Humanized Transgenic Mice Reproduce the Disease Evolution in Severe RA

人源化转基因小鼠重现严重 RA 的疾病演变

• 批准号: 7564889
• 负责人: GRETE SONDERSTRUP
• 金额: $ 40.26万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-10 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7564889
• 关键词: Acute; Alleles; Arthritis; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Binding Sites; Biological Products; Bone Diseases; CD4 Positive T Lymphocytes; Cartilage; Cell Lineage; Cells; Characteristics; Chronic; Chronic Disease; Chronic Phase of Disease; Clinical; Collaborations; Collagen; Development; Disease; Disease Progression; Drosophila genus; Engineering; Evaluation; Evolution; Genes; HLA-DR4 Antigen; Human; Image; Immune system; Immunization; In Vitro; Inbred DBA Mice; Inflammation; Inflammatory; Inflammatory Infiltrate; Interleukin-17; Joints; Laboratories; Luciferases; MHC class II transactivator protein; Modeling; Monitor; Mus; Natural History; Nodule; Pharmaceutical Preparations; Pneumonia; Process; Production; Protocols documentation; Rattus; Reporting; Research; Rheumatoid Arthritis; Rodent Model; Roentgen Rays; Staging; Symptoms; Syndrome; Testing; Th2 Cells; Transgenes; Transgenic Mice; Transgenic Organisms; X-Ray Tomography; Zymosan; arthropathies; base; bone; design; human disease; improved; in vivo; mouse model; promoter; prospective; public health relevance; research study

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.

描述（由申请人提供）：人源化转基因小鼠再现严重RA的疾病演变。风湿性关节炎（RA）是人类常见的自身免疫性疾病，与特定的HLA II类等位基因遗传相关。尽管几种RA小鼠模型出现了与人类RA相似的关节分布症状和临床关节炎，但这些模型都没有准确复制人类中观察到的具有关节外症状的缓慢慢性疾病进展。在最近报道的D1CC转基因小鼠，表达II类反式激活因子（CIITA）下的大鼠II型胶原启动子，我们提出了一种诱导性疾病综合征，非常密切地再现了晚期RA严重的慢性进行性糜烂性疾病，结节，并在一些小鼠自身免疫性肺炎。拟议的研究将通过引入RA易感的HLA-DR *0401基因和荧光素酶转基因（由3个NF：B结合位点激活的最小果蝇启动子控制）进一步推进该小鼠模型，这将促进疾病过程的连续体内监测。第一个目标将是从新的转基因小鼠生产中完成最佳创始品系的选择。第二个目标是使用酵母多糖（先天免疫系统的非特异性刺激物），胶原II/CFA或HCgp 39/CFA（RA中两种关节相关的自身抗原）激活适应性免疫系统来触发关节炎，并使用临床关节炎评分，X射线，X射线断层扫描和荧光素酶成像的组合来开发体内监测方案。第三个目的将是测试1）抗TNF 1阻断（在患有RA的人类中已经很好建立的治疗）和2）抗IL 17阻断对新模型中关节炎进展的作用。IL-17似乎在RA的侵蚀过程中具有特殊的意义，因此，抗IL-17阻断剂可能为攻击该过程开辟新的途径。 公共卫生相关性。本申请描述了一种新的炎性关节炎小鼠模型，其发展了一种疾病综合征，该疾病综合征非常接近地再现了慢性类风湿性关节炎（RA）的自然史，具有侵蚀性骨疾病的进行性发展和人类严重RA特征性的关节外疾病表现。通过在滑膜关节中表达作为转基因的人II类反式激活因子CIITA，发现小鼠获得对发展炎性关节炎的高得多的敏感性，并且该特征在此包括在本申请的人源化HLA-DR 4 CIITA转基因小鼠中。由于CIITA转基因的表达取决于关节中的持续炎症，因此可以推测关节炎综合征可以通过治疗关闭和控制，使小鼠成为评估RA新治疗的理想选择。