Induction of Tolerogenic Dendritic Cells by Vitamin D Receptor Agonists

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Abstract

Dendritic cells induce and regulate T cell responses, and tolerogenic dendritic cells (DCs) can promote the development of regulatory T cells with suppressive activity. Thus, the possibility to manipulate DCs using different pharmacological or biological agents enables them to exert tolerogenic activities, could be exploited to better control a variety of chronic inflammatory conditions, from autoimmune diseases to allograft rejection. A variety of both biological and pharmacological agents can induce tolerogenic DCs, and several in vitro studies have demonstrated that human regulatory T cells can be induced by DCs manipulated to acquire and/or enhance tolerogenic properties, with in vivo data also accumulating. Within this context, we have explored the immunoregulatory activities of vitamin D receptor (VDR) agonists, secosteroid hormones able to induce tolerogenic DCs and regulatory T cells. Tolerogenic DCs induced by a short treatment with VDR agonists promote CD4+ CD25+ Foxp3+ suppressor T cells that are able to mediate transplantation tolerance and to arrest the development of autoimmune diseases. VDR agonists not only favour the induction of CD4+ CD25+ regulatory T cells, but can also enhance their recruitment to inflammatory sites. VDR agonists have been proven effective and safe drugs in a variety of autoimmune disease and graft rejection models, highlighting their potential applicability to chronic inflammatory conditions sustained by autoreactive or alloreactive immune responses. In addition to the topical treatment of psoriasis, a Th1-mediated autoimmune disease of the skin where VDR agonists are the most used topical drugs; these agents might eventually find a broader application in the treatment of inflammatory conditions, where their modulatory effects on DCs enhancing T cells with regulatory functions could turn out to be quite beneficial.