C5a/C5aR补体途径在间充质干细胞治疗cGVHD中的作用机制

间充质干细胞(MSC)独特的免疫特性使其成为防治慢性移植物抗宿主病(cGVHD)的新曙光，但其免疫调节机制尚不明确。研究报道Th17、调节性T细胞(Treg)比例失衡是许多免疫疾病和移植排斥病理新机制；且C5a/C5aR是Th17、Treg细胞分化的核心途径。申请人所在团队在国际上较早观察MSC治疗cGVHD的效果，发现cGVHD患者C5a表达上调、Th17/Treg失衡；而MSC治疗后C5a表达下降、Th17/Treg失衡缓解，cGVHD好转。由此提出MSC通过阻断C5a/C5aR途径，调控Th17/Treg比例，从而抑制cGVHD的新假说。在前期工作基础上，本项目拟结合临床样本和体内外模型深入研究C5a/C5aR的表达与cGVHD的相关性；明确MSC在cGVHD中的调控作用是否是经C5a-C5aR通路介导Th17/Treg平衡。这将有助于揭示MSC免疫调节机制，开拓临床应用MSC新策略

Mesenchymal stem cell (MSC) is charactered by its special immunoregulation and becomes a promising treatment for chronic graft-versus-host disease (cGVHD). However, the immunoregulative mechanism of MSC remains unclear. Emerging evidences demonstrated that the imbalance of Th17 and Treg cells is the main orchestra leader in many immune diseases and transplant rejection. The complement pathway of C5a/C5aR plays a central role in polarizing CD4+T cell differentiate to Th17 or Treg. Our group is one of few groups to evaluate the efficacy and safety of MSC in cGVHD. We found that the expression of C5a is upregulated, along with the proportion of Th17 cells increased and Treg cells decreased in cGVHD patients compared with non-cGVHD patients. Importantly, the expression of C5a decreased after MSC treatment, companied with less Th17 cells and more Treg cells, indicating that MSC may regulate the C5a expression and the proportion of Th17 and Treg cells. Based on our previous work, we hypothesize that "MSC may down-regulated the expression of C5a, which then regulates the balance of Th17 and Treg cells, resulting in alleviation of cGVHD". In this study, we plan to use samples from patients with cGVHD together with in vitro and in vivo models to investigate the expression of C5a/C5aR in cGVHD; the possibility of MSC to inhibit C5a/C5aR and regulate the balance of Th17/Treg in cGVHD. The outcome of this study will not only provide new insight into mechanisms of pathogenesis of cGVHD, but may also lead to better therapeutic opportunities of MSC for the treatment of cGVHD.