Humanized Transgenic Mice Reproduce the Disease Evolution in Severe RA

描述(申请人提供)：人源化转基因小鼠复制严重类风湿性关节炎(RA)的疾病演变。类风湿性关节炎(RA)是一种常见的自身免疫性疾病，与特定的人类白细胞抗原II类等位基因遗传相关。尽管几种类风湿性关节炎小鼠模型出现的症状和临床关节炎与人类类风湿性关节炎的关节分布相似，但这些模型都不能准确复制人类关节外症状的缓慢、慢性疾病进展。在最近报道的在大鼠II型胶原启动子下表达II类反式激活因子(CIITA)的D1CC转基因小鼠中，我们提出了一种诱发性疾病综合征，该综合征非常接近地复制了具有严重的慢性进行性侵蚀性疾病、结节的RA晚期，在一些小鼠中还出现了自身免疫性肺炎。这项拟议的研究将通过引入对RA敏感的HLA-DR*0401基因和荧光素酶转基因(由3个核因子：B结合位点激活的最小果蝇启动子控制)进一步推动这一小鼠模型的发展，这将有助于对疾病过程的连续体内监测。第一个目标将是完成从新的转基因小鼠生产中挑选出最好的创始品系。第二个目标是利用酵母多糖(一种天然免疫系统的非特异性刺激因子)、II型胶原/CFA或HCgp39/CFA(RA中两种关节相关自身抗原)来激活适应性免疫系统，并结合临床关节炎评分、X射线、X射线断层扫描和荧光素酶成像开发体内监测方案。第三个目标将是测试1)抗TNF1阻断(一种已经在患有RA的人类中得到证实的治疗方法)的效果，以及2)在新模型中抗IL17阻断对关节炎进展的影响。IL-17似乎在RA的侵袭过程中具有特殊的意义，因此，抗IL17的阻断可能为攻击这一过程开辟了一条新的道路。 与公共卫生相关。人源化转基因小鼠复制严重类风湿性关节炎的疾病演变这项应用描述了一种新的炎性关节炎小鼠模型，它发展出一种疾病综合征，非常接近地再现了慢性类风湿性关节炎(RA)的自然历史，伴随着人类严重类风湿性关节炎的侵蚀性骨病和关节外疾病的特征的进行性发展。通过在滑膜关节中表达人类第二类反式激活因子CIITA作为转基因，发现小鼠患炎性关节炎的敏感度要高得多，这一特征在本应用的人源化的HLA-DR4，CIITA转基因小鼠中也包括在内。由于CIITA转基因的表达取决于关节的持续炎症，因此关节炎综合症可能可以通过治疗来关闭和控制，这使得小鼠成为评估RA新疗法的理想对象。

DESCRIPTION (provided by applicant): Humanized transgenic mice reproduce the disease evolution in severe RA Rheumatoid arthritis (RA) is a common autoimmune disease in humans genetically associated with specific HLA class II alleles. Although several mouse models of RA develop symptoms and clinical arthritis with similar joint distribution as RA in humans, none of these models accurately replicates the slow, chronic disease progression with extra-articular symptoms seen in humans. In the recently reported D1CC transgenic mice that express the class II transactivator (CIITA) under the rat collagen II promoter, we presented an inducible disease syndrome, which very closely reproduces the late stages of RA with severe chronic progressive erosive disease, nodules, and, in some mice autoimmune pneumonitis. The proposed research will further advance this mouse model by introducing the RA-susceptible HLA- DR*0401 gene and a luciferase transgene (controlled by a minimal Drosophila promoter activated by 3 NF:B binding sites), which will facilitate continuous in vivo monitoring of the disease process. The first aim will be to complete the selection of the best founder lines from new transgenic mouse production. The second aim will be to trigger arthritis using Zymosan (a non-specific stimulator of the innate immune system), collagen II/CFA or HCgp39/CFA (two joint-related autoantigens in RA) that activate the adaptive immune system, and to develop in vivo monitoring protocols using a combination of clinical arthritis scoring, X-rays, X-ray tomography, and luciferase imaging. The third aim will be to test the effects of 1) anti-TNF1 blockade (an already well- established treatment in humans with RA), and 2) anti-IL17 blockade on arthritis progression in the new model. IL-17 seems to have special significance in the erosive process in RA and anti-IL17 blockade may therefore open a new alley for attacking this process. PUBLIC HEALTH RELEVANCE. Humanized transgenic mice reproduce the disease evolution in severe RA This application describes a new mouse model of inflammatory arthritis, which develops a disease syndrome that very closely reproduce the natural history of chronic rheumatoid arthritis (RA) with progressive development of erosive bone disease and extra articular disease manifestation characteristic of severe RA in humans. By expressing, as a transgene, the human Class II transactivator, CIITA, in the synovial joints, it was found that mice attain a much higher sensitivity to develop inflammatory arthritis and this feature is here included in the application's humanized HLA-DR4, CIITA transgenic mice. Since the expression of the CIITA transgene is contingent upon continuous inflammation in the joints, the arthritis syndrome can presumably be turned off and controlled by treatment making the mice ideal for evaluation of new treatments for RA.