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: 9921293
• 负责人: John R. Chan
• 金额: $ 80.65万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 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/9921293
• 关键词: Acute; Agreement; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antimicrobial Effect; Antitubercular Agents; Attenuated; Bacille Calmette-Guerin vaccination; Bacteria; Biochemistry; CD4 Positive T Lymphocytes; Cell Lineage; Cell physiology; Cells; Chimera organism; Chronic; Chronic Phase; Clinical; Collaborations; Complex; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Dioxygenases; Disease; Dose; Elements; Environment; Enzymes; Exhibits; Genetic; Goals; Granulomatous; Host Defense; Human; Immune; Immune response; Immunity; Immunization; Immunologics; Immunosuppression; In Vitro; Infection; Inflammation; Knock-out; Knockout Mice; Kynurenine; Laboratories; Lead; Lung; Lung Inflammation; Mediating; Modeling; Mouse Strains; Mus; Mycobacterium tuberculosis; Myelogenous; Neutrophilia; Pathologic; Pathologic Processes; Pathway interactions; Pharmacology; Phenotype; Physiological; Play; Prevention therapy; Production; Property; Protein Isoforms; Recombinants; Recording of previous events; Regulatory T-Lymphocyte; Reporting; Research; Resistance; Role; Secure; Shapes; Source; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Tryptophan; Tryptophan 2,3 Dioxygenase; Tuberculosis; Vaccinated; Vaccination; Vaccines; Wild Type Mouse; base; cytokine; design; disorder control; heme a; immunogenicity; immunopathology; immunoregulation; immunosuppressed; improved; indoleamine; inhibitor/antagonist; lymph nodes; macrophage; mortality; neutrophil; pathogen; response; transmission process; tuberculosis immunity; tuberculosis treatment

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，2,3-二氧酶（IDO）是催化色氨酸分解代谢的第一步的酶 Kynurenine途径。 IDO的T细胞免疫抑制特性，通过各种 该途径的代谢产物（统称为kynurenines（Kyn））已良好确定。丰富 有证据表明，IDO介导的免疫抑制机制在某些感染中是操作的，并且 可能会损害对病原体的最佳免疫反应。小鼠有两个IDO的同工型， 人类，指定为IDO1和IDO2，具有重叠和独特的免疫调节功能。 这表明IDO调节免疫反应的机制比 以前已被赞赏。 IDO同工型是 由多种细胞表达，酶的细胞来源对于确定很重要 它对免疫反应的影响。我们对抗结核分析（TB）免疫的分析的观察结果 同工型特异性IDO1 - / - 和IDO2 - / - 敲除小鼠提出了两种酶共享的酶以及不同的酶 调节分枝杆菌肺中几个重要的CD4+ T细胞子集的活性 结核病（MTB）感染的小鼠。总体而言，在没有同工型的情况下，Th1，Th17和中性粒细胞 反应被上调，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 - / - 菌株，MTB感染的IDO1 - / - 始终如一 表现出更强的Th1和Th17表型，表明这两种同工型可能介导重叠 和TB中不同的免疫调节功能。值得注意的是，IDO1 - / - 和IDO1 - / - IDO2 - / - 的BCG免疫接种 小鼠引起的TH1反应优于在接种野生型动物中观察到的反应。重要的是， 给予与BCG免疫相关的IDO抑制剂增加了疫苗吸收的TH1 回复。我们还观察到可以通过各种免疫抑制来调节inkt细胞功能 Kyn物种。最后，对涉及高接收感染的IDO1 - / - 小鼠的研究表明 该同工型的抗炎作用。 IDO的观察进一步支持了这个概念 肺中非杂造细胞的表达对于限制结核病中的肺炎炎症至关重要。 后一个结果还表明，IDO的特定功能可能是细胞源依赖性的。基于 上面，我们将生成并使用一组细胞和同工型特异性IDO缺陷小鼠应变 研究提出。我们将专注于研究髓样谱系细胞，因为它们同时表达IDO1和 IDO2并具有有效的免疫调节特性。一系列遗传，药理学和鼠 Chimera方法将用于严格测试MTB激活的假设 免疫抑制IDO途径，以确保受感染的免疫抑制的当地环境 组织，从而促进持久性。我们还将确定IDO途径是否在限制 结核病宿主中过度肺部炎症的发展，并评估操纵的方式 IDO途径和INKT细胞功能增强疫苗免疫原性。该提议汇集了 三个实验室的专业知识，具有悠久的合作历史，以严格研究IDO1的角色 和IDO2在将宿主的免疫力塑造为MTB中。了解IDO介导的机制 免疫抑制将为设计改善疫苗接种和的策略提供有用的信息 预防和治疗结核病的宿主定向疗法。