Osteoimmunological Interactions at the Switch from Acute to Chronic Arthritis

从急性关节炎转变为慢性关节炎时的骨免疫相互作用

• 批准号: 169011477
• 负责人: Professor Dr. Thomas Kamradt
• 金额: --
• 依托单位: Institut für Virologie und Immunbiologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/169011477?language=en
• 关键词: Osteoimmunological; Interactions; Switch; Acute; Chronic

Rheumatoid arthritis is characterised by inflammation, cartilage destruction, and bone erosion. The pathogenic tissue response to inflammatory stimuli is of paramount importance for arthritis pathogenesis. Still, key events in the pathogenesis are not understood. One such unknown key event is the transition from acute to chronic inflammation, and the resistance of chronic inflammation to endogenous mechanisms of regulation and therapeutic suppression. We have found in a mouse model of arthritis that transient early depletion of regulatory T helper lymphocytes switches the usually acute, self-limiting course of arthritis to nonremitting, destructive arthritis. The critical switch in pathogenesis occurs early, in the preclinical phase of arthritis. We now want to use this system, in which arthritis can be switched ad libitum from acute, self limiting, to non-remitting, destructive, to identify the relevant molecular switches for the transition to chronic arthritis. Preliminary data suggest that T helper lymphocytes instruct synovial fibroblasts and osteoclasts to become the drivers of non-remitting destructive arthritis. We aim at defining the instructive signals from pathogenic T-lymphocytes; identify and characterise the molecular alterations in the effector cells responsible for non-remitting destructive arthritis; and find ways to modulate them.

类风湿性关节炎的特征是炎症、软骨破坏和骨侵蚀。致病组织对炎症刺激的反应对于关节炎的发病机制至关重要。尽管如此，发病机制中的关键事件尚不清楚。其中一个未知的关键事件是从急性炎症向慢性炎症的转变，以及慢性炎症对内源性调节和治疗抑制机制的抵抗。我们在关节炎小鼠模型中发现，调节性 T 辅助淋巴细胞的短暂早期耗竭会将通常为急性、自限性的关节炎病程转变为非缓解性、破坏性关节炎。发病机制的关键转变发生在关节炎的早期临床前阶段。我们现在想要使用这个系统，其中关节炎可以随意从急性、自限性转变为非缓解性、破坏性，以识别向慢性关节炎转变的相关分子开关。初步数据表明，T 辅助淋巴细胞指导滑膜成纤维细胞和破骨细胞成为非缓解性破坏性关节炎的驱动因素。我们的目标是定义致病性 T 淋巴细胞的指导信号；识别和表征效应细胞中导致非缓解性破坏性关节炎的分子改变；并找到调节它们的方法。