Tolerance-inducing therapies in coeliac disease - mechanisms, progress and future directions

Coeliac disease is an autoinflammatory condition caused by immune reactions to cereal gluten proteins. Currently, the only available treatment for the condition is a lifelong avoidance of gluten proteins in the diet. There is an unmet need for alternative therapies. Coeliac disease has a strong association with certain HLA-DQ allotypes (DQ2.5, DQ2.2 and DQ8), and these disease-associated HLA-DQ molecules present deamidated gluten peptides to gluten-specific CD4+ T cells. The gluten-specific CD4+ T cells are the drivers of the immune reactions leading to coeliac disease. Once established, the clonotypes of gluten-specific CD4+ T cells persist for decades, explaining why patients must adhere to a gluten-free diet for life. Given the key pathogenic role of gluten-specific CD4+ T cells, tolerance-inducing therapies that target these T cells are attractive for treatment of the disorder. Lessons learned from coeliac disease might provide clues for treatment of other HLA-associated diseases for which the disease-driving antigens are unknown. Thus, intensive efforts have been and are currently implemented to bring an effective tolerance-inducing therapy for coeliac disease. This Review discusses mechanisms of the various approaches taken, summarizing the progress made, and highlights future directions in this field. Coeliac disease is an autoinflammatory disease, with the only available treatment being a lifelong gluten-free diet. Alternative therapeutic approaches are needed. This Review explores the concept of tolerance-inducing therapies for coeliac disease, highlighting the underlying mechanisms, progress, challenges and future directions. Coeliac disease is an autoinflammatory condition caused by hypersensitivity to cereal gluten proteins; gluten-specific CD4+ T cells drive immune reactions leading to an enteropathy and formation of autoantibodies.Currently, the only available treatment is a lifelong gluten-free diet; there is an unmet need for treatment alternatives to this dietary intervention.An antigen-specific therapy aiming to anergize, suppress or delete gluten-specific CD4+ T cells could be a way to treat the disease, such a tolerance-inducing therapy has the potential to become standalone therapy.Various approaches for tolerance-inducing therapies have been designed and are pursued. These are currently in preclinical, phase I or phase II clinical development.The molecular mechanisms involved in the tolerance-inducing therapies are not fully worked out.How to best measure effectiveness of a coeliac disease therapy is debated; end points for phase III trials might not be the same as those used for phase II trials.