Furthermore, Tregs can not only prevent but also cure IBD10 in mouse models. Because Protease Inhibitor Library IBD varies greatly between mice and humans,11 however, there are many outstanding questions that need to be addressed as this therapy is translated to the clinical setting. Because of the risks associated with using cells as a therapy to control immune responses,
the first clinical trials with Tregs are taking place in the context of allogeneic haematopoietic stem cell transplantation for haematological malignancies. These patients are at high risk for life-threatening graft-versus-host disease so there is a better risk–benefit ratio for experimental therapies than in IBD. Phase I/II clinical trials have already begun to evaluate whether infusion of Tregs might ameliorate graft-versus-host
disease following haematopoietic stem cell transplantation,12–15 and these trials have so far shown that infusion of Tregs is safe and possibly efficacious. These results set the stage for future randomized clinical trials to determine whether Treg therapy is an effective front-line means of establishing immune tolerance upon transplantation of allogeneic cells or tissues.16 This review will examine evidence that Treg dysfunction contributes to the perpetuation of IBD, and discuss the strengths and limitations of Treg therapy in this setting. Because Treg therapy NVP-BGJ398 datasheet offers the advantage of antigen specificity and could circumvent the need for global, long-term immunosuppression, Vildagliptin the possible antigens that drive mucosal disease will also be examined as putative targets in this strategy. The intestinal mucosal tissues pose a unique challenge for the maintenance of immune homeostasis. Representing the largest mucosal surface area in the body, these tissues are in direct contact with the external environment and
must simultaneously maintain tolerance to commensal bacteria and food, and the ability to eliminate pathogens.17 Furthermore, the gut must be permeable, to allow for nutrient absorption, while maintaining a tight barrier against pathogens. The gut has therefore developed a complex immune network that can process and respond to an enormous number of stimuli at one time. This network includes intestinal epithelial cells, macrophages, dendritic cells, conventional T cells, and Tregs, with the latter believed to be critical for the maintenance of intestinal immune homeostasis.18 Inflammatory bowel disease, an umbrella term for both Crohn’s disease and ulcerative colitis, is thought to be caused by barrier disruption leading to a change in the intestinal flora and a consequent aberrant activation of the mucosal immune system.19–21 In both diseases, intestinal epithelial cells isolated from patients directly activate CD4+ T cells,22 suggesting that non-immune cells directly contribute to the inappropriate immune activation.