IL18 and complement in collagen induced arthritis

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关节炎（CIA）和类风湿滑膜细胞中诱导IL-1和TNFalpha的作用。IL-1和TNFalpha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，是类风湿性关节炎（RA）和CIA组织损伤的重要介质。这些细胞因子在RA或CIA中过量产生的机制可能是多种的，而且在很大程度上是未知的；IL-18和补体系统是il -1和TNFalpha的两种潜在诱导剂。在这些研究中要检验的假设是，用特异性IL-18结合蛋白（IL-18BP）抑制IL-18，以及用小鼠抑制剂Crry补体抑制IL-18，将减轻CIA的发作或改善CIA的病程。这个问题将通过三个具体目标来解决：1)研究阻止IL-18受体与可溶性IL-18BP结合对小鼠CIA的影响；2)检测CIA对小鼠补体系统和IL-18的阻断作用；3)研究类风湿滑膜组织和细胞中IL-18、TNFalpha和IL-1 β的产生之间的关系。这些实验将利用重组IL-18BP的管理，创造一种或两种蛋白质的转基因小鼠，并研究分离的类风湿滑膜组织和细胞。这些研究与RA相关，其中IL-1和TNFalpha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TNFalpha的重要诱导剂。这些研究进一步与其他自身免疫性和炎症性疾病相关，在这些疾病中，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项目的广泛目标，即研究动物疾病模型和人类疾病中新的介入方法的机制。

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.