8,9 Similarly, in humans, correlative data suggest that Crohn’s disease is driven by exaggerated Th1

and Th17 responses, because inflamed lesions contain increased levels of Th1-associated and Th17-associated DAPT cytokines including interferon-γ, IL-12, IL-17 and IL-18.23–27 In contrast, although ulcerative colitis is in the same family of diseases, it is associated with a Th2 cell profile, and patients have high levels of IL-13 in the mucosa compared with Crohn’s disease patients or healthy controls.19,23,28 Hence, although in most cases T-cell dysfunction is unlikely to be the initiating cause of IBD,29 there is substantial evidence that dysregulated Th cell responses perpetuate the disease and the vicious cycle of chronic inflammation. Under normal conditions, compared phosphatase inhibitor library with all other tissues, the intestinal lamina propria has the greatest proportion of CD4+ Tregs,30 which are thought to be primarily specific for antigens in food and commensal flora.29 As Crohn’s disease and ulcerative colitis are both T-cell-driven diseases, it logically follows that increasing appropriate Treg activity in the gut should help to restore the balance of suppression

in inflamed tissues. However, it is unknown whether the over-abundance of activated T cells in IBD is the result of a numerical lack of Tregs, a defect in their function, resistance of T effector cells to suppression, or a combination of these possibilities. These questions have not been widely studied in animal models, yet they

are key to understanding whether restoring/boosting Tregs is likely to have any effect in treating IBD in humans. There is evidence that simply lacking Tregs leads to IBD. Patients with genetic mutations in FoxP3 who have non-functional or absent Tregs always have severe intestinal inflammation associated with lymphocytic infiltration of the intestinal mucosa.31,32 Similarly, mice lacking Mannose-binding protein-associated serine protease FoxP3+ Tregs,33 or the ability to suppress via Treg-derived cytokines such as IL-10,34,35 IL-35,36 and in some cases TGF-β,37 develop severe colitis. In the more common forms of IBD, however, there is little evidence to suggest that patients simply lack Tregs in the circulation and/or the affected tissues. Maul et al.38 found that although both Crohn’s disease and ulcerative colitis patients had decreased Treg populations in the peripheral blood during active disease, Treg numbers in intestinal tissue biopsies were not substantially different from those in patients with other inflammatory diseases. Other studies corroborate these results, and in most cases show a consistent expansion of Tregs in both inflamed and non-inflamed sections of the gut in adult and paediatric patients with IBD.