IL18 and complement in collagen induced arthritis

IL18 和补体在胶原诱导的关节炎中的作用

• 批准号: 6227682
• 负责人: WILLIAM P AREND
• 金额: $ 25.04万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-28 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6227682
• 关键词: arthritis; collagen; complement; cytokine; disease /disorder model; genetically modified animals; interleukin 1; laboratory mouse; receptor binding; rheumatoid arthritis; synovial fluid; tumor necrosis factor alpha

The long-term objectives of this project are to determine the roles of IL- 18 and the complement system in the induction of IL-1 and TNFalpha in collagen-induced arthritis (CIA) in mice and in rheumatoid synovial cells. IL-1 and TNFalpha are important mediators of tissue damage in rheumatoid arthritis (RA) and in CIA through stimulation of production of metalloproteinases in synovial fibroblasts and chondrocytes. The mechanisms of excess production of these cytokines in RA or CIA are probably multiple and largely unknown; IL-18 and the complement system are two potential inducers of IL1 and TNFalpha. The hypothesis to be examined in these studies is that inhibition of IL-18 with the specific IL-18 binding protein (IL-18BP), and of complement with the murine inhibitor, Crry, will attenuate the onset or ameliorate the course of CIA. This question will be addressed through three specific aims: 1) to examine the effects on CIA in mice of prevention of receptor binding of IL-18 with soluble IL-18BP; 2) to examine the effects of CIA in mice of blocking both the complement system and IL-18; and 3) to examine the relationship between production of IL-18, TNFalpha, and IL- 1beta in rheumatoid synovial tissue and cells. These experiments will utilize the administration of recombinant IL-18BP, the creation of mice transgenic for either, or both, proteins, and studies on isolated rheumatoid synovium tissue and cells. These studies are relevant to RA where IL-1 and TNFalpha are key mediators leading to inflammation and tissue destruction. The complement system and IL-18 may be important inducers of IL-1 and TNFalpha. These studies are further relevant to other autoimmune and inflammatory diseases where inhibition of injurious mechanisms at the proximal levels of complement and IL-18 may be efficacious. This research project will contribute towards the broad objective of the Autoimmunity Centers of Excellence program to study the mechanisms of new interventional approaches in both animal models of disease and in human disease.

该项目的长期目标是确定IL- 18和补体系统在小鼠胶原诱导性关节炎（CIA）和类风湿性滑膜细胞中诱导IL-1和TNF α中的作用。IL-1和TNF α是类风湿性关节炎（RA）和CIA中组织损伤的重要介质，通过刺激滑膜成纤维细胞和软骨细胞中金属蛋白酶的产生。RA或CIA中这些细胞因子过量产生的机制可能是多种的，并且在很大程度上是未知的; IL-18和补体系统是IL 1和TNF α的两种潜在诱导剂。在这些研究中要检查的假设是，用特异性IL-18结合蛋白（IL-18 BP）抑制IL-18和用鼠抑制剂Crry抑制补体将减弱CIA的发作或改善CIA的病程。这个问题将通过三个具体的目的来解决：1）检查用可溶性IL-18 BP阻止IL-18受体结合对小鼠CIA的影响; 2）检查CIA在小鼠中阻断补体系统和IL-18的影响; 3）检查类风湿性滑膜组织和细胞中IL-18、TNF α和IL-1 β产生之间的关系。这些实验将利用重组IL-18 BP的施用，产生对于任一种或两种蛋白质转基因的小鼠，以及对分离的类风湿性滑膜组织和细胞的研究。这些研究与RA相关，其中IL-1和TNF α是导致炎症和组织破坏的关键介质。补体系统和IL-18可能是IL-1和TNF α的重要诱导剂。这些研究还与其他自身免疫性和炎性疾病相关，其中在补体和IL-18的近端水平抑制损伤机制可能是有效的。该研究项目将有助于实现自身免疫卓越中心计划的广泛目标，以研究疾病动物模型和人类疾病中新干预方法的机制。