Human Mesenchymal Stem Cells (MSC) Reciprocally Modulate Th1 and Th17 Responses: Role for PGE2 (IN8-2.005)

Abstract

Objective: To examine a potential role for PGE2 underlying the human MSC capacity to reciprocally modulate effector T cell responses. Background Autologous human MSC are being studied as potential therapy for patients with multiple sclerosis (MS). In MS, disease activity is thought to be mediated by Th1 and Th17 effector T cells. We previously showed that supernatants (sups) from activated human MSC can robustly increase Th17 responses while decreasing Th1 responses. PGE2 has elsewhere been implicated as a reciprocal regulator of Th1 and Th17 responses. Design/Methods: PGE2 concentrations were measured by ELISA in sups of non-activated and activated human adult MSC. The effect of MSC sups on CD4+ Th1 and Th17 proliferation and cytokine responses were compared to the effects of adding exogenous PGE2, or of adding neutralizing anti-PGE2 antibody. Results: Activation of human MSC by pre-exposure to LPS or IL-1β significantly (p Conclusions: MSC exposed to inflammatory molecules can induce Th17 T cell responses through a PGE2 dependent mechanism. The reciprocal effect of activated MSC sups on Th1 and Th17 responses is likely to reflect a direct induction of Th17 responses by PGE2, and an indirect suppression of Th1 responses, secondary to the IL-17 induction. Our mechanistic insights are of relevance as MSC are being considered therapeutically in MS patients. Supported by: NIH. Disclosure: Dr. Darlington has nothing to disclose. Dr. Rozenberg has nothing to disclose. Dr. Boivin has nothing to disclose. Dr. Cohen has received personal compensation for activities with Biogen Idec, Eli Lilly & Company, Novartis, and Vaccinex. Dr. Cohen has received research support for activities with Biogen Idec, BioMS, Genzyme Corporation, Novartis, Synthon, and Teva Neuroscience. Dr. Cohen has received personal compensation for activities with Biogen Idec, Eli Lilly & Company, Novartis, and Vaccinex. Dr. Cohen has received research support for activities with Biogen Idec, BioMS, Genzyme Corporation, Novartis, Synthon, and Teva Neuroscience. Dr. Cohen has received personal compensation for activities with Biogen Idec, Eli Lilly & Company, Novartis, and Vaccinex. Dr. Cohen has received research support for activities with Biogen Idec, BioMS, Genzyme Corporation, Novartis, Synthon, and Teva Neuroscience. Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience. Dr. Cohen has received personal compensation for activities with Biogen Idec, Eli Lilly & Company, Novartis, and Vaccinex. Dr. Cohen has received research support for activities with Biogen Idec, BioMS, Genzyme Corporation, Novartis, Synthon, and Teva Neuroscience. Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience.