Recent discoveries in dendritic cell tolerance-inducing pharmacological molecules.

Dendritic cells (DCs) represent one of the most important biological tools for cellular immunotherapy purposes. There are an increasing number of phase I and II studies, where regulatory or tolerogenic DCs (TolDCs) are utilized as negative vaccines, with the aim of inducing tolerogenic outcomes in patients with various autoimmune or chronic-inflammatory diseases, as well as in transplant settings. The induction of tolerogenic properties in DCs can be achieved by altering their activation state toward expression of immunosuppressive elements and/or by achieving resistance to maturation, which leads to insufficient co-stimulatory signal delivery and inability to efficiently present antigens. In the past, one of the most efficient ways to induce DC tolerance has been the application of selected pharmacological agents which actively induce a tolerogenic transcription program or inhibit major pro-inflammatory transcription factors such as Nf-κB. Important examples include immunosuppressants such as different corticosteroids, vitamin D, rapamycin and others. The quality of TolDCs induced by different approaches is becoming a vital issue and recent evidence suggests substantial heterogeneity between variously-generated TolDCs as evidenced by their transcriptomic profile and function. The possibility of various "flavors" of TolDCs encourages future research in discovery of Tol-DC inducing agents to enrich various ways of DC manipulation. This would enable a broader range of tools to manipulate DC toward specific characteristics desirable in different disease settings. In recent years, several novel small molecules have been identified with the capacity to promote DC tolerogenic characteristics. In this review, we will present and discuss these novel findings and also highlight novel understandings of tolerogenic mechanisms by which DC tolerogenicity is induced by already established agents.