Regulatory T‐cell therapy for inflammatory bowel disease: more questions than answers

Abstract

Summary T regulatory (Treg) cells are critical for maintaining immune homeostasis and establishing tolerance to foreign, non‐pathogenic antigens including those found in commensal bacteria and food. Because of their multiple suppressive mechanisms, Tregs represent a promising strategy for engineering tolerance to self and non‐self antigens in chronic inflammatory diseases. Already in clinical trials in the transplantation setting, the question remains whether this therapy would be effective for the treatment of mucosal inflammatory diseases that do not pose an immediate threat to life. In this review we will discuss evidence from both animal models and patients suggesting that Treg therapy would be beneficial in the context of inflammatory bowel disease (IBD). We will examine the role of T‐cell versus Treg dysfunction in IBD and discuss the putative antigens that could be potential targets of antigen‐directed Treg therapy. Finally, the challenges of using Treg therapy in IBD will be discussed, with a specific emphasis on the role that the microbiota may play in the outcome of this treatment. As Treg therapy becomes a bedside reality in the field of transplantation, there is great hope that it will soon also be deployed in the setting of IBD and ultimately prove more effective than the current non‐specific immunosuppressive therapies.

Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance

“…[41][42][43] Third, depending on the individual potentials, Tr1 or pT reg cells may inhibit autoimmune diseases within a limited range, so it is beneficial to study the mechanisms of associated diseases to facilitate the development of clinical therapy. 44 Moreover, studies of the epigenetic status of DNA, most tT reg and pT reg cells contain T reg -specific de-methylated regions (TSDR), which are critical to stable expression of Foxp3 and the development and functions of most tT reg / pT reg cells. 45,[46][47][48] However, the transcription factor of Tr1 cell has not been determined.…”

The Intersection of TNF, IBD and the Microbiome

“…Evidence (in mice and humans) suggests that lacking Tregs can lead to IBD; however a clear association between a local deficit of Tregs or the presence of defective Tregs and IBD development has not been established. 10 TNF is chronically elevated, locally and systemically, in patients with IBD. [11][12][13] Currently, one of the most effective therapies for treating refractory IBD is suppression of TNF function, but adverse side effects do occur and some patients do not respond to this therapy (reviewed: 14 ).…”

Combination peptide immunotherapy suppresses antibody and helper T-cell responses to the RhD protein in HLA-transgenic mice

“…We cannot exclude the possibility that effector T cells were to some degree depleted after peptide administration in vivo, but this would not necessarily be inimical to regulation, since transient proliferation and activation-induced cell death can presage Treg development. 52 Reports of cellular immunotherapy for autoimmune disease and transplant rejection [53][54][55][56] confirm that tolerance transferred by Treg populations is optimal if specific cells are activated by cognate antigen in association with MHC class II, 53 and our data illustrate that this effect can be achieved by the simple delivery of relevant peptides in vivo.…”

“…Reports of cellular immunotherapy for autoimmune disease and transplant rejection [53][54][55][56] confirm that tolerance transferred by Treg populations is optimal if specific cells are activated by cognate antigen in association with MHC class II, 53 and our data illustrate that this effect can be achieved by the simple delivery of relevant peptides in vivo.…”