异基因脂肪干细胞对狼疮鼠Th17淋巴细胞亚群的调节效应及其机制的研究

Stem cell therapy is a new treatment for autoimmunity diseases.It's a promising treatment that could cure the refractory autoimmunity diseases.By co-culturing adipose-derived stem cells(ADSCs) and peripheral blood mononuclear cells(PBMCs) of patients with active lupus in vitro,we found that allogeneic ADSCs of early passage can downregulate the proportion of Th17 lymphocytes and their abilities to produce IL-17 through cell-cell contact and blocking the functional pathway of IL-23.These results suggest that allogeneic ADSCs of early passage have the potential to be employed in SLE therapy. To shed light on the mechanism of immunoregulation of ADSCs and collect experimental prooves for mesenchymal stem cells therapies, an in vivo experiment is needed to conform the results and look for more precise mechanism. In the present study, we try to investigate and compare the effect of allogeneic ADSCs from different passages on Th17 lymphocyte subset of lupus mice in vivo by ADSC transplantations,and find out its mechanisms.As long as the effect and security of ADSC transplantion in lupus mice were analysed, proportions of Th17 in spleen cells and concentrations of IL-17 in plasma were measured. To investigate the mechanism, concentrations of key cytokines, cell receptors and transcription factors in the differentiation/regulation program of Th17 were analyzed.

干细胞治疗是目前治疗自身免疫性疾病的一个新方向，有望治愈各种慢性、难治性自身免疫性疾病。我们通过细胞体外共培养发现：低代数异基因脂肪干细胞能通过细胞间接触、抑制IL-23功能轴而抑制狼疮患者外周血中Th17淋巴细胞亚群的比例及功能，提示脂肪干细胞具有被应用于红斑狼疮治疗的潜力。然而,脂肪干细胞在红斑狼疮体内是否能发挥相同的作用，其具体机制如何，目前尚不明确。本课题在前期研究的基础上，拟通过对发病期狼疮鼠分别输注不同代数同种异基因脂肪干细胞（移植），评价安全性及疗效的同时，着重观察不同代数脂肪干细胞对红斑狼疮Th17淋巴细胞比例及功能的调节效应。通过检测、比较Th17细胞分化/调控主要细胞因子的浓度及其对应受体的表达、信号传导通路中各转录因子的表达情况，深入探讨相关机制。为阐明脂肪干细胞免疫调节的机制，也为间充质干细胞移植在系统性红斑狼疮治疗中的应用提供实验室依据。

干细胞治疗是目前治疗自身免疫性疾病的一个新方向，有望治愈各种慢性、难治性自身免疫性疾病。本课题在前期研究的基础上，拟通过对发病期狼疮鼠分别输注不同代数同种异基因脂肪干细胞（移植），评价安全性及疗效的同时，着重观察不同代数脂肪干细胞对红斑狼疮Th17淋巴细胞比例及功能的调节效应。通过检测、比较Th17细胞分化/调控主要细胞因子的浓度及其对应受体的表达、信号传导通路中各转录因子的表达情况，深入探讨相关机制。为阐明脂肪干细胞免疫调节的机制，也为间充质干细胞移植在系统性红斑狼疮治疗中的应用提供实验室依据。通过检测狼疮鼠和正常小鼠RORγt、IL-17mRNA提示狼疮鼠肾脏组织RORγt、IL-17mRNA表达量增多，且BATF mRNA的表达量与RORγt、IL-17mRNA表达量呈正相关 [彭宇声，2015]。通过对发病期红斑狼疮动物模型（狼疮鼠）进行P6代同种异基因脂肪干细胞移植脂肪干细胞治疗狼疮鼠可以使IL-17、IL-6分泌下降，下调肾脏组织IL-17mRNA水平，上调Foxp3、ROR-γt、miR-23b mRNA水平，减少TAB 2、IKK-α蛋白的表达[He XL，2016]。结果提示通过异基因脂肪干细胞移植治疗红斑狼疮鼠的安全性及疗效，初步阐释了治疗的机制，为该方法被应用于临床提供实验室证据，具有临床现实意义。