Th1/Th17 Immune Regulation in Severe Allergic Asthma

严重过敏性哮喘中的 Th1/Th17 免疫调节

• 批准号: 10214803
• 负责人: Amarjit Mishra
• 金额: $ 7.45万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-10 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214803
• 关键词: Aconitic Acid; Acute; Address; Adoptive Transfer; Affect; Age; Airway Disease; Allergens; Allergic; Allergic inflammation; Anti-Inflammatory Agents; Antigen-Antibody Complex; Antiinflammatory Effect; Asthma; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic; Clinical; Coupled; Cues; Data; Dendritic Cells; Development; Disease; Economic Burden; Effector Cell; Equilibrium; Esters; Experimental Models; Exposure to; Extrinsic asthma; Foundations; Fumarates; Genes; Goals; Grant; Health; Health Care Costs; Health Status; Hyperactivity; Immune; Immune response; Immunity; Impairment; Infection; Infiltration; Inflammation; Inflammatory Response; Knockout Mice; Knowledge; Lung; Lung infections; Maintenance; Mass Spectrum Analysis; Measures; Mediastinal lymph node group; Mediating; Metabolic; Mitochondria; Molecular; Morbidity - disease rate; Neutrophil Infiltration; Outcome; Pathologic; Pathway interactions; Phase; Phenotype; Play; Population; Prevention; Process; Production; Property; Public Health; Pyroglyphidae; Regulation; Reporting; Research; Resolution; Respiration; Respiratory Tract Infections; Risk; Risk Factors; Role; Signal Transduction; Steroid Resistance; Steroid-resistant asthma; Stimulator of Interferon Genes; T-Lymphocyte; Testing; Th2 Cells; Therapeutic; Therapeutic Intervention; Translating; Treatment Efficacy; Viral Respiratory Tract Infection; adaptive immune response; airborne allergen; airway inflammation; asthma exacerbation; asthmatic; asthmatic airway; base; cell mediated immune response; cell motility; chronic inflammatory disease; clinically relevant; effector T cell; eosinophil; expectation; genetic signature; granulocyte; immune activation; immunoregulation; improved; in vivo; inflammatory milieu; innovation; metabolomics; mouse model; neutrophil; novel; novel therapeutic intervention; prevent; reduce symptoms; response; sensor; therapeutic evaluation; transcriptome

Project Summary/Abstract This is the resubmission of a grant entitled “Th1/Th17 Immune Regulation in Severe Allergic Asthma” (1 RO3 AI163794-01) which focuses on the mechanism of dendritic cell (DCs)-mediated regulation of Th1/Th17 immune response in neutrophilic airway inflammation. The overall goal of the resubmission application is to gain new knowledge about how metabolic reprograming of DCs contribute to immune priming and immune-polarizing effector function(s) and how it predisposes and generate the inflammatory milieu in severe asthmatic airways. We know from clinical and experimental evidence that respiratory infections, which are a common trigger for asthma exacerbations and contribute to severe form of the disease, manifested a mixed granulocytic airway inflammation comprising both neutrophils and eosinophils. Moreover, we believe that asthma exacerbations in presence of infections leads to stimulate innate sensor STING (stimulator of interferon genes) pathways, as well as skewing Th1/Th17 immune response in the airways. We recently reported that not only activation and immune-priming function of DCs are coupled to profound alterations of the cellular metabolic state, but also it comprises a DC-specific response modulated by the endogenous key metabolites (Jaiswal et al., Immun. Inflamm. Dis, 2019). New and exciting preliminary data reveal that DC-specific increase of immune responsive gene1 (Irg1), which decarboxylate cis-aconitate to produce immunoregulatory metabolite itaconate, in Th1/Th17 asthmatic lung relative to naïve controls presumably to help resolve airway inflammation. This induction of Irg1 is coupled with itaconate productions in DCs with house dust mite (HDM) and STING stimulations. Results show that exogenous itaconate treatment restored mitochondrial respiration and the capacity of DCs to polarize CD4+ T cells, suggesting an immunoregulatory role of itaconate on DCs immune-priming function(s). The anti- inflammatory effect of itaconate was translated in vivo, where adoptive transfer of itaconate treated DCs reduced airway inflammation and T cell-mediated immune response relative to vehicle-treated DCs. From these pieces of evidence we hypothesize that itaconate plays a distinct regulatory role in lung DCs and can be induced to limit neutrophilic airway inflammation. To test this hypothesis, in Aim1, we will first determine if endogenous itaconate is required for developing airway inflammation and Th1/Th17 immune response using Irg1 knockout mice. In Aim2, we will determine whether exogenous treatment of the itaconate derivative exerts potential anti- inflammatory properties in vivo. Taken together, these studies will expand on the limited knowledge of how Irg1/itaconate axis regulates DC effector function and whether therapeutic interventions targeting the airways could reduce or abolish Th1/Th17 immune response in severe asthma.

项目摘要/摘要 这是一项名为“重症过敏性哮喘患者的Th1/Th17免疫调节”(1 R03)的拨款的重新提交 AI163794-01)，重点研究了树突状细胞(DC)介导的Th1/Th17免疫调节机制 中性粒细胞呼吸道炎症的反应。重新提交申请的总体目标是获得新的 树突状细胞代谢重编如何促进免疫启动和免疫极化的知识 效应器功能(S)及其如何诱发和产生严重哮喘的炎症环境。 我们从临床和实验证据中了解到，呼吸道感染是引发 哮喘加重并促成疾病的严重形式，表现为混合粒细胞的呼吸道 包括中性粒细胞和嗜酸性粒细胞的炎症。此外，我们认为，哮喘的恶化 感染的存在也会刺激先天感受器刺痛(干扰素基因刺激物)途径。 因为扭曲了呼吸道中的Th1/Th17免疫反应。我们最近报道，不仅激活和 树突状细胞的免疫启动功能不仅与细胞代谢状态的深刻变化有关，而且还与其 包括由内源性关键代谢物调制的DC特异性反应(Jaiswal等人，Immun。 发炎。迪斯，2019年)。新的和令人兴奋的初步数据显示，DC特异性的免疫应答增加 在Th1/Th17中，基因1(IRG1)使顺式乌头脱羧基产生免疫调节代谢物衣康酸 哮喘肺相对于幼稚对照组可能有助于缓解呼吸道炎症。IRG1的这种诱导 与衣康酸在DC中与室内尘螨(HDM)和刺激物的生产相结合。结果显示 外源性衣康酸治疗恢复了线粒体呼吸和DC极化CD4+的能力 T细胞，提示衣康酸对树突状细胞免疫启动功能的免疫调节作用(S)。反- 衣康酸的炎症效应在体内转化，过继转移衣康酸处理的DC减少 与载体处理的DC相关的呼吸道炎症和T细胞介导的免疫反应。从这些碎片中 我们假设衣康酸在肺树突状细胞中起着明显的调节作用，并且可以诱导限制 中性粒细胞呼吸道炎症。为了验证这一假设，在Aim1中，我们将首先确定内源性衣康酸 是使用IRG1基因敲除小鼠发展呼吸道炎症和Th1/Th17免疫反应所必需的。在……里面 AIM2，我们将确定衣康酸衍生物的外源性处理是否发挥潜在的抗 体内炎症特性。综上所述，这些研究将在有限的知识基础上扩展 IRG1/itacate轴调节DC效应器功能以及是否针对呼吸道进行治疗干预 可降低或取消重症哮喘患者的Th1/Th17免疫反应。