Immunoregulation by indoleamine 2,3-dioxygenases in tuberculosis

摘要 吲哚胺2，3-双加氧酶（Indoleamine，2，3-dioxygenase，IDO）是色氨酸分解代谢的第一步酶 犬尿氨酸途径。IDO的T细胞免疫抑制特性，通过各种途径介导， 来自该途径的代谢物（统称为犬尿氨酸（Kyn））已经被充分确立。丰富 有证据表明IDO介导的免疫抑制机制在某些感染中起作用， 可能会损害对病原体的最佳免疫反应。在小鼠中存在两种IDO同种型， 人，命名为IDO 1和IDO 2，其具有重叠和不同的免疫调节功能。 这表明IDO调节免疫应答的机制比IDO调节免疫应答的机制更复杂。 以前就被赞赏过。这种复杂性进一步由于IDO同种型是 由多种细胞表达，并且酶的细胞来源在确定 对免疫反应的影响。本文通过对1995 ~ 1999年山东省部分地区结核病患者的抗结核免疫分析， 同种型特异性的IDO 1-/-和IDO 2-/-敲除小鼠表明这两种酶发挥共同的以及不同的作用。 在调节分枝杆菌肺中几种重要的CD 4 + T细胞亚群的活性中起作用 结核病（Mtb）感染的小鼠。总体而言，在不存在任一同种型的情况下，Th 1、Th 17和嗜酸性粒细胞的表达均降低。 反应被上调，而Treg反应被减弱，反映了免疫抑制作用。 IDO 1和IDO 2的属性。有趣的是，相对于ido 2-/-菌株，Mtb感染的ido 1-/-小鼠始终 显示出更强的Th 1和Th 17表型，表明这两种亚型可能介导重叠 在结核病中有明显的免疫调节作用。值得注意的是，ido 1-/-和ido 1-/-ido 2-/-的BCG免疫 小鼠产生的Th 1应答比在接种的野生型动物中观察到的应答更上级。重要的是， IDO抑制剂联合BCG免疫增强疫苗诱导的Th 1 反应我们还观察到iNKT细胞功能可以通过各种免疫抑制剂调节， Kyn物种。最后，对涉及高接种物感染Mtb的ido 1-/-小鼠的研究显示， 这种异构体的抗炎作用。这一观点得到以下意见的进一步支持： 肺中非造血细胞的表达对于限制TB中的肺部炎症是必需的。 后一结果还表明IDO的特异性功能可能是细胞来源依赖性的。基于 在上文中，我们将产生并使用一组细胞和同种型特异性IDO缺陷小鼠品系用于本发明。 研究提出。我们将集中研究髓系细胞，因为这些细胞既表达IDO 1， IDO 2和具有有效的免疫调节特性。一系列遗传学、药理学和鼠 嵌合体方法将用于严格检验结核分枝杆菌激活 免疫抑制性IDO途径，以确保感染的局部环境免疫抑制 组织，从而促进持久性。我们还将确定IDO途径是否在限制 结核宿主中过度肺部炎症的发展，并评估操纵 IDO途径和iNKT细胞功能增强疫苗免疫原性。该提案汇集了 三个实验室的专业知识，具有长期密切合作的历史，严格研究IDO的作用1 和IDO 2在形成宿主对Mtb的免疫中的作用。了解IDO介导的机制 免疫抑制将为设计改进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。

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.