肾脏固有细胞诱导Th22细胞分化和募集在肾脏炎症损伤中的作用

It is generally accepted that CD4+ T helper (Th) cell-mediated immunity can contribute to renal inflammatory injury. In our previous studies, we found that in the process of renal injury induced by hemolytic streptococcus, renal tissue can secrete cytokines that induced the differentiation of IL-22-producing helper T(Th22) cells and chemokines that promoted the recruitment of Th22 cells. However, the exact pathogenesis and the relationship between Th22 cells and cytokines/chemokines in renal inflammation are unknown. We supposed that resident renal cells may stimulate the differentiation of Th22 cells via antigen presentation and recruit Th22 cells infiltrating to kidney through a chemokine pathway. In order to verify the view above, we intend to do the following: (1) Test the cytokines, chemokines and T-helper subgroup in IgA nephropathy patients, and observe their relationships. (2) Establish an experimental model of IgA nephropathy, and treat them with chemokine antibody to identify if the recruitment of Th22 cells to kidney depending on chemokine pathway. (3) Treat the resident renal cells infected by hemolytic streptococcus with anti-CD80/CD86, CTLA-4Ig and chemokine antibody respectively, and verify the hypothesis that the resident renal cells induce Th22 cells differentiation through antigen presentation, and recruit Th22 cells infiltrating to kidney through a chemokine pathway. This study will clarify the immunological regulation mechanism of Th22 cells involved in the development of renal inflammation, and find new targets to treat the disease.

CD4+T细胞在肾脏炎症损伤中的作用已逐渐被认识。我们在研究链球菌感染诱发肾脏损伤过程中发现，肾组织能够分泌具有诱导Th22细胞分化和募集的细胞因子及趋化因子，但具体机制不清楚。据此推测在肾炎状态下肾脏固有细胞可能通过抗原递呈作用诱导Th22分化并以趋化因子途径募集外周血Th22浸润到肾组织。为证实该假说，本项目拟开展以下工作：1）检测IgA肾病患者体内细胞因子、趋化因子及Th细胞亚群，并明确三者关联；2）建立IgA肾病小鼠模型，用趋化因子抗体干预，检测趋化因子对Th22的趋化性，明确Th22被募集到肾组织是否依赖于趋化因子途径；3）用CD80/CD86抗体或CTLA-4Ig及趋化因子抗体分别干预链球菌感染的肾脏固有细胞，验证这些细胞是否通过抗原递呈作用诱导Th22分化及趋化因子途径动员Th22浸润到肾组织。本项目的完成将阐明Th22参与肾脏炎症损伤的免疫机制，为其防治提供可能的作用靶点。

在前期“链球菌感染诱发肾脏损伤过程中，肾组织能够分泌具有诱导Th22细胞分化和募集的细胞因子及趋化因子”研究的基础上，本项目进一步探讨肾炎状态下肾脏固有细胞可能通过抗原递呈作用诱导Th22分化并以趋化因子途径募集外周血Th22浸润到肾组织的肾损伤机制。开展了以下工作：1）完成了IgA肾病患者外周血和肾组织中细胞因子、趋化因子及 Th 细胞亚群检测，并分析三者间存在的关联；2）建立了IgA肾病小鼠模型，用趋化因子抗体干预，检测趋化因子对Th22的趋化性，明确了Th22被募集到肾组织是否依赖于趋化因子途径；3）建立了链球菌感染肾小球系膜细胞参与作用机制的体外模型，用趋化因子和相关抗体进行干预，检测趋化因子对 Th22的趋化性，通过以上研究，证明了在肾炎状态下肾脏固有细胞可能通过抗原递呈作用诱导Th22分化并以趋化因子途径募集外周血 Th22 浸润到肾组织，导致肾损伤的学说，4）在本课题研究的基础上，项目组还拓展研究，进一步深入探讨中药地黄叶中主要成分毛蕊花糖苷、地塞米松及冬虫夏草在IgA肾病治疗中可能作用及机制，通过临床观察及体外IgA肾病细胞模型研究证实三者均分别可缓解IgA肾病尿蛋白排泄及肾脏炎症损伤；通过本组研究，证明在肾炎状态下，肾脏固有细胞可能通过抗原递呈作用激活CTLA4-CD80/86诱导Th22分化，并通过CCL20/CCR4、CCL22/CCR6、CCL27/CCR10趋化因子途径，募集外周血Th22 浸润到肾组织导致肾损伤的假说，为临床防治IgA肾病提供可能的作用靶点同时也阐明中药地黄叶及经典临床用药激素及冬虫夏草治疗可有效缓解肾脏炎症损伤的药理机制，为其在慢性肾脏疾病的治疗提供了充分的现代医学依据。.本研究共撰写12篇论文，已公开发表11篇。部分研究成果在ASN、CSN及APCN会议上发言或壁报交流并获得优秀壁报奖；课题组培养研究生5名（已毕业博士2名，硕士2名，在读博士生1名）。后续，本课题组将认真整理所有研究内容与资料，拟申报省部级科技成果奖和参与国家重点科研基金项目申报。