II型固有淋巴细胞通过T细胞非依赖途径在特发性肺纤维化中的作用及细胞和分子机制研究

Idiopathic pulmonary fibrosis (IPF) is a devastating treatment-refractory interstitial lung disease of unknown origin. Type 2 cytokines (IL-5, IL-13) secreted from type 2 helper T (Th2) cells were considered as key factors in the pathogenesis of IPF. Recently discovered type 2 innate lymphoid cells (ILC2s) have been showed its ability to mediate numerous type 2 cytokine related diseases, and our previous work also showed it could play a pro-fibrotic role in lung fibrosis model by producing IL-13. But whether adaptive or innate immune response mediates IPF pathogenesis is unknown. The hypothesis of this study is ILC2s could promote T-cell independent lung fibrosis by directly (cell-cell contact) or inderectly (paracrine) activating other fibrosis related cells. This study plan to investigate the role of ILC2s in IPF using co-culture of ILC2s with macrophage/fibroblast and differences of Rag-/- and WT mice in the bleomycin-induced mice lung fibrosis model. The goal of this study is to understanding the mechanisms and functions of ILC2s in IPF, especially ILC2s activate other fibrotic cells whether through paracrine or cell-cell contact. Also improving understand the underlining mechanisms of IPF, determine whether innate or adaptive immune response mediates fibrotic diseases. Finally, this study is to improving the overall understanding of immune system, providing new therapeutic strategy for fibrotic diseases.

特发性肺纤维化（IPF）是一种病因未明，发病机制不清，预后极差的慢性疾病。以往认为获得性免疫系统的T细胞分泌的II类细胞因子在该疾病的病理损伤过程中发挥主导作用。但是II型固有淋巴细胞（ILC2s）的发现及其免疫学功能的新近研究成果对获得性免疫应答在IPF疾病发展中的作用提出了挑战。申请者的前期工作已发现：肺泡上皮细胞损伤后产生的IL-33诱导ILC2s参与了肺纤维化的生成。因此，申请者推测ILC2s通过间接（分泌细胞因子）或直接（细胞间接触）激活其它免疫细胞从而在IPF发病过程中起主导作用。本研究分别从IPF患者血液样本与小鼠肺组织中提取ILC2s，分别与巨噬细胞和成纤维细胞共培养，测定ILC2s是以间接或直接方式激活以上两种细胞；利用T细胞缺陷（Rag-/-）鼠体内实验，综合探讨IPF发病过程中固有免疫应答的作用。最终阐明免疫应答在IPF疾病发展中的作用机制，为纤维化的治疗提供新线索。

特发性肺纤维化（IPF）等肺部慢性疾病是病因尚不十分清除，发病机制不清，预后极差的慢性疾病。以往认为获得性免疫系统的T细胞分泌的II类细胞因子在该疾病的病理损伤过程中发挥主导作用。但是II型固有淋巴细胞（ILC2s）的发现及其免疫学功能的新近研究成果对获得性免疫应答在IPF疾病发展中的作用提出了挑战。研究者的前期工作已发现：肺泡上皮细胞损伤后产生的IL-33诱导ILC2s参与了肺纤维化的生成。本研究分别从IPF患者血液样本与小鼠肺组织中提取ILC2s，发现了过度活化的ILC2s与这些疾病的发生有关，过度活化的ILC2s可以诱导II型免疫应答，从而激活包括Th2型T细胞、M2型巨噬细胞等的免疫细胞，这些免疫细胞可以通过分泌细胞因子和细胞间接触等方法激活成纤维细胞，造成肺部纤维化病变。本研究还发现了，维生素A等营养素摄入的失衡，免疫系统会增强其II型免疫应答，对与肺纤维化、哮喘等肺部慢性疾病的发生和发展起到重要作用。综上，本研究不但探讨了免疫应答在肺部慢性疾病中的作用，还发现了营养素失衡对于这些疾病的可能影响，为这类疾病的预防和治疗提出了新的实验证据。