Gluten-containing cereals have by far the highest concentrations of ATIs that activate TLR4. Orally ingested ATIs are largely resistant to proteases and heat, and increase intestinal inflammation by activating gut and mesenteric lymph node myeloid cells.

Nucleotide signaling molecules contribute to the regulation of cellular pathways. In the immune system, cyclic adenosine monophosphate (cAMP) is well established as a potent regulator of innate and adaptive immune cell functions. Therapeutic strategies to interrupt or enhance cAMP generation or effects have immunoregulatory potential in autoimmune and inflammatory disorders. Here, we provide an overview of the cyclic AMP axis and its role as a regulator of immune functions and discuss the clinical and translational relevance of interventions with these processes.

Dendritic cells (DCs) are highly specialized professional antigen-presenting cells that regulate immune responses, maintaining the balance between tolerance and immunity. Mechanisms via which they can promote central and peripheral tolerance include clonal deletion, the inhibition of memory T cell responses, T cell anergy, and induction of regulatory T cells (Tregs). These properties have led to the analysis of human tolerogenic DCs as a therapeutic strategy for the induction or re-establishment of tolerance. In recent years, numerous protocols for the generation of human tolerogenic DCs have been developed and their tolerogenic mechanisms, including induction of Tregs, are relatively well understood. Phase I trials have been conducted in autoimmune disease, with results that emphasize the feasibility and safety of treatments with tolerogenic DCs. Therefore, the scientific rationale for the use of tolerogenic DCs therapy in the fields of transplantation medicine and allergic and autoimmune diseases is strong. This review will give an overview on efforts and protocols to generate human tolerogenic DCs with focus on IL-10-modulated DCs as inducers of Tregs and discuss their clinical applications and challenges faced in further developing this form of immunotherapy.

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.

IFN-a is an antineoplastic agent in the treatment of several solid and hematologic malignancies that exerts strong immune-and autoimmune-stimulating activity. However, the mechanisms of immune activation by IFN-a remain incompletely understood, particularly with regard to CD4