Abstract Details

Title mTORc1 but not JNK Inhibition Augments Glucocorticosteroid Efficacy in Multiple Sclerosis

Topic Multiple Sclerosis

Presentation(s) S55 - MS Basic Science (4:03 PM-4:14 PM)

Poster/Presentation
Number 004

Background Glucocorticoids are mainly used for treatment of multiple sclerosis relapses. However, increase of disability following acute disease phases is commonly observed.

Objective We investigated potential strategies to enhance steroid efficacy in multiple sclerosis relpases.

Design/Methods

In vitro human and murine T cell apoptosis and in vivo MOG_35-55 Experimental Autoimmune Encephalomyelitis (EAE) were used to investigate if mTORc1 or JNK inhibition increases glucocorticoid efficacy. Positive results of the screening experiments were then in vitro and in vivo confirmed taking advantage of conditional knockout mice with T-cell specific deficiency for mTORc1 or the glucocorticoid receptor. Glucocorticoid receptor concentration was measured using an ELISA. The potential to inhibit mTORc1 was checked by analysing phosphorylation of a downstream target of the mTORc1 pathway.

Results mTORc1 inhibition using different drugs (everolimus, rapamycin, voxtalisib, XL388, vitamin D) but not JNK inhibition by SP600125 (SP) lead to an increase of human T cell apoptosis in vitro. In contrast to SP/glucocorticoids dual treatment, combination therapy of everolimus and methylprednisolone ameliorates EAE disease course compared to respective monotherapies. Mechanistically, the increased effects of glucocorticoids were caused by an upregulation of the glucocorticoid receptor protein via mTORc1. Relevance of the glucocorticoid receptor was validated in mice with T-cell specific glucocorticoid receptor deficiency. Here methylprednisolone treatment had no therapeutic effect on EAE disease course. Finally, in addition to pharmacological inhibition the relevance of the mTORc1 pathway was also investigated using mice with T-cell specific deficiency of mTORc1 activity. In these mice, the pharmacological inhibition of mTORc1 did not lead to an upregulation of the glucocorticoid receptor and combination therapy with methylprednisolone did not ameliorate clinical course of EAE disease.

Conclusions mTORc1 inhibition seems to increase therapeutic efficacy of glucocorticoids via an upregulation of the glucocorticoid receptor. Our data suggest that transient mTORc1 inhibition might be used to overcome glucocorticoid resistance in patients with multiple sclerosis.

Authors/Disclosures
Robert Hoepner PRESENTER	Robert Hoepner has nothing to disclose.
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Anke Salmen (St. Josef-Hospital, Ruhr -University Bochum)	The institution of Anke Salmen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neuraxpharm. Anke Salmen has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb. Anke Salmen has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Anke Salmen has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Neuraxpharm. Anke Salmen has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. The institution of Anke Salmen has received research support from Regional association of the German MS Society (DMSG Landesverband NRW).
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Helmut Butzkueven, MD, MBBS (Alfred Hospital)	Dr. Butzkueven has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Oxford Health Policy Forum. The institution of Dr. Butzkueven has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. The institution of Dr. Butzkueven has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Merck. The institution of Dr. Butzkueven has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. The institution of Dr. Butzkueven has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche. Dr. Butzkueven has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for MSBase . The institution of Dr. Butzkueven has received research support from NHMRC. The institution of Dr. Butzkueven has received research support from Biogen. The institution of Dr. Butzkueven has received research support from Roche. The institution of Dr. Butzkueven has received research support from Novartis.
Ralf Gold, MD (Neurologische Universitaetsklinik)	Dr. Gold has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen . Dr. Gold has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Gold has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. Dr. Gold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genzyme. Dr. Gold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bayer Vital. Dr. Gold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai Pharamaceuticals. Dr. Gold has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Gold 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. Gold has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for SAGE Publishers. Dr. Gold has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Novartis. Dr. Gold has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Biogen. The institution of Dr. Gold has received research support from Novartis. The institution of Dr. Gold has received research support from Biogen.
Fred Luhder (IMSF)	No disclosure on file
Andrew Chan	The institution of Andrew Chan has received research support from UCB. The institution of Andrew Chan has received research support from Biogen. The institution of Andrew Chan has received research support from Sanofi Genzyme.

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