IL-23/IL-23R-γδ T--Th17/Treg轴致儿童原发肾病综合征（PNS）发生、发展的新机制

Primary nephrotic syndrome (PNS) is the most important etiology of children with chronic renal failure in China. Immuno-inflammation is the fundamental pathological processes of PNS in children, which also play an important role in kidney injury and even contribute to the progression of glomerulosclerosis and subsequent chronic renal failure. Previous studies by our group (NO:81070563, completed) have confirmed that the imbalance of Th17/Treg was an important immune mechanism of the occurrence and development of PNS in children, and abnormal activation of IL-23?Th17/IL-17 axis in regional kidney was closely associated with the sensitivity of glucocorticoid treatment, pathological types, and prognosis in children with PNS. At present, it is unclear that the sources of IL-17 in reginal kidney and the immune mechanism of predominant activation of IL-23-Th17/IL-17 axis. However, most recently, our group find that circulating frequencies of IL-23R+ γδ T cell cells is higher in the PNS than in the normal children. Keep in step with recent research progress and the existing research findings by our study group, we put forward a scientific hypothesis: abnormal activation of γδ T cell mediated by IL-23-IL-23R signaling pathway is an important immune mechanism in early stage of PNS in children, which also an upstream signaling pathway lead to imbalances in Th17/Treg. In this study, using mice model with adriamycin nephropathy, T-cell receptor δ knockout (TCR δ-/-) mice and renal biopsy specimens of children with PNS, we will show that the upstream of immune response as a new perspective to thoroughly expound the mechanism of occurrence, development, and progressive kidney damage of PNS in children. It will provide an opportunity to exploit a novel therapeutic strategies for immune-mediated pathological damages in early stage, and prevent or slow down the progression to glomerulosclerosis in PNS.

原发性肾病综合征(PNS)是我国儿童慢性肾衰竭的重要病因。本课题组已证实Th17/Treg免疫失衡、IL-23－Th17/IL-17轴异常活化是儿童PNS发病的重要机制。但目前对于肾脏局部IL-17来源及IL-23-Th17/IL-17轴优势活化的途径及机制尚不清楚；新近本研究组在儿童PNS初发期外周血发现IL-23R+γδT细胞水平上调，提示γδ T细胞参与PNS早期发病。紧密结合研究进展及本课题组现有研究，我们提出：IL-23/IL-23R通路介导γδ T细胞异常活化是儿童PNS早期发病的重要免疫机制，同时是启动儿童PNS Th17/Treg免疫失衡的上游信号通路。本项目拟用TCRδ敲除小鼠、阿霉素肾病模型、PNS肾标本等进行体内外实验，以新的视角从免疫应答上游为研究出发点，深入阐释儿童PNS发生、发展及肾脏进行性损害的免疫学机制，最终为改善其预后提供新的干预靶点及治疗途径。

原发性肾病综合征(PNS)是我国儿童慢性肾衰竭的重要病因。本课题组已证实Th17/Treg 免疫失衡、IL-23－Th17/IL-17 轴异常活化是儿童 PNS 发病的重要机制。但目前对于肾脏局部IL-17 来源及IL-23—Th17/IL-17 轴优势活化的途径及机制尚不清楚；本研究组前期在儿童 PNS 初发期外周血发现 IL-23R+γδT 细胞水平上调，提示γδ T 细胞参与 PNS早期发病。紧密结合研究进展及本课题组现有研究，我们提出科学假说：IL-23/IL-23R 通路介导γδT 细胞异常活化是儿童 PNS 早期发病的重要免疫机制，同时是启动儿童 PNS Th17/Treg 免疫失衡的上游信号通路。.本项目采用阿霉素肾病、TCR δ敲除小鼠、不同病理类型儿童PNS外周血、肾标本等进行体内外实验，得到以下结论：1.IL-23/IL-23R-γδT-Th17/Treg轴参与早期阿霉素肾病的发生与发展，是阿霉素肾病发生发展的重要机制通路之一。早期足量应用强的松治疗可通过干预IL-23/IL-23R-γδT-Th17/Treg轴发挥肾脏保护作用。2. L-23/IL-23R-γδT-Th17/Treg轴参与了儿童不同病理类型PNS的发生与发展，是儿童PNS发生发展的重要机制通路之一。通过干预IL-23−IL-23R信号通路可影响γδT细胞活化及功能，进而调控儿童PNS下游Treg/Th17细胞免疫平衡。3. γδT细胞可通过CD28/B7-1激活足细胞内phosphor-SRC激酶通路导致足细胞损伤。CTLA4-Ig可通过阻断CD28/B7-1的相互作用从而减轻足细胞的损伤。.综上所述，本项目研究发现IL-23−IL-23R信号通路是影响γδ T细胞活化及免疫调节功能的关键，进而参与儿童PNS早期免疫性炎症发生及下游Th17/ Treg细胞免疫失衡的启动；而通过干预IL-23−IL-23R信号通路调控γδ T细胞功能状态，可以有效减轻或延缓儿童PNS肾脏进行性损害，进而为临床提供新的干预靶点及治疗途径。