Differential Effects of Natalizumab and Fingolimod on the Innate Immune System of MS Patients (P04.125)

Abstract

Objective: To investigate effects of natalizumab (NA) and fingolimod (FTY) on the innate immune system (IIS) in Multiple Sclerosis (MS) patients. Background Dendritic cells (DC) and monocytes (MO) are professional antigen-presenting-cells (APC) orchestrating the IIS and can have profound effects on T- and B-cell effector-function. SlanDC as major human blood-DC population are potent APC and cytokine-producing effector cells taking part in pro-inflammatory processes in MS. As FTY and NA are primarily drugs interfering with lymphocyte redistribution between lymphoid organs vs. blood (FTY) resp. lymphocyte migration throughout the blood-brain-barrier (NA), little is known about effects on the IIS. Design/Methods: SlanDC and MO of healthy controls, untreated MS-patients and MS-patients treated with NA or FTY were analyzed regarding frequency and activation-status. In addition, they were isolated by immunomagnetic-cell-sorting. After stimulation with TLR-ligands, they were analyzed with and without FTY720, FTY720-phosphate or S1P regarding their cytokine-release, T-cell-programming and –priming. Results: Natalizumab-treatment did not change frequency of slanDC, MO and DC1/2 in blood, but lead to reduced monocyte frequency in CSF. Natalizumab could be demonstrated on the surface of all IIS cells. During NA-treatment, no differences in cytokine-release like TNF-a, IL10, IL6 or IL12 and activation-phenotype could be described for slanDC and MO compared to healthy- and untreated-controls. In contrast, fingolimod-treatment lead to an increase of slanDC and MO, whereas DC1/DC2 frequencies were stable. In FTY-treated-patients, pro-inflammatory cytokine-secretion of TNF-a and IL12 was inhibited in slanDC, but not modulated in MO. By in vitro experiments using sorted slanDC and MO, S1P increased and FTY decreased pro-inflammatory cytokine-profiles. FTY impaired the induction of IFN-gamma-producing Th1-cells after LPS-stimulation. Conclusions: Natalizumab only lead to a frequency reduction of cells of the IIS in CSF. FTY did not only modulate T- and B-lymphocyte trafficking, but also effect APC frequency and function. Our results suggest an impact of FTY on T-cell-programming and cytokine-secretion of DCs. Supported by: Novartis. Disclosure: Dr. Thomas has received research support from Teva Neuroscience. Dr. Sehr has nothing to disclose. Dr. Hainke has nothing to disclose. Dr. Schultheiss has nothing to disclose. Dr. Ziemssen has received personal compensation for activities with Biogen Idec, Bayer Healthcare, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, and Synthon. Dr. Ziemssen has received research support for from Bayer Healthcare, Biogen Idec, Novartis, Teva Neuroscience, and Sanofi-Aventis Pharmaceuticals, Inc.