Abstract
Dendritic cells (DCs) are central players in the initiation and control of responses, regulating the balance between tolerance and immunity. Tolerogenic DCs are essential in the maintenance of central and peripheral tolerance by induction of clonal T cell deletion and T cell anergy, inhibition of memory and effector T cell responses, and generation and activation of regulatory T cells. Therefore, tolerogenic DCs are promising candidates for specific cellular therapy of allergic and autoimmune diseases and for treatment of transplant rejection. Studies performed in rodents have demonstrated the efficacy and feasibility of tolerogenic DCs for tolerance induction in various inflammatory diseases. In the last years, numerous protocols for the generation of human monocyte-derived tolerogenic DCs have been established and some first phase I trials have been conducted in patients suffering from autoimmune disorders, demonstrating the safety and efficiency of this cell-based immunotherapy. This review gives an overview about methods and protocols for the generation of human tolerogenic DCs and their mechanisms of tolerance induction with the focus on interleukin-10-modulated DCs. In addition, we will discuss the prerequisites for optimal clinical grade tolerogenic DC subsets and results of clinical trials with tolerogenic DCs in autoimmune diseases.
Highlights
The antigen-specific induction of immunological tolerance in the context of autoimmune and allergic diseases, which are driven by undesired immune responses against the body’s own or foreign antigens, has long been described as ultimate solution for the treatment of excessive immune activation
Decrease in Crohn’s Disease Activity Index (CDAI) (p = 0.3) and Crohn’s Disease Endoscopic Index of Severity (p = 0.4), lesions improved markedly in three patients (33%)
High-throughput approaches, e.g., in form of genomics and proteomics, will be of great help to analyze critical pathways contributing to programming and function of human tolerogenic Dendritic cells (DCs) [122]
Summary
The antigen-specific induction of immunological tolerance in the context of autoimmune and allergic diseases, which are driven by undesired immune responses against the body’s own or foreign antigens, has long been described as ultimate solution for the treatment of excessive immune activation. IL-10 DCs were identified as the most suitable candidate for DC-mediated tolerance-vaccination therapies as was shown by a comprehensive study by Boks et al They compared five protocols for ex vivo induction of human tolerogenic DCs (through VitD3, dexamethasone, TGF-β, rapamycin, and IL-10) with regard to prerequisites for clinical applications in humans such as potent migratory capacity, sufficient Treg induction, and the stability of the tolerogenic phenotype under inflammatory conditions to guarantee the safety of the therapy [13, 15]. With regard to allergic diseases, ex vivo models have shown that human tolerogenic IL-10 DCs from atopic donors suppressed TH2 immune responses by induction of FOXP3+ Tregs and dexamethasone-induced tolerogenic DCs activated IL-10 producing Tregs, specific for the latex Hev b 5 antigen, in rubber latex allergic patients [106, 107]. The DAS was decreased within 1 month in vaccinated patients with active rheumatoid arthritis, indicating the biological and clinical activity of this therapy
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