MSCs调控1型调节性T细胞治疗干燥综合征的作用及机制研究

Sjogren's syndrome (SS) is a chronic inflammatory autoimmune disease. The specific mechanism responsible for its pathogenesis remains to be elucidated. Previous studies have suggested that decreased proliferation and differentiation of T regulatory type 1 (Tr1) cells played a vital role on the pathogenesis of SS. Interleukin 27 is the key molecular for the induction of Tr1 cells in vivo. Our recent study showed that the level of IL-27 was significantly decreased and correlated with the disease activity of SS. The results also showed that the Tr1 in labial gland positively correlated with IL-27 levels. Our previous study has demonstrated that mesenchymal stem cell (MSC) transplantation had beneficial effects on the SS model and patients and regulated the Tr1 and IL-27. However, whether the therapeutic effects of MSCs on SS are mediated by inducing Tr1 directly or indirectly through up-regulation of IL-27 remains to be explored. The present program intends to explore this mechanism. To investigate the Tr1-inducing effects of MSCs and its molecular mechanism and to unveil the therapeutic effect of MSCs transplantation on SS, the regulation of MSCs on Tr1 cell differentiation was studied in SS animal model and patients in vivo and in vitro. The results of the present study will expand the novel immune modulation effects of MSCs. This study also may provide evidence for treatment of SS with MSCs.

干燥综合征(SS)是一种慢性炎症性自身免疫病，发病机制尚未阐明。已有报道1型调节性T细胞（Tr1）功能降低是SS发病重要机制；白细胞介素-27（IL-27）是诱导Tr1分化的关键因子。我们的实验发现SS患者IL-27显著降低，并与疾病活动度相关；且唇腺中Tr1数目与IL-27水平也呈正相关。特别是我们前期发现间充质干细胞（MSC）移植可以改善SS症状，且MSC能促进Tr1分化及IL-27水平。可是，MSC是否通过调控IL-27分泌，进而上调Tr1，抑或直接调节Tr1治疗SS尚不清楚。故本项目拟以SS患者为研究对象，并结合MSC移植野生和IL-27敲除SS鼠，探索MSC与IL-27及Tr1细胞的关系，揭示SS发生发展过程中MSC调控Tr1分化的机制，可望解释MSC移植改善SS的机理，并提出治疗SS的新策略。本研究不仅拓展MSC免疫调控功能新理论，还可为MSC临床治疗SS提供依据。

干燥综合征（SS）是一种慢性系统性自身免疫病，主要侵犯唾液腺、泪腺等外分泌腺，典型症状表现为口、眼干燥。SS发病机制至今尚不清楚，而且缺乏有效的治疗手段。间充质干细胞（MSC）通过调节淋巴细胞功能、诱导免疫耐受和抑制自身免疫反应治疗SS等多种自身免疫病。但是，MSC改善SS的具体机制不明。本项目研究了SS患者和模型小鼠中外周淋巴细胞亚群，尤其是1型调节性T细胞（Tr1）、髓源抑制性细胞（MDSCs）、Th17和Treg细胞的变化，并分析了这四种淋巴细胞与SS症状的相关性；检测了MSC移植治疗SS患者和模型小鼠后的Tr1、MDSCs、Th17和Treg细胞变化与疗效的关系；探索了导致SS淋巴细胞失衡和MSC修复淋巴细胞平衡的分子机制。研究结果发现随着患者和模型小鼠的SS症状和病情进展，Tr1和Treg细胞数量下降，而Th17细胞和MDSCs数目增加；MSC移植SS小鼠4周后，唾液流量增加，颌下腺和泪腺中淋巴细胞浸润明显减少；Tr1和Treg细胞数量升高，而Th17细胞和MDSCs数目降低；深入探索SS淋巴细胞失衡和MSC修复淋巴细胞平衡机制，发现SS患者血清白细胞介素-27（IL-27）下降与Tr1和Treg细胞减少及Th17细胞增加相关。IL-27基因敲除的NOD小鼠，唾液流量较野生型减少，颌下腺和泪腺中淋巴细胞浸润增多，伴有Tr1和Treg细胞数目显著减少，致炎性Th17细胞数目明显增多。体外实验表明IL-27促进Tr1和Treg细胞分化和生成，抑制Th17细胞分化。MSC移植SS患者和模型小鼠后，血清IL-27增加，共培养实验结果表明MSC通过分泌IFN-β等促进树突状细胞生成IL-27。本项目的研究结果提示，IL-27通过调节Tr1、MDSCs、Th17和Treg细胞参与SS的发病和进展。MSC通过促进树突状细胞产生IL-27，进而发挥免疫调节功能，最终治疗SS。这些发现不仅具有阐明SS发病的新机制，揭示MSC改善SS新分子机制的理论意义，而且具有为临床SS治疗提供新靶向和推广MSC治疗的实际意义。