3. Discussion
gluten-induced mucosal damage, ZED1227-TG2, CeD, celiac disease
CELIAC DISEASE, REMISSION, PATHOGENESIS
The efficacy of TG2 inhibitor ZED1227 to attenuate gluten-induced mucosal damage was previously reported in a proof-of-concept, randomized, double-blind, placebo-controlled, 6-week phase 2 trial in 160 patients with celiac disease in remission who were challenged with 3 g of gluten per day [At the subcellular level, the orally administered TG2 inhibitor ZED1227 was trapped in the luminal brush border compartment, along with the partly digested immunogenic gliadin peptides detected by immunofluorescence staining. Despite the lack of direct evidence, most review articles suggest that gliadin peptide deamidation by TG2 occurs in the lamina propria since the lamina propria harbors the T cells that drive CeD pathogenesis [The disproportional distribution of TG2 protein and ZED1227-TG2 may have several underlying explanations. First, the half-life of TG2 in the extracellular space of the lamina propria is probably short due to high calcium concentrations compared to the usually low calcium in the intestinal lumen [Our results showed that ZED1227, due to covalent binding to TG2, is still detectable 24 h after the last drug dose in the villus epithelium. It is possible that we have missed a time point of maximal drug concentration in the lamina propria if TG2 turnover there is more rapid. Nonetheless, persistent TG2 activity and ZED1227 binding occur on the luminal side of the intestinal epithelium, indicating a relevant contribution of epithelial TG2 to CeD pathogenesis. This may have important implications for the treatment of CeD with oral TG2 inhibitors.