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.