艾拉莫德抑制系统性红斑狼疮浆细胞成熟及功能的机制研究

Iguratimod is a novel small molecular drug, being proved with multiple immunomodulatory effects. In our previous study for rheumatoid arthritis both basically and clinically, we found an inhibitory effects of this drug on humoral immunity. Then we chose another disease model characterized by highly activated B cells and a spectrum of autoantibody, systemic lupus erythematosus, to further investigate its mechanism. Through MRL/lpr mice with spontaneous lupus-like disease, we found that iguratimod could reduce plasma cell, especially mature plasma cell in the mice, as well as antibody levels both in sera and tissue, and thus ameliorate immune nephritis in these mice. However, no significant decrease in total B cell or activated B cell were observed, which are the upstream of plasma cell differentiation; also, no significant suppressive effects on B cell proliferation or apoptosis were found in vitro. According to these data, we infer that iguratimod may have inhibitory effects on maturation of plasma cells or function of them when they get matured. Hence we designed a study to investigate mechanism of inhibition on plasma cells by iguratimod through molecular, cellular and systemic aspects, using human peripheral blood, MRL/lpr mice with spontaneous lupus like disease and blood samples from SLE patients receiving iguratimod treatment. We hope that this study would provide a theoretic fundamental for an effective and economic new therapy for autoimmune diseases.

艾拉莫德是一种新型的小分子DMARD，被证明有多重免疫调节作用。本课题组在前期的类风关研究中发现此药可有效抑制体液免疫，遂以此为出发点，选择以B细胞异常活化及自身抗体为特征的SLE为疾病模型进一步研究其机理。我们利用自发狼疮MRL/lpr小鼠，发现艾拉莫德能够降低其浆细胞、特别是成熟浆细胞的比例，显著降低组织与体液中抗体水平，改善免疫性肾炎，但对浆细胞上游的B细胞数量、增殖凋亡及活化B细胞比例均无明显影响。故我们推测对浆细胞的成熟及功能的抑制可能是艾拉莫德抑制浆细胞的原理。据此本研究计划采用人外周血B细胞体外诱导分化、成熟浆细胞、MRL/lpr小鼠类狼疮样疾病及SLE患者，从分子、细胞、及整体水平研究艾拉莫德对浆细胞成熟及功能的作用机制，初步阐明艾拉莫德抑制浆细胞的机理。鉴于浆细胞正在成为自身免疫病治疗的新热点，本研究将为探索有效而经济的新治疗方案奠定理论基础。

艾拉莫德是一种新型小分子免疫调节剂，现在的研究已证明此药具有多种免疫调节功能，目前批准用于类风湿关节炎的治疗。鉴于 RA 和 SLE 具有包括自身抗体在内的多种共同发病机制，我们推测艾拉莫德对 SLE 可能亦存在治疗作用。本研究选择MRL/lpr 小鼠，系统观察了艾拉莫德对其的治疗作用，并初步探讨了这个药物在此模型中可能的作用机理。同时在体外细胞模型中验证该药物对浆细胞分化成熟的影响和作用机制。结果提示：艾拉莫德可缓解 MRL/lpr 小鼠类狼疮样疾病，其机制可能通过非抗增殖的方式纠正 MRL/lpr 小鼠异常的 B 细胞分化功能发挥作用。体外研究中发现艾拉莫德对人浆细胞分化功能有显著的抑制作用，其具体体制可能通过抑制上游的EGR1来抑制Blimp1来发挥功效。本研究的结果提示艾拉莫德可能用于治疗狼疮等其他免疫疾病，为该类疾病探索出治疗新策略。