Arrest of the diabetogenic T-cell response using IL-27-treated tolerogenic dendritic cells loaded with β-cell antigens

IL-27 controls pathogenic Th1 and Th17 responses in vivo, supporting its therapeutic use for the treatment of autoimmunity. IL-27, however, has also been reported to act directly on T cells to boost CD8+ T-cell responses, suggesting that IL-27 administration has the potential to worsen autoimmune disorders. We found that IL-27 induces tolerogenic dendritic cells (DCs) that arrest the development of autoimmune inflammation. DC vaccination has been successfully used to induce immunity against tumors and pathogens, indeed, the US Food and Drug Administration has recently approved the use of a DC vaccine for the treatment of advanced prostate cancer. Conversely, vaccination with tolerogenic DCs has been shown to induce antigen specific tolerance in humans and experimental models of autoimmunity. Based on our preliminary data we hypothesize that vaccination with tolerogenic IL-27 conditioned DCs loaded with β-cell antigens will have an ameliorating effect in NOD diabetes. Thus, in this project we propose to study the therapeutic potential of vaccination with tolerogenic DCs induced with IL-27, to exploit the anti-inflammatory activities of IL-27 while avoiding its potential pathogenic effects. Specifically, we propose to study the use of DCs pretreated with IL-27 and loaded with β-cell specific antigens (insulin or a mimotope) to control the diabetogenic T cell response.