Foxp3+ regulatory T cell-dependent treatment of allergic inflammation by glucocorticoids

Foxp3 调节性 T 细胞依赖性糖皮质激素治疗过敏性炎症

基本信息

  • 批准号:
    10218031
  • 负责人:
  • 金额:
    $ 54.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-10-21 至 2023-07-31
  • 项目状态:
    已结题

项目摘要

Abstract Asthma is a chronic inflammatory disease of the airways, affecting >25 million Americans. The annual economic cost for asthma exceeds 50 billion dollars, making asthma one of the most common and costly disease. Allergen specific Th2 type CD4 T cell activation and eosinophil infiltration are hallmarks of asthmatic inflammation. Oral or inhaled glucocorticoids have been the frontline treatment to effectively manage asthma for more than 50 years. Yet, the precise mechanisms underlying glucocorticoid-mediated treatment are not well understood. In addition, a cohort of asthmatic patients develops steroid-resistant asthma. Unlike conventional eosinophil-dominant Th2 type inflammation, steroid-resistant asthmatic inflammation is associated with neutrophilic infiltration with effector CD4 T cells displaying Th17 type signature. The current application is built upon unexpected observations that synthetic glucocorticoid, dexamethasone, fails to inhibit eosinophilic airway inflammation in the absence of Foxp3+ Tregs, a CD4 T cell subset that plays a central role in regulating immunity and tolerance. Adoptive Treg transfer into this condition restores dexamethasone treatment effects, supporting the role of Tregs. We also found that neutrophilic airway inflammation model that is dexamethasone resistant is attenuated upon treating with dexamethasone combined with IL-27, a cytokine essential for Treg suppressive functions. Dexamethasone/IL-27-mediated treatment of neutrophilic inflammation also failed in Treg-depleted or in Treg-specific Il27ra-/- mice, suggesting key roles of Tregs and of IL-27 signaling in Tregs. These preliminary results have led us to propose that Dex signaling induces Treg suppressive functions that limit eosinophilic inflammatory responses whereas control of neutrophilic inflammatory responses by Dex requires additional signals conferred by IL-27 to the Tregs. Three specific aims are proposed to test the hypothesis. Aim 1 is to test the hypothesis that that Dex downregulates eosinophilic airway inflammation by targeting Tregs. Aim 2 is to test the hypothesis that neutrophilic inflammation subverts Dex-induced Treg control of airway inflammation, resulting in Dex resistance. Aim 3 is to test the hypothesis that IL-27 signaling improves Dex responsiveness in Tregs to inhibit Dex-resistant neutrophilic inflammation. Completing the proposed studies will uncover the previously unknown mechanisms by which Tregs regulate both GC susceptible and GC resistant allergic airway inflammation, opening new opportunities to develop novel approaches to improve GC’s therapeutic efficacy and to overcome GC resistance by targeting Tregs.
摘要 哮喘是一种慢性气道炎症性疾病,影响超过2500万美国人。年度 哮喘的经济成本超过500亿美元,使哮喘成为最常见和最昂贵的疾病之一。 疾病过敏原特异性Th 2型CD 4 T细胞活化和嗜酸性粒细胞浸润是哮喘的标志 炎症口服或吸入糖皮质激素一直是有效管理哮喘的一线治疗方法 50多年了然而,糖皮质激素介导的治疗的确切机制还不清楚, 明白此外,一组哮喘患者出现类固醇耐药性哮喘。不同于常规 嗜酸性粒细胞占主导地位的Th 2型炎症,类固醇抵抗性哮喘炎症与 显示Th 17型特征的效应CD 4 T细胞的嗜中性浸润。当前应用程序已构建 在意外观察到合成糖皮质激素地塞米松不能抑制嗜酸性气道 Foxp 3 + T细胞亚群是一种CD 4 T细胞亚群,在调节炎症中起核心作用。 免疫力和耐受性。连续性Treg转移到这种病症中恢复了地塞米松治疗效果, 支持Tibet的角色。我们还发现,地塞米松是一种嗜酸性的气道炎症模型, 在用地塞米松与IL-27(Treg必需的细胞因子)组合治疗后, 抑制功能。地塞米松/IL-27介导的嗜酸性炎症治疗也失败, Treg缺失或Treg特异性Il 27 ra-/-小鼠中,表明TcB和IL-27信号传导在TcB中的关键作用。 这些初步结果使我们提出Dex信号传导诱导Treg抑制功能, 限制嗜酸性粒细胞炎症反应,而地塞米松控制嗜酸性粒细胞炎症反应, 需要由IL-27赋予T细胞的额外信号。提出了三个具体目标,以测试 假说.目的1是检验Dex通过下调气道嗜酸性粒细胞炎症的假设, 目标是泰瑟姆目的2是检验嗜酸性炎症破坏Dex诱导的Treg的假设 控制气道炎症,导致Dex抵抗。目的3是检验IL-27信号转导 改善TcB中的Dex反应性,以抑制Dex耐药的嗜中性炎症。完成 拟议中的研究将揭示以前未知的机制,即TGFAP调节GC和GC的机制。 敏感和GC耐药的过敏性气道炎症,开辟了新的机会,开发新的 通过靶向TGFAP来提高GC的治疗效果和克服GC耐药性的方法。

