新型双抗关节炎分子共表达系统介导CTLA4-FasL和TNFR-Fc协同抗类风湿关节炎效应及机制研究

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。