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Indoleamine 2,3-dioxygenase-dependent expansion of T-regulatory cells maintains mucosal healing in ulcerative colitis.
Therap Adv Gastroenterol 2018; 11:1756284818793558TA

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.

Authors+Show Affiliations

Center for Molecular Medicine and Stem Cell Research, University of Kragujevac, Kragujevac, Serbia.Center for Molecular Medicine and Stem Cell Research, University of Kragujevac, Kragujevac, Serbia.Department of Genetics, University of Kragujevac, Kragujevac, Serbia.Center for Molecular Medicine and Stem Cell Research, University of Kragujevac, Kragujevac, Serbia.Department of Histology and Embryology, University of Kragujevac, Kragujevac, Serbia.Center for Molecular Medicine and Stem Cell Research, University of Kragujevac, Kragujevac, Serbia.Center for Gastroenterology, Clinical Center Kragujevac, Kragujevac, Serbia.Center for Gastroenterology, Clinical Center Kragujevac, Kragujevac, Serbia.Center for Molecular Medicine and Stem Cell Research, University of Kragujevac, Kragujevac, Serbia.Regenerative Processing Plant, LLC, Palm Harbor, FL, USA.Regenerative Processing Plant, LLC, Palm Harbor, FL, USA.State University of Novi Pazar, Department of Biomedical Sciences, Novi Pazar, Serbia.Institute of Anatomy, University of Bern, Baltzerstrasse, Switzerland.Center for Molecular Medicine and Stem Cell Research, University of Kragujevac, Kragujevac, Serbia.Center for Molecular Medicine and Stem Cell Research, University of Kragujevac, Kragujevac, Serbia.Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30159037

Citation

Acovic, Aleksandar, et al. "Indoleamine 2,3-dioxygenase-dependent Expansion of T-regulatory Cells Maintains Mucosal Healing in Ulcerative Colitis." Therapeutic Advances in Gastroenterology, vol. 11, 2018, p. 1756284818793558.
Acovic A, Simovic Markovic B, Gazdic M, et al. Indoleamine 2,3-dioxygenase-dependent expansion of T-regulatory cells maintains mucosal healing in ulcerative colitis. Therap Adv Gastroenterol. 2018;11:1756284818793558.
Acovic, A., Simovic Markovic, B., Gazdic, M., Arsenijevic, A., Jovicic, N., Gajovic, N., ... Volarevic, V. (2018). Indoleamine 2,3-dioxygenase-dependent expansion of T-regulatory cells maintains mucosal healing in ulcerative colitis. Therapeutic Advances in Gastroenterology, 11, p. 1756284818793558. doi:10.1177/1756284818793558.
Acovic A, et al. Indoleamine 2,3-dioxygenase-dependent Expansion of T-regulatory Cells Maintains Mucosal Healing in Ulcerative Colitis. Therap Adv Gastroenterol. 2018;11:1756284818793558. PubMed PMID: 30159037.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Indoleamine 2,3-dioxygenase-dependent expansion of T-regulatory cells maintains mucosal healing in ulcerative colitis. AU - Acovic,Aleksandar, AU - Simovic Markovic,Bojana, AU - Gazdic,Marina, AU - Arsenijevic,Aleksandar, AU - Jovicic,Nemanja, AU - Gajovic,Nevena, AU - Jovanovic,Marina, AU - Zdravkovic,Natasa, AU - Kanjevac,Tatjana, AU - Harrell,C Randall, AU - Fellabaum,Crissy, AU - Dolicanin,Zana, AU - Djonov,Valentin, AU - Arsenijevic,Nebojsa, AU - Lukic,Miodrag L, AU - Volarevic,Vladislav, Y1 - 2018/08/24/ PY - 2018/01/31/received PY - 2018/06/21/accepted PY - 2018/8/31/entrez PY - 2018/8/31/pubmed PY - 2018/8/31/medline KW - T-regulatory cells KW - indolamine 2,3-dioxygenase KW - kynurenine KW - mucosal healing KW - ulcerative colitis SP - 1756284818793558 EP - 1756284818793558 JF - Therapeutic advances in gastroenterology JO - Therap Adv Gastroenterol VL - 11 N2 - 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. SN - 1756-283X UR - https://www.unboundmedicine.com/medline/citation/30159037/Indoleamine_23_dioxygenase_dependent_expansion_of_T_regulatory_cells_maintains_mucosal_healing_in_ulcerative_colitis_ L2 - http://journals.sagepub.com/doi/full/10.1177/1756284818793558?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -