Indoleamine 2,3-dioxygenase-dependent expansion of T-regulatory cells maintains mucosal healing in ulcerative colitis.
Indoleamine 2,3-dioxygenase-dependent expansion of T-regulatory cells maintains mucosal healing in ulcerative colitis.
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DOI：
10.1177/1756284818793558
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发表时间：
2018
影响因子：
4.2
通讯作者：
Volarevic V
中科院分区：
文献类型：
--
作者：
Acovic A;Simovic Markovic B;Gazdic M;Arsenijevic A;Jovicic N;Gajovic N;Jovanovic M;Zdravkovic N;Kanjevac T;Harrell CR;Fellabaum C;Dolicanin Z;Djonov V;Arsenijevic N;Lukic ML;Volarevic V
树突状细胞（DC）衍生的吲哚胺2，3-双加氧酶（IDO）将色氨酸降解为犬尿氨酸，其促进免疫抑制性调节性T细胞（T细胞）中炎性T细胞的转化。我们分析了IDO：Treg轴在溃疡性结肠炎（UC）中诱导和维持粘膜愈合的意义。使用了右旋糖酐硫酸钠（DSS）诱导的BALB/c小鼠（粘膜愈合模型）和C57 BL/6小鼠（持续性疾病模型）结肠炎。分析了65例溃疡性结肠炎粘膜愈合或持续性结肠炎患者的血清、粪便样本和结肠浸润免疫细胞。与C57 BL/6小鼠相比，DSS处理的BALB/c小鼠中犬尿氨酸的血清水平显著更高，并且炎性细胞因子下调。在BALB/c DC中观察到的IDO活性增加和抗原呈递和炎性细胞因子产生能力减弱，随后在DSS处理的BALB/c小鼠的结肠中炎性T辅助细胞1（Th 1）和Th 17细胞的数量显著减少，并且T辅助细胞的数量显著增加。DCs和TdR对维持粘膜愈合至关重要，因为它们的消耗会加重结肠炎。当将BALB/c DC转移到DC耗尽或Treg耗尽的DSS处理的BALB/c小鼠中时，重新建立了粘膜愈合，随后犬尿氨酸和肠TdR增加。这种现象被IDO抑制剂完全消除。在具有粘膜愈合的UC患者中观察到犬尿氨酸的血清和粪便水平显著较高，伴随肠THP的存在增加，并且与疾病严重程度、粪便钙卫蛋白、结肠浸润干扰素γ和白细胞介素-17产生细胞、炎性细胞因子的血清和粪便水平呈负相关。应进一步探索内源性TdR的IDO依赖性扩增作为诱导和维持UC患者粘膜愈合的新方法。
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). 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. 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. 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.
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影响因子：
7.8
作者：
Ma DY;Clark EA
通讯作者：
Clark EA
影响因子：
29.4
作者：
Gurtner, GJ;Newberry, RD;Stenson, WF
通讯作者：
Stenson, WF
DOI：
10.1073/pnas.0708469104
发表时间：
2007-10-23
影响因子：
11.1
作者：
Abe, Kazumichi;Nguyen, Kim Phung;Raz, Eyal
通讯作者：
Raz, Eyal
影响因子：
3.1
作者：
Hall, Lindsay J.;Faivre, Emilie;Melgar, Silvia
通讯作者：
Melgar, Silvia
影响因子：
4.4
作者：
Hwu, P;Du, MX;Young, HA
通讯作者：
Young, HA