诱导性多能干细胞来源的间充质干细胞对变应性鼻炎Ⅱ型固有淋巴细胞的免疫调控作用

Conventionally, allergic rhinitis and asthma are characterized as allergen-specific Th2 response. However, group 2 innate lymphoid cells (ILC2) was recently reported to be initated by the epithelial cell-derived cytokines and play the key role in the allergic airway inflammation via producing a lot of canonical type 2 cytokines IL-5,13. We firstly reported that mesenchymal stem cells (MSC) derived from induced pluripotent stem cells (iPSC) prevented allergic airway inflammation, decreased the levels of IL-5 and IL-13. However, the effects of iPSC-MSC on ILC2 is still unclear. We previously found that the ILC2 precentage was more higher in AR and asthma mice compared to normal control mice. However, iPSC-MSC treatment dramaticlly decreased ILC2. It indicates that ILC2 may be a novel mechanism of allergic airway inflammation and may be the new target for the treatment. This project will use co-cell culture system and a mouse model of AR and asthma to investigate (1) ILC2 expression in AR patients and animals; (2) the role of ILC2 in the allergic airway inflammation via transplanting ILC2; (3) the immunomodulation of iPSC-MSC on ILC2 and the possible mechnism via normal and Rag-/- mice; (4) the relationship between ILC2 and epithlial cells. This project will be provide a new target with ILC2 to treat allergic airway inflammtion in the future.

变应性鼻炎(AR)和哮喘经典发病机制为获得性免疫的Th2优势，但近期报道II型固有淋巴细胞（ILC2）起着等同甚或更强的作用，其可经受损上皮细胞刺激而暴发性地分泌Th2型细胞因子IL-5、13进而引发一系列级联反应。我们首次报道了iPSC来源的间充质干细胞（MSC）可有效抑制AR及哮喘炎症，下调IL-5、13水平，但其对ILC2的作用尚未知。我们前期发现AR及哮喘小鼠ILC2比例显著上调，而iPSC-MSC处理后又显著下调，这提示ILC2在AR发病中起重要作用且可能是MSC的作用靶点。本课题拟应用细胞共培养及小鼠AR和哮喘模型系统探讨ILC2的表达；过继输注ILC2探讨其在变应性炎症发病中的作用；应用正常及免疫缺陷小鼠明确iPSC-MSC对ILC2的免疫调节作用及具体的分子机制；明确ILC2与上皮细胞的关系，以为将来AR及哮喘的防治提供新的有效的靶点，具有重要的理论创新性及潜在的临床应用性。

固有II型淋巴细胞（ILC2s）及其在气道变应性疾病（主要为变应性鼻炎和哮喘）中的免疫调控作用是当今研究的热点问题。本课题研究发现固有II型淋巴细胞（ILC2s）在变应性鼻炎和哮喘患者的外周血中均表达升高，且与TH2型细胞因子水平（以IL-13为代表）呈现线性关系。进一步的我们采取体外培养刺激细胞的体系，发现变应性鼻炎和哮喘患者的外周血单个核细胞和经过流式分选提纯后的ILC2s细胞均能在上皮细胞来源的细胞因子（以IL-2/25/33为代表）刺激下爆发性分泌TH2型细胞因子（主要为IL-5和IL-13）。而激素对于变应性呼吸道疾病的转归临床证明是有效的，我们发现激素可以抑制变应性鼻炎和哮喘患者的外周血单个核细胞和纯化后的ILC2s细胞分泌TH2型细胞因子（主要为IL-5/9/13），且此种抑制作用是通过激活MEK/JAK-STAT细胞通路来实现的。以上的研究为变应性呼吸道疾病的发病机制提出了新的致病因素和治疗靶点，为临床上对于变应性呼吸道疾病的精准治疗提供了理论依据，具有临床转化的前景。