treated MS patients for methylation analysis. Immunophenotyping was performed at the human immune core at Mount Sinai hospital. DNA methylation of CD4 T cells was analyzed at 850k CpG sites throughout the entire genome by utilizing the Infinium MethylationEPIC BeadChip array.
Results: DMF reduced the total number of CD4 and CD8 T cells in the blood of treated MS patients compared to naïve MS patients. Furthermore, DMF was able to reduce the percentage of both CCR6+CCR4+ (Th17) and CCR6-CCR4+ (Th2) CD4 T cell subtypes compared to treatment naïve patients. CD4 T cells from DMF-treated patients had hypermethylated DNA at promoters of several T cell pro-survival and pro-inflammatory genes compared to treatment-naïve MS patients.
Conclusions: CD4 T cells from patients taking DMF demonstrated hypermethylated DNA at promoters of several pro-survival and pro-inflammatory genes compared to treatment naïve MS patients. This suggests that by modulating DNA methylation in CD4 T cells, DMF could reduce the expression of pro-survival and pro-inflammatory genes in CD4 T cells, which could potentially explain the cytotoxic and/or immunomodulatory effect of DMF in CD4 T cells in MS.
Disclosure: Achilles Ntranos: nothing to disclose, Vasilis Ntranos: nothing to disclose, Yunjiao Zhu: nothing to disclose, Corey Watson: nothing to disclose, Ilana Katz-Sand: nothing to disclose, Patrizia Casaccia: has received grants from Biogen for another study
Abstract: P1912
Type: Poster
Abstract Category: Late breaking news
Background: Dimethylfumarate (DMF) is metabolized to monomethylfumarate (MMF) by esterases in the intestine and absorbed in the blood, where it is rapidly metabolized to fumarate and citric acid via the tricarboxylic acid (TCA) cycle. Intracellular accumulations of fumarate, however, have been shown to hypermethylate DNA by inhibiting multiple α-ketoglutarate (α-KG)-dependent dioxygenases, including DNA demethylases, in certain cancer cells. Here we investigated whether fumaric acid esters could also modulate DNA methylation levels in CD4 T cells.
Methods: PBMCs were collected from 57 Naive and 49 DMF treated MS patients for immunophenotyping and CD4 T cells were isolated from 36 Naïve and 44 DMF treated MS patients for methylation analysis. Immunophenotyping was performed at the human immune core at Mount Sinai hospital. DNA methylation of CD4 T cells was analyzed at 850k CpG sites throughout the entire genome by utilizing the Infinium MethylationEPIC BeadChip array.
Results: DMF reduced the total number of CD4 and CD8 T cells in the blood of treated MS patients compared to naïve MS patients. Furthermore, DMF was able to reduce the percentage of both CCR6+CCR4+ (Th17) and CCR6-CCR4+ (Th2) CD4 T cell subtypes compared to treatment naïve patients. CD4 T cells from DMF-treated patients had hypermethylated DNA at promoters of several T cell pro-survival and pro-inflammatory genes compared to treatment-naïve MS patients.
Conclusions: CD4 T cells from patients taking DMF demonstrated hypermethylated DNA at promoters of several pro-survival and pro-inflammatory genes compared to treatment naïve MS patients. This suggests that by modulating DNA methylation in CD4 T cells, DMF could reduce the expression of pro-survival and pro-inflammatory genes in CD4 T cells, which could potentially explain the cytotoxic and/or immunomodulatory effect of DMF in CD4 T cells in MS.
Disclosure: Achilles Ntranos: nothing to disclose, Vasilis Ntranos: nothing to disclose, Yunjiao Zhu: nothing to disclose, Corey Watson: nothing to disclose, Ilana Katz-Sand: nothing to disclose, Patrizia Casaccia: has received grants from Biogen for another study