Th1/Th17 Immune Regulation in Severe Allergic Asthma

严重过敏性哮喘中的 Th1/Th17 免疫调节

基本信息

  • 批准号:
    10348780
  • 负责人:
  • 金额:
    $ 7.45万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-02-10 至 2024-01-31
  • 项目状态:
    已结题

项目摘要

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 这是授予“严重过敏性哮喘中的TH1/TH17免疫调节”的赠款(1 RO3) AI163794-01),重点介绍树突状细胞(DCS)介导的TH1/TH17免疫调节的机理 中性粒气道注射中的反应。重新提取申请的总体目标是获得新的 有关DC的代谢重编程如何有助于免疫启动和免疫偏振的知识 效应子功能及其如何在严重的哮喘气道中产生和产生炎症环境。 我们从临床和实验证据中知道,呼吸道感染是常见的触发因素 哮喘加剧并导致严重的疾病形式,表现出一条混合的粒细胞气道 炎症完成了嗜中性粒细胞和嗜酸性粒细胞。而且,我们认为哮喘加剧 感染的存在导致刺激先天传感器刺激(干扰素基因的刺激剂)途径 随着气道中的TH1/TH17免疫响应偏向。我们最近报道了不仅激活和 DC的免疫促进功能与细胞代谢状态的深刻改变,但也是如此 包括由内源性钥匙代谢物调节的DC特异性反应(Jaiswal等人,免疫。 发炎。 Dis,2019)。新的令人兴奋的初步数据表明,直流特定的免疫反应增加 基因1(irg1),脱羧酸酯顺式抗性产生免疫调节的代谢产物itaconate,在Th1/th17中 相对于幼稚的控制,哮喘性肺可能有助于解决气道注射。 IRG1的这种诱导 与DC中的Itaconate Productions一起使用,带有家用尘螨(HDM)和刺激刺激。结果显示 这种外源性主统治处理恢复了线粒体呼吸和DC的能力极化CD4+ T细胞,表明Itaconate在DCS免疫促进功能(S)上发挥了免疫调节作用。反 - Itaconate的炎症作用在体内翻译,其中Itaconate处理的DC的自适应转移减少了 气道炎症和T细胞介导的免疫响应相对于媒介物处理的DC。从这些作品中 我们假设Itaconate在肺DC中起独特的调节作用,可以限制证据。 中性粒细胞炎症。为了检验这一假设,在AIM1中,我们将首先确定内源性ITACONES是否为 使用IRG1敲除小鼠开发气道注射和TH1/TH17免疫响应所需。在 AIM2,我们将确定对Itaconate衍生物的外源治疗是否发挥潜在的抗 体内炎症特性。综上所述,这些研究将扩大有关如何 IRG1/Itaconate轴调节直流效应子功能以及针对气道的治疗干预措施是否针对 可能会减少或废除严重哮喘的TH1/TH17免疫反应。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Short palate, lung, and nasal epithelial clone 1 (SPLUNC1) level determines steroid-resistant airway inflammation in aging.
Development of OX40 agonists for canine cancer immunotherapy.
  • DOI:
    10.1016/j.isci.2022.105158
  • 发表时间:
    2022-10-21
  • 期刊:
  • 影响因子:
    5.8
  • 作者:
    Ruiz, Damien;Haynes, Chloe;Marable, Jonathan;Pundkar, Chetan;Nance, Rebecca L.;Bedi, Deepa;Agarwal, Payal;Suryawanshi, Amol S.;Mishra, Amarjit;Smith, Bruce F.;Sandey, Maninder
  • 通讯作者:
    Sandey, Maninder
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