1011 - Analysis of the Bioactive Molecules That Promote the Induction of Human Tolerogenic Dendritic Cells

Monday, November 7, 2011: 9:00 AM-6:00 PM
Hall F2 - Poster Hall (McCormick Place West)
Takuya Matsumoto, Hitoshi Hasegawa, Jin Lei, Koichiro Suemori, Sachiko Onishi and Masaki Yasukawa, Ehime University Graduate School of Medicine, Toon, Japan
Presentation Number: 1011

Background/Purpose: Tolerogenic dendritic cells (DCs) and regulatory T cells (Treg) play a critical role in immune tolerance and are involved in the pathogenesis of autoimmune diseases such as rheumatoid arthritis. Suppression by tolerogenic DCs is primarily mediated via the induction of Treg cells. Tolerogenic DCs and Treg cells are induced or differentiated in the presence of specific biological agents, but little is known about harmless, potent inducers, especially in humans. Previously we isolated some agents that induced human Treg cells and reported that peroxisome proliferator-activated receptor (PPAR) agonist together with TGF-beta induced functional human Treg cells. Therefore, in this study, we screened the molecules that enhanced induction of tolerogenic DCs and analyzed the mechanism of these molecules in induction of tolerogenic DCs.

Method: DCs were prepared from human monocytes by treatment of GM-CSF and IL-4 for 5 days, and then cultured with TNF-alpha for 48h, in the presence of the molecule. From the libraries of lipids, nuclear receptor ligands, and kinase inhibitors, we screened the molecules that suppressed the expression of CD80, CD83, and CD86 for immature DCs and that induced the production of IL-10 for IL-10-producing DCs. Furthermore, we examined the effects of these molecules on stability and plasticity of DCs, antigen presenting, allogenic T cell response, and induction of cytokines and Treg cells.

Result: We screened 24 kinds of lipids, nuclear receptor ligands, and kinase inhibitors that  suppressed the expression of CD80, CD83, and CD86 similar to the phenotype of immature DCs. DCs treated with PPAR-gamma, dexamethazone, and indirubin remained phagocytosis, suppressed allogenic T cell responses and production of IL-12, and enhanced induction of Treg cells. On the other hand, we screened 10 kinds of the molecules that produced IL-10 from DCs. DCs treated with prostaglandin and GSk 3-beta inhibitor such as kenpaullone decreased allogenic T cell responses and enhanced induction of Tregs through IL-10 production. Moreover, induction of tolerogenic DCs was enhanced by combination with two molecules. We show the details of mechanism and other molecules in congress.

Conclusion: We identified some bioactive molecules that promoted the induction of tolerogenic DCs. We aim at the development of efficient induction of both human tolerogenic DCs and Treg cells using these molecules.

Keywords: T cells, autoimmune diseases, dendritic cells and regulatory cells

Disclosure: T. Matsumoto, None; H. Hasegawa, None; J. Lei, None; K. Suemori, None; S. Onishi, None; M. Yasukawa, None.