二级淋巴器官靶向迁移的CCR7+MSC对B细胞的影响及治疗系统性红斑狼疮的机制

Unfortunately, though lots of evidence show that mesenchymal stem cells (MSC) have potent immunoregulatory capacity in vitro, most of clinical trials of MSCs in immune disease have only met safety endpoints, efficacy has not been demonstrated. The sites of organized lymphoid cell accumulation are termed primary and secondary lymphoid organs (SLOs). SLOs, including spleen (SP), lymphoid nodes (LN), mesenteric lymphoid nodes (MLN), Peyer’s Patches (PP), and so forth, are similarly organized with T cells, B cells, antigen presenting cells, stromal cells as well as a vascular supply. Therefore, SLOs are the niches to generate immune responses or tolerance. The reported work of applicant showed that the infused MSCs/CCR7 tartly migrate to SLOs, relocate in proximity with T lymphocytes, therefore, potently inhibited their proliferation, activation, and cytotoxicity. The infusion of MSCs/CCR7 potently prolonged the survival of GvHD mouse model than normal MSCs. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is known to be associated with polyclonal B-cell hyper-reactivity. B cells are initially activated by T helper cells in SLOs. Therefore, we hypothesis that it is a novel strategy to lead MSCs targeted migrate to SLOs after infusion. This project will further investigate the effect of CCR7+MSC on the B cells, the relationship of CCR7+MSC distribution pattern with T and B cells in SLOs after infusion. The detailed immunoregulatory mechanism of CCR7+MSC on B cells will also be investigated. The result of his study would provide a new method to treat SLE patient clinically.

间充质干细胞（MSC）治疗临床免疫性疾病的统计结果显示：MSC的体内免疫调节效果并不理想。二级淋巴器官结构相似，由T、B、抗原呈递细胞等组成，是体内细胞和体液免疫反应启动的场所。申请人已发表工作首次证明：CCR7+MSC具有二级淋巴器官靶向迁移的特性，可在T细胞免疫的起始阶段发挥近距离高效调节。系统性红斑狼疮（SLE）是典型的B细胞活化为主的体液免疫性疾病，B细胞首先亦是在二级淋巴器官中通过T细胞依赖途径活化的。因此，我们设想：MSC输注后的靶向性二级淋巴器官迁移是提高MSC治疗SLE更为有效的途径。本课题拟进一步考察CCR7+MSC对B细胞的影响；利用体内示踪、外源细胞定量技术考察输注后的CCR7+MSC在SLE小鼠二级淋巴器官中与T、B细胞的时空动态分布规律；并进一步探索CCR7+MSC体内对B细胞体液免疫调节的关键途径及生物学机制。本研究有望为提高MSC治疗SLE效果提供新思路。

间充质干细胞（MSC）治疗临床免疫性疾病的统计结果显示：MSC输注后的体内免疫调节效果并不理想。二级淋巴器官（SLOs）结构相似，由T、B、抗原呈递细胞等组成，是体内细胞和体液免疫反应启动的场所。申请人已发表工作首次证明：CCR7+MSC具有SOLs靶向迁移的特性，可在T细胞免疫的起始阶段发挥近距离高效调节。血管化复合同种异体移植（VCA）是由T淋巴细胞介导的免疫排斥反应。人脂肪干细胞（hASCs）具有简便易行、免疫调节能力强等优点，但其在VCA中的治疗效果目前尚不明确。趋化因子受体7（CCR7）能特异性地引导免疫细胞向SLOs迁移。慢病毒转染获得hASCs/CCR7和hASCs/GFP。hASCs/CCR7具有多种分化和免疫调节能力，但获得二级淋巴器官趋化因子（SCL）（CCR7配体）诱导的体外迁移能力。值得注意的是，静脉注射的hASCs/CCR7靶向地重新定位在SLOs的T细胞区。在大鼠VCA模型中，hASCs/GFP输注对移植血管复合物的影响很小,然而，hASCs/CCR7能显著延长移植物的存活时间。观察其病理改变及外周血炎性细胞因子的变化,Th1/Th2和Treg/Th17轴在SLOs中的改变可能是下调的排斥反应的基础。此外，脾脏T淋巴细胞的蛋白组学结果也证实hASCs/CCR7降低了与胞质分裂、淋巴细胞增殖、分化和凋亡过程的相关蛋白。我们的研究表明hASCs/CCR7向SLOs的靶向迁移增强了体内免疫调节作用，希望这种SLOs靶向策略在免疫性疾病治疗中发挥强大作用。我们亦围绕MSC对B细胞的影响及机制展开系列研究。在MHC完全不匹配的小鼠aGvHD模型中，我们发现MSC共转移显著延长了受者的存活时间。更有趣的是，MSC移植抑制脾细胞表面CD69（早期激活标志物）和CD86（共刺激分子）的表达下降，且主要为供体来源的B淋巴细胞。此外，B淋巴细胞IL-4的mRNA水平下降，而IL-10增加，这可能是B淋巴细胞活性降低的原因。宿主B淋巴细胞去除，无论是否给予MSC，均能进一步延长aGvHD小鼠的存活时间。因此，B淋巴细胞在aGvHD的发生发展中起重要作用，是MSC调节免疫应答的靶细胞体内级联，本研究可为人类临床aGvHD的治疗提供一定的机制线索。

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