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.

摘要 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通过多种途径调节T细胞免疫抑制作用 这一途径的代谢物(统称为犬尿氨酸(Kyn))已得到很好的证实。富饶 有证据表明，IDO介导的免疫抑制机制在某些感染和 可能会影响对病原体的最佳免疫反应。在小鼠体内有两种IDO亚型 人类，命名为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 此前一直受到赞赏。这种复杂性由于IDO亚型是 在各种各样的细胞中表达，这种酶的细胞来源在确定 它对免疫反应的影响。年抗结核免疫分析中的观察 异构体特异性的ido1-/-和ido2-/-基因敲除小鼠表明这两种酶既有共同的作用，也有不同的作用 分枝杆菌在调节肺内几个重要的CD4+T细胞亚群活性中的作用 结核(Mtb)感染的小鼠。总体而言，在缺乏任何一种异构体的情况下，Th1、Th17和中性粒细胞 反应上调，而Treg反应减弱，反映免疫抑制 IDO1和IDO2的属性。有趣的是，相对于ido2-/-菌株，结核分枝杆菌感染的ido1-/-小鼠 表现出较强的Th1和Th17表型，表明这两种异构体可能介导重叠 在结核病中具有独特的免疫调节功能。值得注意的是，ido1-/-和ido1-/-ido2-/-的卡介苗免疫 小鼠产生的Th1反应优于接种疫苗的野生型动物。重要的是 IDO抑制剂与卡介苗联合应用可增强疫苗诱导的Th1 回应。我们还观察到iNKT细胞的功能可以受到各种免疫抑制的调节。 Kyn物种。最后，对ido1/-小鼠涉及高接种量结核分枝杆菌感染的研究揭示了 这种异构体的抗炎作用。IDO的观察进一步支持了这一观点 非造血细胞在肺中的表达对于限制肺结核的肺部炎症是必不可少的。 后者的结果也表明IDO的特定功能可能是细胞来源依赖的。基于 上面，我们将生成并使用一组特定于细胞和异构体的IDO缺陷小鼠品系 研究建议。我们将重点研究髓系细胞，因为它们同时表达IDO1和 IDO2，并具有强大的免疫调节特性。一系列遗传学、药理学和小鼠 嵌合体方法将被用来严格检验结核分枝杆菌激活 免疫抑制IDO途径，以确保感染患者免疫抑制的局部环境 组织，从而促进持久力。我们还将确定IDO途径是否在限制 在结核宿主中过度的肺部炎症的发展，并评估操纵 IDO途径和iNKT细胞具有增强疫苗免疫原性的功能。这项建议汇集了 三个有着长期密切合作历史的实验室的专业知识，以严格研究IDO1的作用 和IDO2在形成对结核分枝杆菌的宿主免疫中的作用。理解IDO介导的机制 免疫抑制将为设计改进疫苗接种和预防接种的战略提供有用的信息 预防和治疗结核病的宿主导向疗法。