Human Rheumatoid Arthritis in Mice

描述(申请人提供)：该项目的目标是创建一种新的人类类风湿性关节炎模型，将在真实患者和科学研究之间建立一座桥梁，并最终彻底改变类风湿性关节炎(RA)的临床治疗。类风湿关节炎是一种慢性自身免疫性疾病，累及多个器官和系统，但主要累及滑膜关节，导致关节软骨破坏和变形，导致慢性疼痛、严重残疾和死亡率增加。RA影响了全球约1%的人口和约130万美国人，主要发生在他们的工作年限，并造成了巨大的社会负担。尽管最近取得了进展，但RA仍有几个问题需要解决。首先，我们对这种疾病的起源的了解还远远不完整。需要调查个体遗传和环境因素(如吸烟和空气污染)的作用及其相互作用。最近的发现也表明，类风湿性关节炎不是单一的统一疾病，而是由不同的亚型组成，具有不同的病因、临床病程和治疗反应，即ACPA+和ACPA-关节炎。重要的是，ACPA+亚群与RA的强烈遗传易感性相关。其次，目前还没有针对RA的预测性筛查试验，这使得早期诊断(在不可逆转的关节损伤之前)是不可能的。最后，高达20%-40%的患者在现有的RA治疗方法上没有得到充分的控制。拥有一个好的RA动物模型将有助于找到上述问题的答案。不幸的是，由于人类和小鼠免疫系统之间的巨大差异，目前可用的动物模型永远不会完全概括人类疾病。更重要的是，这些模型对发现生物标记物或测试新疗法没有用处。因此，我们将在小鼠体内建立一种新的具有临床意义的人类类风湿关节炎模型。我们将从脐带血中分离干细胞，并将它们移植到免疫缺陷的小鼠宿主中，用瓜氨酸胶原或纤维蛋白原免疫将诱发类风湿性关节炎。为了研究易感遗传因素在RA发病中的作用，我们将从具有强烈RA遗传易感性的母亲出生的孩子的脐带血中分离干细胞，并将它们移植到免疫缺陷的小鼠宿主中。随着时间的推移，移植的细胞将植入并发育成功能齐全的人类免疫系统。对这一模型的详细研究将在分子和细胞水平上提高我们对RA发病机制的理解。它还将促进 搜索生物标记物，将成为发现新疗法的宝贵工具，包括根据特定患者的需求开发“个性化”疗法。

DESCRIPTION (provided by applicant): The aim of this project is to create a novel model of human RA that will create a bridge between real patients and scientific research and eventually revolutionize clinical treatment for rheumatoid arthritis (RA). RA is a chronic autoimmune disease, which affects many organs and systems, but mainly attacks synovial joints and leads to cartilage destruction and deformation of the joint, resulting in chronic pain, severe disability an increased mortality. RA affects about 1% of the world's population and about 1.3 million of Americans, mainly during their working-years and has a great social burden. Despite recent progress there are several issues in RA that need to be solved. First, our understanding of the origins of this disease is still far from complete. The roles of individual genetic and environmental factors (such as smoking and air pollution) and their interactions need to be investigated. Also recent findings suggest that RA is not a single uniform disease, but comprises distinct subsets with different causes, clinical course, and response to therapy, namely ACPA+ and ACPA- arthritis. Importantly, the ACPA+ subset correlates with strong genetic susceptibility to RA development. Secondly, there are no predictive screening tests available for RA, which makes early diagnosis (prior to irreversible joint damage) impossible. Finally, up to 20-40% of patients are inadequately controlled on currently available treatments for RA. Having a good animal model of RA would help to find answers to the aforementioned questions. Unfortunately, because of the dramatic differences between human and murine immune systems, currently available animal models will never fully recapitulate human disease. More importantly, these models have no use for discovery of biomarkers or for testing new therapies. Therefore, we will create a new clinically relevant model of human RA in mouse. We will isolate stem cells from cord blood and transplant them into an immunodeficient mouse host, RA-like disease will be induced by immunization with citrullinated collagen or fibrinogen. To study the role of the predisposing genetic factors in development of RA, we will isolate stem cells from cord blood of children being born from mothers with strong genetic predisposition to RA and transplant them to an immunodeficient mouse host. Over time, the transplanted cells will engraft and develop into a fully functional human immune system. Detailed studies of this model will improve our understanding of RA pathogenesis on both molecular and cellular levels. It will also facilitate the search for biomarkers and will be valuable tool for discovery of new therapies, including development of "personalized" treatments tailored to the needs of specific patients.