Tolerogenic Dendritic Cells for Therapy of Immune-Mediated Inflammatory Diseases

Abstract

Within the complex array of numerous immunological processes that protect the host from invading pathogens and at the same time avoid excessive immune reactions with induction and maintenance of tolerance to self, the dendritic cells (DCs) have been designated as central players. Discovered and morphologically described by Steinman and Cohn almost 30 years ago, DCs have gained an ever-increasing interest from the scientific community (Steinman, Topliss et al. 1973). This has been even more pronounced throughout the last decade with the discovery that DCs not only serve as primary initiators of antigen (Ag)specific immune responses, but can also induce immunological tolerance and contribute to immune homeostasis maintenance by various mechanisms, including induction of regulatory T cells (Treg) (Steinman, Hawiger et al. 2003). Indeed, the DCs possess a unique set of biological tools that allows them to present Ag information to effector cells of the immune system in a way to promote tolerance induction by functional mechanisms such as T-cell anergy, deletion, apoptosis and instruction of different Treg types. Direct delivery of tolerogenic signals by DCs, most commonly to respective Ag-specific T cells, is in a great way determined by the DCs preliminary activation state, which itself is orchestrated by various environments that DCs find themselves in under both physiological and pathophysiological conditions. Today it is well-documented, that a number of immunosuppressive factors, either related to specific tissue microenvironments, microbial components or pharmacological immunosuppressants, can act on DCs in a way to cause their alternative activation or tolerogenic state (Weiner 2001; Hackstein and Thomson 2004; Rutella, Danese et al. 2006). In addition to immature (iDCs) which are known to act in an immunosuppressive fashion, the tolerogenic DCs (TDCs) can be said to do the same but in an even more efficient manner. Whereas tolerance induction by iDCs seems to rely mostly on insufficient delivery of co-stimulatory signals, TDCs express more elements of active tolerance induction, including surface inhibitory molecules and production of antiinflammatory cytokines, that are expressed depending on the nature of DC activation and/or development. With DCs able to achieve greatly opposing states regarding their immunostimulatory status, together with the notion of manipulating DC function in the lab, scientists have put ongoing efforts into resolving the underlying mechanisms of DC-mediated tolerance induction. The