72 Also similar to IBD, patients suffering from untreated coeliac disease have increased numbers of FoxP3+ Tregs and IL-10-producing Tr1 cells in the intestine,73–77 the latter known to be

gliadin specific.78 The failure Fulvestrant cost of Tregs to control inflammation in this disease may therefore be a consequence of their functional impairment or target resistance. Circulating FoxP3+ CD4+ T cells from patients with active coeliac disease do not efficiently inhibit autologous effector T cells, but they are functional when co-cultured with T cells from healthy donors.77 Moreover, Tregs from healthy adults fail to suppress effector T cells isolated from coeliac patients.77 Analogous to the data from IBD studies, these data suggest that in coeliac disease the immune defect is not intrinsic to the Tregs, but rather is related to the resistance of effector T cells to suppression. Coeliac disease therefore represents an ideal setting in which to test whether antigen-specific Treg cell therapy can reverse established mucosal disease. Not only is the antigen well-defined, but it could also be administered

and removed as necessary. The availability of tetramers to track gliadin-specific T-cell responses would also allow quantitative Selleckchem Compound Library monitoring of crucial components of the response to therapy in these patients.79 Inflammatory bowel disease is thought to be a multi-step process involving an initial barrier injury, leading to a shift in the normal intestinal microbiota,20,80 increasing numbers of Enterobacteriaceae and reducing the species thought to protect from IBD, such as Faecalibacterium and Roseburia.20 The microbiota facilitate post-thymic education of the immune system and are important for tolerance to microbial antigens,81 so changes in the

gut flora in IBD may be a driving force for effector T-cell responses through against commensal bacteria and must therefore be considered in the context of cellular therapy. Indeed, in mice, colitis does not occur unless microbial antigens are present to drive activation and differentiation of T cells.82 The intestinal microbiota also plays an important role in modulating Tregs. For example, certain species of commensal bacteria specifically promote FoxP3+ Tregs in the colon,83,84 and some species of bacteria induce tolerance by signalling through TLR2 on Tregs.85 Hence, depending on the balance of species, microbial communities may either drive pathogenic T-cell responses or induce Tregs in a normal homeostatic environment. It follows that for Treg cellular therapy to be effective in IBD, microbial communities may need to be shifted towards a balance of species that is more permissive of tolerance. One way that the microbiome could be manipulated is by administration of probiotics.