类风湿关节炎小鼠模型的验证,使用NOD-scid il - 2r - γ缺失小鼠重建患者pbmc。

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Paula Schuster-Winkelmann, Veronika Weß, Marietta Schindler, Morten Ø Jensen, David E Shaw, Paolo Alberton, Hendrik Schulze-Koops, Silvia Schoenthaler, Andreas Weinhaeusel, Matthias Siebeck, Roswitha Gropp, Attila Aszodi
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引用次数: 0

摘要

类风湿性关节炎(RA)是一种以炎症和关节破坏为特征的慢性自身免疫性疾病。然而,由于疾病的异质性,在动物模型中复制类风湿关节炎的人类表现仍然具有挑战性。本研究利用NOD-scid IL2Rnull (NSG)小鼠移植RA患者外周血单个核细胞(PBMCs),建立了人源化RA小鼠模型并进行了验证。使用脂多糖和抗II型胶原抗体鸡尾酒诱导RA症状。采用Luminex、RT-PCR和RNA-seq对后爪肿胀的临床评分、组织分析以及血浆和关节中ra特异性标志物的评估来评估病理表现。NSG-RA小鼠表现出ra特异性标志物水平升高,炎症细胞涌入滑膜,骨侵蚀和人类自身抗体水平升高。富集RNA-seq通路分析显示RA疾病通路以及TNF和IL-17信号通路的激活。用强的松龙或英夫利昔单抗治疗可改善疾病症状并降低炎症标志物水平。这些发现表明NSG-RA模型为研究RA的发病机制和测试新的治疗方法提供了一个翻译工具。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Validation of a rheumatoid arthritis mouse model that uses NOD-scid IL2Rγnull mice reconstituted with patient PBMCs.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and joint destruction. Replicating human manifestations of RA in animal models remains challenging, however, due to heterogeneity of the disease. In this study, a humanized mouse model for RA was developed and validated using NOD-scid IL2Rnull (NSG) mice engrafted with peripheral blood mononuclear cells (PBMCs) from RA patients (NSG-RA). RA symptoms were induced using lipopolysaccharide and a cocktail of antibodies against type II collagen. Pathological manifestations were assessed through clinical scoring of hind paw swelling, histological analysis, and evaluation of RA-specific markers in plasma and joints using Luminex, RT-PCR, and RNA-seq. NSG-RA mice exhibited increased levels of RA-specific markers, an influx of inflammatory cells into the synovium, bone erosion, and elevated levels of human autoantibodies. Enriched RNA-seq pathway analysis revealed activation of the RA disease pathway, along with the TNF and IL-17 signaling pathways. Treatment with prednisolone or infliximab ameliorated disease symptoms and decreased levels of inflammatory markers. These findings indicate that the NSG-RA model offers a translational tool for studying RA pathogenesis and testing novel therapeutic approaches.

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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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