Tr1 cell clone administration was tolerated and showed dose-dependent efficacy in patients
suffering from severe disease.62 These data represent the first bench-to-bedside test of Tregs as a therapy for IBD and set the stage for more comprehensive trials. Recent work in the field of transplantation and autoimmunity has shown that antigen-specific Tregs are much more effective at preventing graft rejection or diabetes than are polyclonal populations;16 significantly fewer antigen-specific Tregs are required to mediate potent suppression, and the delivery of antigen-specific PF-02341066 clinical trial cells decreases the risk of global immunosuppression and the possibility of increased risk of infection and cancer. Notably, antigen-specific Tregs can prevent colitis, as demonstrated by the adoptive transfer of OVA-specific Tregs64 or Tr1 cells,65 but because OVA is unlikely to be Napabucasin concentration a disease-driving antigen in IBD, the question of whether OVA-specific Tregs would be effective at suppressing established effector responses directed at pathogenic antigens remains outstanding. To develop antigen-specific Treg therapy at least some of the dominant antigens that perpetuate effector T-cell responses in the intestine need to be identified. Using T-cell clones isolated from IBD patients, Duchmann et al.66 found that many of the clones were specific for commensal gut flora, including species of Enterobacteriaceae, Bacteroides
and Bifidobacterium. Corroborating these data, Cong et al.67 found that T cells specific for enteric bacterial flora drive disease in spontaneously colitic C3H/HeJBir mice. It was subsequently demonstrated that
bacterial flagellin, a protein present on all flagellated bacteria including commensal species found in the gut, is a dominant antigen in these mice. In addition, flagellin expressed by a Clostridium species, known as CBir, is targeted by antibodies in colitic mice and humans,68 and transfer of CBir-specific CD4+ T-cell lines into immunodeficient mice causes severe colitis.68 Further evidence that T cells that recognize flagellin are relevant in colitis comes from studies with Escherichia coli-derived flagellin, the delivery of Endonuclease which exacerbates dextran sodium sulphate-induced colitis in a TLR5-independent manner.69,70 Although this is a new and rapidly evolving field, these data collectively suggest bacterial flagellin as a candidate antigen to target for Treg cellular therapy of IBD. Although dominant antigens that drive IBD are still being discovered, and there are likely to be many different disease-relevant antigens, antigen-directed Treg therapy could currently be tested in a chronic inflammatory gastrointestinal disease that shares similar defects in immune regulation to IBD. Coeliac disease is a chronic immune-mediated inflammatory disorder initiated by wheat gliadin and related proteins in barley and rye.
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