Oral tolerance: can we make it work?

Mucosal tolerance remains an attractive approach for the treatment of autoimmune and inflammatory diseases. The agents used in these treatments lack toxicity, can be easily administered, and enable the promotion of antigen-specific immune responses. The limited success of clinical trials over the past 2 decades has led to the fear that the beneficial effect observed in animal models cannot be repeated in humans. Successful application of mucosal tolerance for the treatment of human diseases will depend on strategies that target the correct cells in the gut-liver axis, improve antigen presentation, alter the administered dose and formulations, utilize potent mucosal adjuvants, develop immune biomarkers enabling follow-up of the effect, utilize combination therapies with other immune modulatory agents, and target the right patient populations. Here, we discuss 12 of the major questions related to oral tolerance and its clinical application to humans with immune-mediated disorders.