ALCAM/CD6 interactions in airway inflammation and remodeling

摘要 这项拟议的研究的目标是确定调节呼吸道的新机制。 重症哮喘的炎症和重塑。第二组天然淋巴样细胞(ILC2s)和CD4Th2 细胞被认为促进了一大批重症哮喘患者的呼吸道炎症，新发现 控制ILC2s和Th2细胞以及呼吸道平滑肌(ASM)重塑的分子， 可能代表治疗靶点。我们在肺部炎症中发现了一种新的双向途径。 和受配体/受体对alcam(表达于平滑肌)和CD6调节的重塑 (表达于ILC2和Th2细胞)。我们推测alcam在肺结构细胞上表达。 (平滑肌)和CD6在ILC2和Th2细胞上的表达可能是一条新的途径，推动前两者的表达。 炎症反应和组织重塑。我们将对人肺进行体外研究， 肺淋巴结外周血ILC2s和Th2细胞经alcam-Fc刺激(刺激 CD6)或表达alcam的ASM细胞，并检测ILC2和Th2细胞细胞因子的产生和 扩散。此外，我们将用CD6-Fc(刺激alcam)以及 CD6表达的淋巴细胞，并测定其增殖/肥大和炎症水平 调解人表达。将对哮喘患者和对照组的组织和呼吸道样本进行评估 CD6在ILC2和Th2细胞上的表达水平，以及ALCAM在ASM上的表达水平。最后，我们 将使用CD6基因敲除小鼠的先天和慢性过敏原挑战模型来测试CD6在 ILC2/Th2细胞增殖和细胞因子的产生以及气道平滑肌重塑，肺 炎症和高反应性。由于抗CD6治疗在其他疾病中已显示出安全性和有效性 包括严重牛皮癣在内的人类免疫性疾病，我们的研究旨在揭示其发病机制 ALCAM/CD6在哮喘中的相互作用可能为重症哮喘的治疗提供一种新的策略。

Abstract The goal of the proposed research is to identify novel mechanisms that regulate airway inflammation and remodeling in severe asthma. Group 2 innate lymphoid cells (ILC2s) and CD4+ Th2 cells are thought to promote airway inflammation in a large subset of severe asthmatics and novel molecules that control both ILC2s and Th2 cells, as well as airway smooth muscle (ASM) remodeling, may represent therapeutic targets. We have identified a novel bidirectional pathway in lung inflammation and remodeling regulated by the ligand/receptor pair ALCAM (expressed on smooth muscle) and CD6 (expressed on ILC2s and Th2 cells). We hypothesize that ALCAM expressed on lung structural cells (smooth muscle) and CD6 expressed on ILC2 and Th2 cells may be a novel pathway to drive both pro- inflammatory responses as well as tissue remodeling. We will perform in vitro studies with human lung, lung lymph node, and peripheral blood ILC2s and Th2 cells stimulated with ALCAM-Fc (that stimulates CD6) or ALCAM-expressing ASM cells and measure ILC2 and Th2 cell cytokine production and proliferation. Further, we will culture human ASM cells with CD6-Fc (that stimulates ALCAM) as well as CD6-expressing lymphocytes and determine levels of hyperplasia/hypertrophy and inflammatory mediator expression. Tissue and airway samples from asthmatics and controls will be assessed for levels of CD6 expression on ILC2s and Th2 cells, as well as ALCAM expression on ASM. Finally, we will use innate and chronic allergen challenge models with CD6 knockout mice to test the role of CD6 in ILC2/Th2 cell proliferation and cytokine production as well as airway smooth muscle remodeling, lung inflammation, and hyperresponsiveness. As anti-CD6 therapy has shown safety and efficacy in other human immune diseases including severe psoriasis, our studies to uncover the mechanisms of ALCAM/CD6 interactions in asthma may lead to a novel therapeutic strategy for severe asthma.