Abstract Details

Title SlanDCs as Crucial Target of the MS-Immunmodulator Laquinimod

Topic MS and Related Diseases

Presentation(s) P05 - (-)

Poster/Presentation
Number 156

Objective

Background BACKGROUND: Laquinimod (LAQ) is an innovative oral drug under development for the treatment of relapsing remitting multiple sclerosis (MS). The mechanism of action is still under investigation. Whereas on the T cell level, a cytokine shift towards T-helper-2 (Th2) cells was observed, LAQ demonstrated significant effects on the innate immune system as well. Recently antigen presenting cells (APC) populations were reported to be altered in function and frequency by LAQ therapy in experimental autoimmune encephalomyelitis (EAE) model.

Design/Methods DESIGN/METHODS: Patients treated with different doses of LAQ (0.6 mg to 2.7 mg) as part of the MTD trial were analysed before and after 4 weeks on daily LAQ treatment. Frequencies and activation markers of monocytes (MO) and different dendritic cell (DC) populations were analysed. Additionally cytokine release and apoptotic signal of MO and DC were analyzed after immunomagnetic isolation (MACS) and activation by TLR-4 or TLR-7/8 ligands in the presence and absence of LAQ in-vitro.

Results RESULTS: We could demonstrate a highly significant decrease of slanDC after 4 weeks of LAQ treatment (0.32% to 0.12%) while MO were unaffected (7.0% to 7.4%). In-vitro experiments demonstrated increase apoptosis signals in slanDCs incubated with LAQ in comparison to untreated slanDC. Ex-vivo analysis revealed a significant effect of LAQ on activation markers (CD83, CD150, TNF) of slanDC and in smaller amount of MO, while first experiments did not show an in-vitro effect of LAQ coincubation on cytokine markers of sorted slanDC nor MO.

Conclusions CONCLUSIONS: We could demonstrate a significant effect of LAQ on a new proinflammatory dendritic cell population which is specifically decreased by LAQ in comparison to MO which are not affected. Cell frequency and activation of these cells were decreased. The mechanism and functional impact of this effect need further investigations.

Authors/Disclosures
Tony Sehr PRESENTER	No disclosure on file
Katja Thomas, MD (Centre of Clinical Neuroscience, Neurological University Clinic)	No disclosure on file
John Ko, PharmD, MS (Alnylam)	Dr. Ko has received personal compensation for serving as an employee of Alnylam Pharmaceuticals. Dr. Ko has received personal compensation for serving as an employee of Novartis. Dr. Ko has received stock or an ownership interest from Alnylam Pharmaceuticals. Dr. Ko has received stock or an ownership interest from Novartis.
Liat Hayardeny Nisimov, PhD (Teva)	No disclosure on file
Tjalf Ziemssen, MD, FAAN (University Clinic Dresden)	Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche. Dr. Ziemssen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Ziemssen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS . Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merck. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Roche. Dr. Ziemssen has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Dr. Ziemssen has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Sanofi. Dr. Ziemssen has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for TEVA. Dr. Ziemssen has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for Dresden Internation University. The institution of Dr. Ziemssen has received research support from Novartis. The institution of Dr. Ziemssen has received research support from Merck. The institution of Dr. Ziemssen has received research support from Sanofi. The institution of Dr. Ziemssen has received research support from BMS. The institution of Dr. Ziemssen has received research support from Roche.

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