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Background and aims: Coeliac disease is a common small intestinal inflammatory disorder that results from a breach of intestinal tolerance to dietary gluten proteins, driven by gluten-reactive effector T cells. We aimed to assess the pathogenic role of gluten-reactive T cells and to generate a model of gluten-induced enteropathy. Methods: CD4+CD25− T cell fractions were adoptively transferred into lymphopenic mice, leading to “baseline” small intestinal inflammation. Results: Rag1−/− recipients of gliadin-presensitised CD4+CD45RBlowCD25− T cells, but not CD4+CD45RBhigh naive T cells, gained less weight and suffered from more severe duodenitis when challenged with oral gluten than recipients on gluten-free diet, or recipients of control (ovalbumin)-presensitised T cells. This was accompanied by deterioration of mucosal histological features characteristic of coeliac disease, and increased Th1/Th17 cell polarisation in the duodenum and the periphery. Interestingly, reintroduction of a gluten-free diet led to weight gain, improvement of histological duodenitis, and a decrease in duodenal interferon γ and interleukin 17 transcripts. Moreover, B cell-competent nude recipients of gliadin-presensitised CD4+CD45RBlowCD25− T cells produced high levels of serum anti-gliadin immunoglobulin A (IgA) and IgG1/IgG2c only when challenged with oral gluten. Conclusions: CD4+ T cell immunity to gluten leads to a breach of oral gluten tolerance and small intestinal pathology in lymphopenic mice, similar to human coeliac disease. This model will be useful for the study of coeliac disease pathogenesis, and also for testing novel non-dietary therapies for coeliac disease.

Celiac disease has become one of the best-understood HLA-linked disorders. Although it shares many immunologic features with inflammatory bowel disease, celiac disease is uniquely characterized by (1) a defined trigger (gluten proteins from wheat and related cereals), (2) the necessary presence of HLA-DQ2 or HLA-DQ8, and (3) the generation of circulating autoantibodies to the enzyme tissue transglutaminase (TG2). TG2 deamidates certain gluten peptides, increasing their affinity to HLA-DQ2 or HLA-DQ8. This generates a more vigorous CD4+ T-helper 1 T-cell activation, which can result in intestinal mucosal inflammation, malabsorption, and numerous secondary symptoms and autoimmune diseases. Moreover, gluten elicits innate immune responses that act in concert with the adaptive immunity. Exclusion of gluten from the diet reverses many disease manifestations but is usually not or less efficient in patients with refractory celiac disease or associated autoimmune diseases. Based on the advanced understanding of the pathogenesis of celiac disease, targeted nondietary therapies have been devised, and some of these are already in phase 1 or 2 clinical trials. Examples are modified flours that have been depleted of immunogenic gluten epitopes, degradation of immunodominant gliadin peptides that resist intestinal proteases by exogenous endopeptidases, decrease of intestinal permeability by blockage of the epithelial ZOT receptor, inhibition of intestinal TG2 activity by transglutaminase inhibitors, inhibition of gluten peptide presentation by HLA-DQ2 antagonists, modulation or inhibition of proinflammatory cytokines, and induction of oral tolerance to gluten. These and other experimental therapies will be discussed critically. © 2009 AGA Institute.