Exploring novel therapies for celiac disease centered around the autoantigen transglutaminase 2

Celiac disease is affecting 1-2% of the population. Today the only existing treatment for the widespread disorder is a lifelong gluten-free diet. There is a need to develop alternative treatments. Recent research has revealed that the enzyme transglutaminase 2 plays a central role in the development of the disease. This enzyme alters gluten so that the immune system of celiacs can react to it. This celiac specific immune response involves B cells. B cells produce antibodies, and celiacs have B cells and antibodies that are directed against transglutaminase 2. In the project, we want to take this knowledge in the direction of developing new treatment principles. Part of the project concerns inhibition of the enzyme activity of transglutaminase 2 and aims to uncover where in the body the transglutaminase activity should be inhibited. Another part of the project relates to finding a method that can eliminate the B cells that recognize transglutaminase 2. The project will study cells and tissues from celiacs as well as mice that have been genetically modified to express receptors used by celiacs to recognize gluten and transglutaminase 2.

Celiac disease is a prevalent autoinflammatory condition caused by immune reaction to dietary gluten proteins. The only available treatment is lifelong avoidance of dietary gluten. However, symptoms and enteropathy often persist in patients who attempt to adhere to a gluten-free diet. Thus, there is a need to develop non-dietary therapies for celiac disease. The enzyme transglutaminase 2 (TG2) has critical roles in celiac disease pathogenesis. The enzymatic activity of TG2 creates by deamidation gluten peptides that have high affinity for disease-predisposing HLA-molecules, and these deamidated peptides are recognized by the disease-driving CD4+ T cells. Moreover, TG2 is the target of a highly specific autoantibody response. In this project we will explore two novel treatment avenues focused on TG2. In the first approach, we seek to develop novel immunotherapeutic molecules, Bispecific AutoAntigen T-cell Engagers (BiAATEs), to specifically eliminate the subset of autoreactive TG2-specific B cells while avoiding general immunosuppression. The results will be important not only for celiac disease but also for other autoimmune diseases having cytosolic autoantigens. Second, we will explore therapeutic inhibition of TG2. ZED1227, an irreversible inhibitor of TG2, was recently shown in a phase 2 clinical trial to prevent gluten-induced intestinal damage in celiac disease patients. It is however unknown where in the body the drug is active. Our group has obtained evidence that the gut lumen likely is the relevant site where TG2 is active and encounters gluten peptides for deamidation. We will test the new hypothesis that TG2 in gut lumen is pathogenic in celiac disease and will explore inhibition of gut luminal TG2 as therapy. Both arms of the project will combine studies on patient samples with mechanistic experiments in state-of-the art humanized mouse models that we recently developed.