Unravelling the mechanisms underlying the induction and immunological function of tolerogenic dendritic cells by immunomodulators.

Abstract

Autoimmune diseases such as rheumatoid arthritis are severe and common diseases that together affect ~3-5% of the population, and for which a new treatment strategy is needed. Current treatments are associated with side effects caused by broad immunosuppression, and are ineffective for some patients. Tolerogenic dendritic cells have the potential to induce antigen-specific tolerance and thereby restore the immune balance without side effects caused by broad immunosuppression. Tolerogenic dendritic cell-therapy is currently investigated in early-phase clinical trials. Tolerogenic dendritic cells induced using immunosuppressants have shown promising results in these clinical trials and other experiments. These include, dexamethasone, Vitamin D3 (1,25(OH)2D3), and all-trans retinoic acid. However, the exact mechanisms through which these tolerogenic dendritic cells are induced, and through which they exert their immunologic functions are largely unknown. Therefore, with this proposal, we aim to study the molecular mechanisms underlying antigen-specific tolerogenic dendritic cell induction by dexamethasone, Vitamin D3, and all-trans retinoic acid. We will do this in both murine and human cells. In addition, we aim to study the effects of these induced antigen-specific tolerogenic dendritic cells on other immune cells and rheumatoid arthritis development in an in vivo model. The end goal of this research is to contribute to improving tolerogenic dendritic cell therapies and to contribute to finding the optimal tolerogenic dendritic cell strategy for specific autoimmune diseases, such as rheumatoid arthritis