类风湿关节炎（RA）发病机制复杂，其中TNFα和自身反应性T细胞发挥了关键作用。抗TNFα生物制剂在RA治疗中已取得较大成功，但其治疗作用仍存在局限性，因此迫切需要改进的治疗方法。已有研究提示，拮抗T细胞可增强TNF抑制剂的抗炎作用。为此，我们前期构建了对T细胞具有双重抑制功能的CTLA4-FasL分子，首次报道了其抗关节炎作用以及抗炎效果强于单独FasL分子。为进一步获得同时拮抗TNF和T细胞、因而更具抗炎优势的重组表达系统，我们创建了介导TNFR-Fc和CTLA4-FasL独立共表达的新型双抗炎分子表达系统。应用该系统和已建立的RA动物模型，本项目旨在明确CTLA4-FasL和TNFR-Fc协同抗关节炎效果、揭示二者协同作用的体内细胞与分子机制，并由此提出CTLA4-FasL联合TNF抑制剂协同治疗RA的新思路，同时推出自主知识产权、新型高效重组表达系统，为治疗RA提供新策略和新选择。

The pathogenesis of rheumatoid arthritis (RA) is complex, among which TNFα and autoreactive T lymphocytes are believed to play vital roles. Though having gained an undoubted success in the treatment of RA, TNFα blocking agents are limited in their therapeutic effectiveness and therefore there is a compelling need to continue identification of improved therapeutic strategies. Several studies provide a hint for us that antagonizing T lymphocytes can produce enhanced benefit of TNF antagonists in suppressing arthritis. For this purpose, we previously constructed the CTLA4-FasL fusion product, a bifunctional inhibitory molecule against T cells, and then firstly demonstrated that CTLA4-FasL efficiently prevents animal arthritis and is superior to FasL alone in blocking the progress of arthritis. To further obtain the recombinant expression system with more antiinflammatory advantages by antagonizing both TNF and T cells, we established a novel expression system of two antiarthritic molecules, mediating the separate coexpression of TNFR-Fc (a desirable TNF inhibitor) and CTLA4-FasL. Using the expression system and established animal model of RA, the project is aimed to make sure the synergistically antiarthritic effects produced by the combination of CTLA4-FasL and TNFR-Fc, reveal the in vivo cellular and molecular mechanisms based upon the combined usage, and thus put forward an innovative idea for synergic treatment of RA by using CTLA4-FasL combining with TNF inhibitors, and at mean while a novel recombinant expression system with our own intellectual property right and competitive advantages, providing a new strategy or choice for the treatment of RA.

类风湿性关节炎(rheumatoid arthritis ,RA)是一种主要累及关节的慢性自身免疫性疾病，由于不明原因的致病因素，使得自身免疫系统紊乱，导致活动关节内炎性细胞浸润和滑膜增生，引起关节软骨和骨的侵蚀和破，有些病人还会累及全身多个系统。RA在全球的患病率约为0.5~1%，我国患病率约为0.3%，有400~500万RA病人罹患病痛之苦。RA的临床特点是滑膜慢性炎症而导致关节软骨破坏，关节周围骨质侵蚀和永久性畸形，并伴有发热、淋巴结和脾肿大，皮肤溃疡等全身症状。由于RA是一种慢性消耗性疾病，随着疾病的发展，会出现身体衰弱，体重减轻等症状，严重影响病人的生活质量和预期寿命，如果不经治疗，大概有80%的病人会逐渐丧失生活能力，给家庭和社会带来严重危害，因此寻找RA有效的治疗方法是研究人员亟待解决的问题,本研究通过观察双融合分子在关节炎大鼠体内的治疗作用以及相关分子机制研究创新性研制出一种融合分子疫苗，从而为RA治疗提供一种新思路和新选择。