抗IL-6Rβ(gp130)功能域单抗干预CAIA模型小鼠的分子学机制研究

The aims of this study are using anti-collagen II domain antibody induced RA liked mouse model (CAIA) and RANKL induced osteoclast precursor to osteoclast differentiation method to analyse the immunopathology mechanism of CAIA presented the IL-6Rβ(gp130)-RANKL-WNT5A signaling pathway under immune dysfunction by many pro-inflammatory factors, which the abnormal osterolcast activation in mouse model towards to bone metabolism imbalance.To reveal the roles of IL-6Rβ(gp130)-RANKL-WNT5A signaling pathway in RA development, the anti-IL-6Rβ(gp130) mAbs（Proprietary intellectual property rights） would be used to inhibit the positive feedback regulations that are associated with immune dysfunction and bone metablolic problems in RA like mouse model.This study would provide sufficient experiment data and possibly a new theory of IL-6Rβ(gp130)-RANKL-WNT5A pathway. The IL-6Rβ(gp130) mAbs would be used as a new drug for potential RA treatment and also as a tool to research RA immune dysfunction and bone metabolic imbalances in common autoimmune diseases.

本申请旨在应用由抗胶原Ⅱ功能域抗体诱导建立的类风关（RA）样模型小鼠(CAIA)和由RANKL介导其破骨细胞前体细胞分化技术；分析RA样模型小鼠免疫功能紊乱所呈现出众多促炎因子，特别是IL-6Rβ-WNT5A-RANKL信号通路的紊乱，致使RA样模型小鼠破骨细胞功能异常活化，从而导致其骨代谢失衡的免疫病理学机制。揭示 IL-6Rβ-WNT5A-RANKL信号通路在RA发病机制中所起的重要作用，应用抗IL-6Rβ(gp130)功能域单抗（具有自主知识产权）阐明这一与RA样模型小鼠免疫功能紊乱和骨代谢失衡密切关联的正反馈调节环路异常的免疫病理学机制，揭示IL-6Rβ-RANKL-WNT5A可能成为新药物靶点以及用抗IL-6Rβ(gp130)功能域治疗性单抗干预类风湿性关节炎这一以患者免疫功能紊乱和骨代谢失衡为主要特征的常见自身免疫性疾病提供新的理论基础和实验依据。

经过两年的研究，本项目研究梯队基本完成和达到了原申请的项目计划和任务书的目地、要求和指标。其研究的成果主要体现在应用课题组前期建立的由抗胶原Ⅱ功能域单抗诱导建立的类风关样模型小鼠(CAIA)和用来源于RA患者关节滑液FLS在体外诱导建立的破骨前体细胞分化的两个成熟技术；分析了他们由于异常免疫功能所呈现出众多促炎因子与由IL-6Rβ-WNT5A-RANKL信号通路密切关联的信号传导的紊乱，从而导致了RA样小鼠破骨细胞功能异常活化并发生RA患者骨代谢失衡的关键所在。应用本项目组研发的抗IL-6Rβ(gp130)功能域单抗（原创性）调控这一与RA样模型小鼠免疫功能紊乱和骨代谢失衡密切关联的正反馈调节环路中牵涉到的几个异常靶点表明；IL-6Rβ-RANKL-WNT5A极有可能将/ 或成为具有成药性的抗IL-6Rβ(gp130)功能域单抗干预治疗RA的系列新药物靶点，也为临床研究和治疗中替代或找到——以免疫干预调节为理念的全新的拮抗RA的且以IL-6Rβ、RANKL、WNT5A以及下游的破骨细胞功能异常等多靶点为治疗目地的新理论和手段提供了实验依据。