IFN-γ通过上调IL4I1表达增强MSC免疫调节功能在类风湿关节炎治疗中的作用及机制研究

类风湿关节炎（RA）是因免疫失衡导致的最常见的炎性风湿病。前期研究发现间充质干细胞（MSC）移植治疗RA安全且有效，且MSC+IFN-γ联合治疗策略可进一步提高疗效。IL4I1在抑制机体适应性免疫中发挥重要作用，然而对于其在MSC移植治疗RA中的作用和机制尚缺乏研究。预实验发现IFN-γ可诱导MSC高表达IL4I1，干扰IL4I1的表达会削弱MSC抑制T细胞增殖的能力，提示IL4I1在MSC免疫调节功能中发挥重要作用。因此，本项目提出“IFN-γ通过STAT/NF-B上调IL4I1表达，进而参与MSC抗炎和免疫调节功能，介导MSC移植恢复RA患者T细胞及其功能亚群平衡并抑制机体炎症反应”的假设。为证实此假设，本研究拟应用IL4I1敲除MSC，从分子、细胞和动物水平，探索IL4I1在IFN-γ增强MSC免疫调节功能及其移植治疗RA疗效中的作用及机制，为提高MSC的临床疗效提供新的理论支撑。

Rheumatoid arthritis (RA) is the most common inflammatory rheumatic disease caused by immune imbalance. Previous studies have found that mesenchymal stem cell (MSC) transplantation is safe and efficacy in the treatment of RA, and its efficacy can be further improved with MSC+IFN-γ combined therapy strategy. Interleukin 4 inducible gene 1 (IL4I1) plays an important role in inhibiting adaptive immunity. However, the function and mechanism of IL4I1 in the treatment of MSC transplantation for RA remain largely unknown. Our previous study found that IFN-γ induced a significantly upregulated of IL4I1 in MSCs, interfering the expression of IL4I1 weakened the ability of MSC to inhibit T cell proliferation, suggesting that IL4I1 plays an important role in the immunomodulatory capacity of MSC. Therefore, we propose the hypothesis that “IFN-γ upregulates the expression of IL4I1 through STAT/NF-kB pathway, which involved in the anti-inflammatory and immunomodulatory functions of MSC and mediated the transplantation of MSC to restore the balance of T cells and their functional subsets and inhibit the inflammatory response in RA patients”. To prove this hypothesis, this study intends to use IL4I1 knock-out strategy to clarify the role of IL4I1 in IFN-γ enhancing the immunomodulatory function and the efficacy of MSC in the treatment of RA, in order to provide new theoretical support for improving the clinical efficacy of MSCs.