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Abstract Details

Dimethyl fumarate treatment alters T cell metabolism in multiple sclerosis
Multiple Sclerosis
P6 - Poster Session 6 (12:00 PM-1:00 PM)
9-004

DMF is a treatment for relapsing-remitting multiple sclerosis (RRMS). In neurons, the protective benefits of DMF are associated with Nrf2, a transcription factor that induces expression of antioxidative stress-response genes. However, DMF has no protective effect on peripheral T cells but leads to reduced cell numbers of memory T cells (TM) while naïve T cells (TN) were less affected. Interestingly, it is known that murine TM cells display an increased metabolic capacity compared to TN cells.

In order to investigate the molecular mechanism of dimethyl fumarate (DMF) in different T cell subsets, we examined metabolic effects and their potential link to cellular stress-response leading to apoptosis.
T cells were isolated from MS patients before/during DMF treatment and healthy donors. To determine functional metabolism and metabolite composition Seahorse technology and untargeted metabolomics were used, respectively. Apoptosis was assessed by flow-cytometric analysis of caspases 3/7.
T cells from DMF-treated MS patients displayed a decreased mitochondrial respiration as compared to pretreatment. In vitro administration of DMF reduced mitochondrial respiration in TM and TN subsets, however, TM cells were more susceptible than TN cells due to their 2-fold increased metabolic capacity. Furthermore, mitochondrial stress-response illustrated by elevated ROS levels was enhanced in DMF-treated TM but not TN cells corroborating again that TM cells display an enhanced sensitivity towards DMF. Interestingly, incubation of DMF-treated T cells with the antioxidant N-acetylcysteine completely restored the reduction of maximal respiration and reduced the increased apoptosis rate to control level.

These data illustrate that the effect of DMF on mitochondrial functions are reversible by application of N-acetylcysteine indicating that metabolic dysfunction and enhanced stress-response is linked to apoptosis. Importantly, TM cells display an enhanced sensitivity and stress-response following DMF treatment, which might be a potential mechanism explaining the increased apoptosis and vulnerability of TM cells in DMF-treated MS patients.

Authors/Disclosures
Luisa H. Klotz, MD (Uniklinik Münster)
PRESENTER
Dr. Klotz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bayer. Dr. Klotz has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Klotz has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genzyme. Dr. Klotz has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bristol Myers Squibb. Dr. Klotz has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Merck Serono. Dr. Klotz has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Dr. Klotz has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. Dr. Klotz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Klotz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Klotz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Klotz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Klotz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Dr. Klotz has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Klotz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon. Dr. Klotz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Viatris. Dr. Klotz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BMS. The institution of Dr. Klotz has received research support from Immunic AG. The institution of Dr. Klotz has received research support from Merck.
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
Andreas Schulte-Mecklenbeck No disclosure on file
Nicholas Schwab The institution of Nicholas Schwab has received research support from Biogen. The institution of Nicholas Schwab has received research support from Roche.
No disclosure on file
No disclosure on file
No disclosure on file
Sven G. Meuth (Uniklinik Düsseldorf, Klinik für Neurologie) Sven G. Meuth has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Merck. Sven G. Meuth has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Sven G. Meuth has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Almirall. Sven G. Meuth has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Celgene. Sven G. Meuth has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genzyme. Sven G. Meuth has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Sven G. Meuth has received personal compensation in the range of $500-$4,999 for serving as a Consultant for TEVA. Sven G. Meuth has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche.
Heinz Wiendl, MD, FAAN (University of Muenster) Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bristol Myers Squibb. Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Immunovant. Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Johnson&Johnson / Janssen. Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for UCB. Dr. Wiendl has received personal compensation in the range of $0-$499 for serving as a Consultant for Idorsia. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Argenx. Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Immunic. Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merck. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NexGen. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Worldwide Clinical Trials. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BD. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lundbeck. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gossamer Bio. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for LTS. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Samsung. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sangamo. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck Serono. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Janssen. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Wiendl has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bristol Myers Squibb. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sandoz. Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sandoz-Hexal. Dr. Wiendl has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cellerys. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Dianthus. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Toleranzia. Dr. Wiendl has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Uniqure. The institution of Dr. Wiendl has received research support from Biogen. The institution of Dr. Wiendl has received research support from Roche. The institution of Dr. Wiendl has received research support from Deutsche Forschungsgemeinschaft. The institution of Dr. Wiendl has received research support from European Union. The institution of Dr. Wiendl has received research support from Argenx. The institution of Dr. Wiendl has received research support from CSL Behring. The institution of Dr. Wiendl has received research support from Merck. The institution of Dr. Wiendl has received research support from UCB. Dr. Wiendl has received publishing royalties from a publication relating to health care. Dr. Wiendl has received publishing royalties from a publication relating to health care.