MSC外泌体经miR-27b/IRF4轴调控Tfh/Tfr细胞稳态治疗cGVHD的作用及机制研究

MSC免疫调节双向性导致其治疗cGVHD的临床疗效不稳定，而MSC来源的外泌体(MSC-exo)具有安全、稳定、标准化优势，是一种更具潜力的无细胞生物治疗新模式。我们前期应用MSC-exo可有效缓解cGVHD小鼠病理损伤。另外，预实验发现Tfh↑/Tfr↓细胞失衡是cGVHD免疫损伤新的重要病理机制。由此，提出本项目科学问题：MSC-exo是否及如何调控Tfh/Tfr细胞平衡缓解cGVHD？IRF4转录因子被认为是Tfh/Tfr细胞失衡的关键基因，我们前期通过芯片分析发现MSC-exo富含miR-27b，而miR-27b具有调控IRF4潜能。因此，本项目拟通过体内外研究，探索并验证如下新假说：MSC-exo经miR-27b/IRF4轴调控Tfh/Tfr细胞平衡，发挥免疫调节功能，减缓cGVHD的病理进程。研究成果将为MSC-exo免疫制剂治cGVHD奠定理论与应用基础，拓展防治新途径。

Mesenchymal stromal cells (MSC) is a promising therapy for Chronic graft versus host disease (cGVHD) treatment but still face the challenge of unstable clinical efficacy due to the dual effect of immunomodulation. However, the exosome derived from MSC (MSC-exo) exhibits better stability, safety and standardization advantages, representing a new type of cell-free biological therapy with more potential. Our previous application of MSC-exo can effectively alleviate pathological damage in cGVHD mice. In addition, our preliminary data showed that the imbalance of Tfh and Tfr cell with upregulated Tfh and downregulated Tfr ones is an important pathological feature of cGVHD. Therefore, we propose the key scientific question of this project as below: Whether and how does MSC-exo regulate the balance of Tfh and Tfr cell and prevent cGVHD? Our previous microarray analysis showed that MSC-exo is rich in miR-27b, and miR-27b has the potential to regulate IRF4, one transcription factor considered to be a key gene of imbalance of Tfh and Tfr cell. Therefore, this project intends to explore and verify the new hypothesis through in vivo and in vitro studies: miR-27b enriched in MSC-exo could regulate the balance of Tfh and Tfr cell via targeting IRF4, preventing the pathological process of cGVHD. The expected results will provide evidence to expand new ways of cGVHD treatment and lay the theoretical and application basis for MSC-exo treatment of cGVHD.