JCI Insight. 2023 Jan 24;8(2):e163101. doi: 10.1172/jci.insight.163101.
The expression of indoleamine 2,3-dioxygenase (IDO), a robust immunosuppressant, is significantly induced in macaque tuberculosis (TB) granulomas, where it is expressed on IFN-responsive macrophages and myeloid-derived suppressor cells. IDO expression is also highly induced in human TB granulomas, and products of its activity are detected in patients with TB. In vivo blockade of IDO activity resulted in the reorganization of the granuloma with substantially greater T cells being recruited to the core of the lesions. This correlated with better immune control of TB and reduced lung M. tuberculosis burdens. To study if the IDO blockade strategy can be translated to a bona fide host-directed therapy in the clinical setting of TB, we studied the effect of IDO inhibitor 1-methyl-d-tryptophan adjunctive to suboptimal anti-TB chemotherapy. While two-thirds of controls and one-third of chemotherapy-treated animals progressed to active TB, inhibition of IDO adjunctive to the same therapy protected macaques from TB, as measured by clinical, radiological, and microbiological attributes. Although chemotherapy improved proliferative T cell responses, adjunctive inhibition of IDO further enhanced the recruitment of effector T cells to the lung. These results strongly suggest the possibility that IDO inhibition can be attempted adjunctive to anti-TB chemotherapy in clinical trials.
吲哚胺 2,3-双加氧酶（IDO）的表达在猕猴结核病（TB）肉芽肿中被显著诱导，其在 IFN 反应性巨噬细胞和髓系来源的抑制性细胞上表达。IDO 的表达在人类 TB 肉芽肿中也被高度诱导，并且在 TB 患者中检测到其活性产物。体内阻断 IDO 活性导致肉芽肿重新组织，更多的 T 细胞被募集到病变的核心。这与更好的 TB 免疫控制和减少肺部结核分枝杆菌负担相关。为了研究 IDO 阻断策略是否可以转化为 TB 临床环境中的真正的宿主导向治疗，我们研究了 IDO 抑制剂 1-甲基-D-色氨酸辅助亚最佳抗 TB 化疗的效果。虽然三分之二的对照组和三分之一的化疗组动物进展为活动性 TB，但 IDO 抑制辅助相同的治疗方案保护了猕猴免受 TB 的侵害，这可以通过临床、放射学和微生物学特征来衡量。尽管化疗改善了增殖性 T 细胞反应，但 IDO 抑制的辅助作用进一步增强了效应 T 细胞向肺部的募集。这些结果强烈表明，IDO 抑制可以在临床试验中辅助抗 TB 化疗进行尝试。
