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

摘要 哮喘是一种慢性呼吸道炎症性疾病，影响着2500万美国人。一年一度的 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Th2型CD4T细胞活化和嗜酸性粒细胞浸润是哮喘的特征 发炎。口服或吸入糖皮质激素一直是有效控制哮喘的一线治疗方法 已经有50多年了。然而，糖皮质激素介导的治疗的确切机制还不是很好。 明白了。此外，还有一组哮喘患者患上了类固醇抗药性哮喘。与传统不同 嗜酸性粒细胞占优势的Th2型炎症、激素抵抗型哮喘炎症与 中性粒细胞浸润，效应者CD4T细胞呈Th17型特征。当前应用程序已构建 在意想不到的观察中发现，合成糖皮质激素地塞米松未能抑制嗜酸性呼吸道 缺乏Foxp3Tregs的炎症反应，Foxp3Tregs是一种CD4T细胞亚群，在调节 豁免权和宽容。在这种情况下采用Treg转移可以恢复地塞米松的治疗效果， 支持特雷格的角色。我们还发现，中性粒细胞气道炎症模型即地塞米松 地塞米松联合IL-27治疗后耐药性减弱，IL-27是Treg必不可少的细胞因子 抑制功能。地塞米松/IL-27介导的中性粒细胞炎症治疗也失败 在Treg耗尽或Treg特异的Il27ra-/-小鼠中，提示Treg和IL-27信号在Treg中的关键作用。 这些初步结果使我们提出，Dex信号诱导Treg抑制功能， 限制嗜酸性炎症反应，而地塞米松控制嗜中性炎症反应 需要IL-27传递给特雷格人的额外信号。提出了三个具体的目标来测试 假设。目的1是验证地塞米松通过以下途径下调嗜酸性气道炎的假设 目标是特雷格。目的2是验证中性粒细胞炎症破坏地塞米松诱导的Treg的假设 控制呼吸道炎症，导致地塞米松耐药。目标3是测试IL-27信号的假设 改善Tregs的地塞米松反应性，以抑制耐地塞米松的中性粒细胞炎症。完成 拟议的研究将揭示先前未知的Tregs调节两种GC的机制 易感和抗GC过敏性呼吸道炎症，为开发新的 通过靶向Tregs来提高GC的疗效和克服GC耐药的方法。

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.