Testing the safety of alternative wheat species and cultivars for consumption by celiac patients

See corresponding article on page 1339. Celiac disease is currently treated with a strict gluten-free diet, which can be both costly and difficult to maintain (1). Interestingly, only one species of wheat, Triticum aestivum, is predominantly used in the modern industrialized world, due to its increased protein production as well as its hardiness in colder climates. It has also been determined that the proteins that are the most immunogenic for celiac disease reside in the gliadin fraction of T. aestivum (2). However, there are almost 20 other species of wheat that are either not being cultivated by modern societies or are cultivated in select regions of the world (3). With such a large number of wheat species available, a significant amount of research has been done in the past 20 y that explores the use of different species and cultivars of wheat as an alternative to a strict gluten-free diet for celiac patients. The first study that proposed using wheat species and cultivars that lacked the immunogenic proteins found in T. aestivum for treating celiac patients was conducted by Auricchio et al (4) in 1982. In that report, it was shown that peptic-tryptic-cotazym digests of Triticum monococcum did not cause villous atrophy in jejunal biopsies of rats nor in the jejunal biopsies of children with celiac, whereas treatment with peptic-tryptic-cotazym digests of T. aestivum (Mentana and San Pastore) resulted in complete villous atrophy of the jejunal biopsies. A later report by van Herpen et al (5) showed that the genomes of T. monococcum (a diploid species) contained a different repertoire of immunogenic epitopes as compared with that of T. aestivum (hexaploid), and the authors suggested that genomic analysis may be an approach to identifying nontoxic cultivars of wheat. The authors did caution, however, that the effect of innate immune responses to gliadin may play a significant role in the generation of adaptive T cell responses by celiac patients to wheat-derived proteins. Indeed, in an article in this issue of the Journal, Gianfrani et al (6) clearly show that despite the genetic differences to the epitopes found to be immunogenic in T. aestivum, the peptic tryptic digests of the T. monoccum cultivars (Monlis and ID331) did cause an expansion of CD3+ cells in in vitro cultures of biopsies taken from the small intestines of celiac patients. The Monlis digests also induced a significant production of IFN-γ and IL-15; therefore, the article by Gianfrani et al shows that innate immunity probably is playing a crucial role in the development of inflammatory T cells specific for gliadin. As the authors point out, use of these cultivars of T. monoccum would not be safe for celiac patients. However, this does not diminish the value for the pursuit of alternative lines of wheat for use with celiac patients or the pursuit of wheat with less immunogenicity given the increasing prevalence of celiac disease and gluten sensitivity (7). Another publication in 2005 by Molberg et al (8) showed that there are many different species of wheat that have the potential to be nontoxic for celiac patients. In that article, Triticum urartu, Triticum tauschii, Ae speltoides, and Triticum dicoccoides were analyzed in addition to T. monococcum and Triticum durum. Interestingly, the results with T. monococcum were different between the Molberg and Gianfrani groups, but this may be due to either of 2 reasons. The first potential reason would be the experimental design. In the Molberg et al article, T cell lines were used together with an antigen presenting cell line generated from DQ2+ B cells, whereas in the Gianfrani et al article, whole intestinal biopsies were used. The second reason may be that, as Gianfrani et al’s article suggests, even among the different cultivars of T. monococcum, there are differences in the ability of the gliadin digests to stimulate the innate immune system and propagate the activated T cells. As such, it is still entirely possible that cultivars exist in species of wheat that lack both the immunogenic epitopes required for the activation of T cells specific for gliadin as well as the epitopes that are stimulatory of the innate immune response that skew the gliadin-responsive T cells toward an inflammatory phenotype. Thus, the Gianfrani et al article provides us with the important result that the identification of nonimmunogenic cultivars of wheat requires rigorous testing of both the adaptive T cell response as well as the innate immune response to all the peptides that are generated in the digestion of gliadin. Most important, the 2 articles provide a good algorithm for identifying nontoxic cultivars of wheat. The Molberg et al article can be used as a guide for identifying the best choices for a nontoxic wheat species on the basis of the presence or absence of T cell–activating epitopes. The Gianfrani et al article could then be used as a model for testing the innate immune response against the peptides generated by intestinal digestion of the gliadin fraction of the proposed nontoxic wheat species, and more specifically for testing each cultivar. With this algorithm, we can still be hopeful of finding cultivars of wheat species that are nontoxic for celiac patients, especially because there are so many more species of wheat and cultivars that can still be tested (3). Whether these novel culivars could ever compete with regular wheat for yield or disease resistance is doubtful, but they may find a role given the increased interest in a gluten-free diet.