Indoleamine 2,3-dioxygenase-dependent expansion of T-regulatory cells maintains mucosal healing in ulcerative colitis

Abstract

Background:Dendritic cell (DC)-derived indolamine 2,3-dioxygenase (IDO) degrades tryptophan to kynurenine, which promotes conversion of inflammatory T cells in immunosuppressive regulatory T cells (Tregs). We analyzed the significance of the IDO:Treg axis for inducing and maintaining mucosal healing in ulcerative colitis (UC).Methods:Dextran sodium sulphate (DSS)-induced colitis in BALB/c mice (model for mucosal healing) and C57BL/6 mice (model for persistent disease) was used. Serum, fecal samples and colon-infiltrating immune cells of 65 patients with UC with mucosal healing or persistent colitis were analyzed.Results:Significantly higher serum levels of kynurenine and downregulated inflammatory cytokines were noticed in DSS-treated BALB/c mice compared with C57BL/6 mice. Increased IDO activity and attenuated capacity for antigen presentation and production of inflammatory cytokines, observed in BALB/c DCs, was followed by a significantly lower number of inflammatory T helper 1 (Th1) and Th17 cells and a notably increased number of Tregs in the colons of DSS-treated BALB/c mice. DCs and Tregs were crucially important for the maintenance of mucosal healing since their depletion aggravated colitis. Mucosal healing, followed by an increase in kynurenine and intestinal Tregs, was re-established when BALB/c DCs were transferred into DC-depleted or Treg-depleted DSS-treated BALB/c mice. This phenomenon was completely abrogated by the IDO inhibitor. Significantly higher serum and fecal levels of kynurenine, accompanied by an increased presence of intestinal Tregs, were noticed in patients with UC with mucosal healing and negatively correlated with disease severity, fecal calprotectin, colon-infiltrating interferon γ and interleukin-17-producing cells, serum and fecal levels of inflammatory cytokines.Conclusion:IDO-dependent expansion of endogenous Tregs should be further explored as a new approach for the induction and maintenance of mucosal healing in patients with UC.

Role of indoleamine 2,3-dioxygenase in pathology of the gastrointestinal tract

“…In inflamed mucosa of IBD patients, increased IDO1 activity was observed in colon epithelial cells, particularly at borders of crypt abscesses or at sites where epithelial cells flanked ulcers, suggesting involvement of the IDO1/KYN pathway in the repair process of mucosal healing. 59 In line with these observations are our recently published results 50 that indicate the importance of IDO1-dependent expansion of endogenous Tregs as a possible new therapeutic approach for the induction of mucosal healing. We demonstrated that colon-infiltrating DCs, through the production of KYN, induced expansion of Tregs that promote mucosal healing in the injured colons.…”

“…25,56 Tregs, in a CTLA-4 and IL-10-dependent manner, suppress activation of gut-infiltrated Th1 and Th17 cells, contributing to the attenuation of colitis. 57 We 50 and others 49,58 noticed significantly higher serum and fecal levels of KYN and higher presence of IDO-producing DCs and Tregs in the lamina propria of IBD patients compared with healthy subjects that might represent a compensatory mechanism for functional induction of tolerance in active IBD, due to the increase in absolute number of colon-infiltrating, IFN-γ-producing Th1 and IL-17-producing Th17 inflammatory cells.…”

“…25,47,48 Conversely, increased IDO1 activity and elevated serum levels of KYN were accompanied with increased presence of immunosuppressive Tregs in the injured gut, resulting in the attenuation of colon inflammation. 50 Enhanced IDO1 activity was noticed in colon-infiltrating immune cells and in colon epithelial cells of IBD patients and significantly decreased after treatment with steroids and salicylates. 51 Wolf and colleagues were first to show increased production of IDO1 in CD123(+) mononuclear cells infiltrating the submucosal areas of the inflamed lesions.…”

“…We demonstrated that colon-infiltrating DCs, through the production of KYN, induced expansion of Tregs that promote mucosal healing in the injured colons. 50 Both IDO1-producing DCs and immunosuppressive Tregs were crucially important for the maintenance of mucosal healing and recovery from DSS-induced colitis, since depletion of each cell population led to the significant aggravation of disease. 50 Keeping in mind that clinical application of Tregs in IBD patients is not easy to perform given their rarity in peripheral blood, 60 we propose that IDO1-dependent expansion of endogenous Tregs should be further explored as a potentially new approach for the induction and maintenance of mucosal healing in IBD patients.…”

IDO Targeting in Sarcoma: Biological and Clinical Implications

“…IDO1 is a major regulator of the Tryptophan (Trp) catabolism pathway that has been linked to impairment of anti-tumor immunity and tumor growth in several models (13,14). Kynurenine, which is notably produced by IDO1, is a key metabolite of this pathway that can promote selective expansion of regulatory T cells (Tregs) (15). Strikingly, we found a statistically significant increase in the kynurenine/tryptophan ratio, a robust pharmacodynamic marker of the IDO1/Kynurenine pathway (KP), between pretreatment and on-treatment plasma samples of sarcoma patients treated with Pembrolizumab.…”