SELECTIVE INHIBITION OF GLIADIN IMMUNE REACTIVITY BY TRANSAMIDATION OF WHEAT FLOUR WITH MICROBIAL TRANSGLUTAMINASE

Celiac disease (CD) is an immune-mediated enteropathy caused by the ingestion of wheat gluten. The modification of gluten by intestinal tissue transglutaminase (tTGase) plays a crucial role in CD pathogenesis. In this study, we observed that extensive transamidation of wheat flour with lysine ethyl ester (K-C2H5) by microbial TGase (mTGase) yielded water-soluble (spf) and insoluble transamidated gliadin (K-gliadins) fractions. Using DQ8 transgenic (tg) mice as a model of gluten sensitivity, we observed a dramatic reduction in IFN? production in gliadin-specific spleen cells challenged with spf and K-gliadins in vitro (N=12; median values: 813 vs. 29 and 99; control vs. spf and K-gliadins, P=0.012 for spf, P=0.003 for K-gliadins). We also observed an increase in the IL-10/IFN? protein ratio (N=12; median values: 0.3 vs. 4.7, control vs. spf, P=0.005). In intestinal biopsies from untreated CD patients challenged in vitro with gliadins (N=10), K-gliadins dramatically reduced the levels of antigen-specific IFN? mRNA in all specimens responsive to native gliadins (4/10; P <0.05). In addition, the analysis of glutathione-S transferase (GST) and caspase-3 activities in the enterocytic Caco-2 cells showed that neither activities were modified by flour transamidation. In conclusion, we found that K-C2H5 cross-linking via mTGase specifically affected gliadin immunogenicity, reversing the inducible inflammatory response in models of gluten sensitivity without influencing the cytotoxic properties of gliadins.