项目成果

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Booki Min其他文献

Booki Min的其他文献

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{{ truncateString('Booki Min', 18)}}的其他基金

miR-342, a novel glucocorticoid-responsive miRNA necessary for Foxp3+ regulatory T cell function
miR-342,一种新的糖皮质激素反应性 miRNA,是 Foxp3 调节 T 细胞功能所必需的
  • 批准号:
    10671943
  • 财政年份:
    2023
  • 资助金额:
    $ 54.4万
  • 项目类别:
Foxp3+ regulatory T cell-dependent treatment of allergic inflammation by glucocorticoids
Foxp3 调节性 T 细胞依赖性糖皮质激素治疗过敏性炎症
  • 批准号:
    10447598
  • 财政年份:
    2020
  • 资助金额:
    $ 54.4万
  • 项目类别:
Foxp3+ regulatory T cell-dependent treatment of allergic inflammation by glucocorticoids
Foxp3 调节性 T 细胞依赖性糖皮质激素治疗过敏性炎症
  • 批准号:
    9982786
  • 财政年份:
    2019
  • 资助金额:
    $ 54.4万
  • 项目类别:
The role of IL-27/Lag3 axis in regulating Foxp3+ regulatory T cell function
IL-27/Lag3轴在调节Foxp3调节性T细胞功能中的作用
  • 批准号:
    10264303
  • 财政年份:
    2017
  • 资助金额:
    $ 54.4万
  • 项目类别:
Mechanism of basophil mediated immune modulation
嗜碱性粒细胞介导的免疫调节机制
  • 批准号:
    7897737
  • 财政年份:
    2009
  • 资助金额:
    $ 54.4万
  • 项目类别:
Mechanism of basophil mediated immune modulation
嗜碱性粒细胞介导的免疫调节机制
  • 批准号:
    7737907
  • 财政年份:
    2009
  • 资助金额:
    $ 54.4万
  • 项目类别:
Homeostatic Regulation of T Lymphocytes
T 淋巴细胞的稳态调节
  • 批准号:
    7576472
  • 财政年份:
    2008
  • 资助金额:
    $ 54.4万
  • 项目类别:
Homeostatic Regulation of T Lymphocytes
T 淋巴细胞的稳态调节
  • 批准号:
    8390491
  • 财政年份:
    2008
  • 资助金额:
    $ 54.4万
  • 项目类别:
Homeostatic Regulation of T Lymphocytes
T 淋巴细胞的稳态调节
  • 批准号:
    7991375
  • 财政年份:
    2008
  • 资助金额:
    $ 54.4万
  • 项目类别:
Homeostatic Regulation of T Lymphocytes
T 淋巴细胞的稳态调节
  • 批准号:
    7740877
  • 财政年份:
    2008
  • 资助金额:
    $ 54.4万
  • 项目类别:

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