Immunoregulation by indoleamine 2,3-dioxygenases in tuberculosis

结核病中吲哚胺 2,3-双加氧酶的免疫调节

• 批准号: 10527562
• 负责人: John R. Chan
• 金额: $ 29.99万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527562
• 关键词: Immunoregulation; indoleamine; dioxygenases; tuberculosis

Abstract Indoleamine, 2,3-dioxygenase (IDO) is the enzyme that catalyzes the first step of the tryptophan catabolic kynurenine pathway. The T cell immunosuppressive properties of IDO, mediated through various metabolites from this pathway (collectively known as kynurenines (Kyn)), are well established. Abundant evidence shows that IDO-mediated immunosuppressive mechanisms are operative in certain infections and may compromise optimal immune responses to pathogens. There are two isoforms of IDO in mice and humans, designated IDO1 and IDO2, which possess overlapping and distinct immunoregulatory functions. This suggests that the mechanisms by which IDO modulates immune responses are more complex than has been previously appreciated. This complexity is further compounded by the fact that IDO isoforms are expressed by a wide variety of cells, and the cellular source of the enzyme can be important in determining its impact on immune responses. Our observations from analyses of anti-tuberculosis (TB) immunity in isoform-specific ido1-/- and ido2-/- knockout mice suggest the two enzymes exert shared as well as distinct functions in regulating the activities of several important CD4+ T cell subsets in the lungs of Mycobacterium tuberculosis (Mtb)-infected mice. Overall, in the absence of either isoform, the Th1, Th17 and neutrophilic responses are up-regulated, while the Treg response is attenuated, reflecting the immunosuppressive property of IDO1 and IDO2. Interestingly, relative to the ido2-/- strain, Mtb-infected ido1-/- mice consistently display a stronger Th1 and Th17 phenotypes, suggesting that the two isoforms may mediate overlapping and distinct immunomodulating functions in TB. Of note, BCG immunization of ido1-/- and ido1-/-ido2-/- mice elicits a Th1 response that is superior to that observed in vaccinated wild-type animals. Importantly, administration of IDO inhibitors concomitant with BCG immunization augments vaccine-elicited Th1 response. We have also observed that iNKT cell function can be regulated by various immunosuppressive Kyn species. Finally, study of the ido1-/- mouse involving a high inoculum infection with Mtb revealed an anti-inflammatory role of this isoform. This notion is further supported by the observation that IDO expression by non-hematopoietic cells in the lungs is essential for restricting pulmonic inflammation in TB. This latter result also suggests that specific function of IDO may be cell source-dependent. Based on the above, we will generate and use a panel of cell- and isoform-specific IDO-deficient mouse strains for the studies proposed. We will focus on studying myeloid lineage cells, since these express both IDO1 and IDO2 and possess potent immunoregulatory properties. A range of genetic, pharmacologic and murine chimera approaches will be used to stringently test the hypothesis that Mtb activates the immunosuppressive IDO pathway in order to secure an immunosuppressed local environment in infected tissues, thereby promoting persistence. We will also determine if the IDO pathway plays a role in restricting the development of excessive lung inflammation in a tuberculous host, and assess ways of manipulating the IDO pathway and iNKT cell functions to augment vaccine immunogenicity. This proposal brings together the expertise of three laboratories with a long history of close collaboration to rigorously study the roles of IDO1 and IDO2 in shaping host immunity to Mtb. Understanding the mechanisms of IDO-mediated immunosuppression will provide useful information for the design of strategies for improving vaccination and host-directed therapies for prevention and treatment of TB.

抽象的 吲哚胺，2,3-双加氧酶 (IDO) 是催化色氨酸分解代谢第一步的酶 犬尿氨酸途径。 IDO 的 T 细胞免疫抑制特性通过多种途径介导 该途径的代谢物（统称为犬尿氨酸 (Kyn)）已得到充分证实。丰富 有证据表明，IDO 介导的免疫抑制机制在某些感染和 可能会损害对病原体的最佳免疫反应。小鼠体内有两种 IDO 亚型 人类，指定为 IDO1 和 IDO2，具有重叠和不同的免疫调节功能。 这表明 IDO 调节免疫反应的机制比 IDO 更复杂 之前已经受到赞赏。 IDO 同工型的事实进一步加剧了这种复杂性 由多种细胞表达，并且酶的细胞来源对于确定 它对免疫反应的影响。我们对抗结核（TB）免疫分析的观察结果 异构体特异性 ido1-/- 和 ido2-/- 敲除小鼠表明这两种酶发挥共同和不同的作用 调节分枝杆菌肺部几个重要 CD4+ T 细胞亚群的活性 感染结核病（Mtb）的小鼠。总体而言，在缺乏任一亚型的情况下，Th1、Th17 和中性粒细胞 反应上调，而 Treg 反应减弱，反映了免疫抑制 IDO1 和 IDO2 的属性。有趣的是，相对于 ido2-/- 品系，Mtb 感染的 ido1-/- 小鼠始终如一 显示出更强的 Th1 和 Th17 表型，表明这两种亚型可能介导重叠 以及结核病中独特的免疫调节功能。值得注意的是，卡介苗免疫了 ido1-/- 和 ido1-/-ido2-/- 小鼠引发的 Th1 反应优于在接种疫苗的野生型动物中观察到的反应。重要的是， 与 BCG 免疫同时施用 IDO 抑制剂可增强疫苗诱发的 Th1 回复。我们还观察到iNKT细胞功能可以通过多种免疫抑制来调节 金种。最后，对 ido1-/- 小鼠进行的涉及 Mtb 高接种量感染的研究揭示了 该亚型的抗炎作用。 IDO 的观察进一步支持了这一观点 肺部非造血细胞的表达对于限制结核病肺部炎症至关重要。 后一个结果还表明 IDO 的特定功能可能依赖于细胞来源。基于 如上所述，我们将生成并使用一组细胞和异构体特异性 IDO 缺陷的小鼠品系 提出的研究。我们将重点研究骨髓谱系细胞，因为它们表达 IDO1 和 IDO2 并具有有效的免疫调节特性。一系列遗传、药理学和小鼠 嵌合体方法将用于严格检验 Mtb 激活 免疫抑制 IDO 途径，以确保感染者的免疫抑制局部环境 组织，从而促进持久性。我们还将确定 IDO 途径是否在限制中发挥作用 结核病宿主肺部过度炎症的发展，并评估控制肺部炎症的方法 IDO 途径和 iNKT 细胞发挥增强疫苗免疫原性的作用。该提案汇集了 三个长期密切合作的实验室的专业知识，严格研究 IDO1 的作用 和 IDO2 在塑造宿主对 Mtb 的免疫力方面。了解 IDO 介导的机制 免疫抑制将为设计改善疫苗接种和疫苗接种的策略提供有用的信息。 用于预防和治疗结核病的宿主导向疗法。