间充质干细胞通过Treg对呼吸道变应性炎症Ⅱ型固有淋巴细胞作用的研究

The prevalence of allergic rhinitis (AR) and asthma are high in people's daily life. Currently, the main treatment in the clinics is focusing on the symptoms. Recently, type Ⅱ innate lymphoid (ILC2) has been found to play a key role in the pathogenesis of AR and asthma, it can be used as an important target for the prevention and treatment of the diseases. We have previously reported that mesenchymal stem cells (MSC) can effectively inhibit AR and asthma inflammation by regulating immune imbalance, but whether MSC can inhibit ILC2 is still unknown. According to our preliminary data, MSC can effectively inhibit the function of ILC2 from AR and asthma patients, ILC2 level in the allergic airway inflammatory mouse is also decreased by MSC. However, MSC requires the involvement of regulatory T cells (Treg) to exhibit the inhibitory functions on ILC2. Such finding needs to be further confirmed and explained. This study intends to systematically investigate the function of MSCs on ILC2 via Treg in allergic airway inflammation, both AR/asthma patient samples and genetic mouse models with Treg adoptive infusion will be used. The molecular mechanisms of the interaction among MSC, Treg and ILC2 will be studied. This research will provide a scientific basis for the MSC treatment strategy by targeting ILC2, which has important theoretical significance.

变应性鼻炎(AR)和哮喘患病率高，目前临床上主要是对症治疗，新近发现Ⅱ型固有淋巴细胞(ILC2)在其发病中起关键作用，可作为防治AR和哮喘的重要靶点。我们前期报道了间充质干细胞(MSC)可通过调节免疫失衡而有效抑制AR及哮喘炎症，但MSC是否作用于ILC2还未为可知。我们预实验发现MSC可有效抑制AR及哮喘患者来源ILC2功能，并可抑制ILC2优势的小鼠呼吸道变应性炎症，不过进一步发现MSC是需要调节性T细胞(Treg)的辅助而对ILC2发挥上述作用，这还需进一步确证并揭示其作用机制。本课题拟应用AR及哮喘患者标本及小鼠模型系统探讨呼吸道变应性炎症中MSC通过Treg抑制ILC2的功能，并应用T、B细胞免疫缺陷小鼠及Treg过继输注进一步确证；并从分子水平阐明MSC、Treg及ILC2三者间的互相作用关系及机制。本课题将为以ILC2为靶点的MSC的治疗策略提供科学依据，具有重要的理论意义。

Ⅱ型固有淋巴细胞(ILC2)在变应性鼻炎(AR)和哮喘发病过程中发挥关键作用，可作为防治AR和哮喘的重要靶点。我们前期报道了间充质干细胞(MSC)可通过调节免疫失衡而有效抑制AR及哮喘炎症，但是MSC对ILC2的免疫调控作用还未有报道。本项目应用鼻炎（AR）及哮喘患者标本及小鼠模型系统探讨在呼吸道变应性炎症中MSC通过调节性T细胞（Treg）调控ILC2的功能，并应用T、B细胞免疫缺陷小鼠及Treg过继输注进一步确证；并从分子水平阐明MSC、Treg及ILC2三者间的互相作用关系及机制。重点研究了MSC通过Treg对ILC2功能的调控抑制的作用和机制：(1).体外探究呼吸道变应性炎症中iPSC-MSC可抑制ILC2的功能，探讨iPSC-MSC对 ILC2功能的影响；(2).确定Treg在iPSC-MSC调控抑制 ILC2细胞免疫功能中所发挥的作用；(3).明确iPSC-MSC调控ILC2免疫功能的具体机制，包括细胞表面标记物和细胞内相关信号通路蛋白的表达情况；(4).确定外周血中其他淋巴细胞在iPSC-MSC调控抑制ILC2细胞免疫功能中所发挥的作用；(5).利用T、B细胞免疫缺陷小鼠建立以ILC2为主导的变应性呼吸道炎症模型，为在体内验证MSC通过Treg抑制ILC2功能奠定基础。项目研究工作严格按照计划进行，已完成了所有的研究任务，并对部分研究内容进行了拓展性研究。在基础理论和方法研究方面，系统总结了基于MSC细胞疗法的保护作用的潜在机制，并研究了CysLT1R在ILC2上的表达及CysLT1R拮抗剂对变应性鼻炎患者ILC2活性的影响。本项目的执行，在阐明MSC在呼吸道变应性炎症中对ILC2的具体免疫调节作用及机制，全面了解MSC在治疗过敏性疾病中的机制，拓展其临床应用具有重要意义等方面取得了重要研究进展。