Mucosal tolerance therapy in humans: Past and future

Abstract

AbstractMucosal tolerance refers to the physiological process by which exposure of proteins to the mucosal surface preferentially induces tolerance. The route of mucosal administration can determine the type of regulatory T (Treg) cells induced, with the oral route inducing transforming growth factor‐β‐producing Treg cells and the nasal route inducing interleukin‐10‐secreting Treg cells. Previous studies of oral tolerance to autoantigens in humans, including patients with multiple sclerosis, rheumatoid arthritis and diabetes, led to mixed results and negative phase III trials, although oral immunotherapy for food allergy has met with success. A great deal has been learned since initial trials were carried out, and new approaches to mucosal tolerance are now being planned. For example: (i) successful oral tolerance might involve an understanding of the microbiome, and it appears that abnormalities in the microbiome that occur in autoimmune disease might have a negative impact on oral tolerance; (ii) individuals with autoimmune illnesses might have ongoing inflammation and therapy to downregulate the inflammatory milieu before inducing tolerance might be required. We have recently discovered that oral or nasal anti‐CD3 monoclonal antibody (mAb) induces Treg cells at the mucosal system, and these cells travel systemically to suppress inflammatory diseases, including models of multiple sclerosis, diabetes, lupus, arthritis and colitis. Trials of nasal anti‐CD3 are planned for patients with progressive multiple sclerosis, and oral anti‐CD3 is planned for patients with inflammatory bowel disease and non‐alcoholic steatohepatitis. With our new understanding of the mucosal immune system and new approaches, mucosal tolerance has the potential to be successfully applied to patients with a wide variety of diseases.