PO.IM02.02 · 免疫学
一种由TNF-alpha过表达驱动的自发性关节炎小鼠模型
A spontaneous arthritis mouse model driven by TNF-alpha overexpression
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
类风湿关节炎（RA）是最常见的自身免疫性关节病，其特征为持续性炎症、疼痛、肿胀以及滑膜关节的进行性破坏。肿瘤坏死因子α（TNFalpha）在导致RA的自身免疫应答中起核心作用，其抑制所观察到的显著治疗益处即为佐证。然而，某些靶向人TNFalpha（hTNFalpha）的抑制剂（如英夫利昔单抗Infliximab）无法交叉中和小鼠TNFalpha（mTNFalpha）。这一局限阻碍了hTNFalpha抑制剂在体内的机制和治疗研究，因此需要开发表达hTNFalpha的人源化小鼠模型。在此，我们在C57BL/6背景上开发了一种hTNFalpha转基因小鼠模型（hTNFalpha-Tg），其携带人TNFalpha基因的天然启动子和编码序列，从而驱动人TNFalpha的强健过表达，作为RA的相关模型。通过在LPS刺激后经ELISA检测血清hTNFalpha水平，我们证实了hTNFalpha和内源性mTNFalpha的显著过表达。在RA表型方面，关节炎的宏观评估显示，与野生型小鼠相比，hTNFalpha-Tg小鼠出现可见的关节肿胀。Micro-CT成像进一步证实了hTNFalpha-Tg小鼠中显著的关节骨丢失，验证了其作为RA小鼠模型的效用。为评估hTNFalpha靶向抑制剂的体内疗效，我们对hTNFalpha-Tg小鼠给予英夫利昔单抗，观察到英夫利昔单抗显著降低了关节肿胀和爪厚度的病理评分，同时体重增加显著。同时，治疗小鼠表现出由骨破坏或炎症引起的关节间隙增宽的改善，以及指骨畸形的缓解。总体而言，我们的hTNFalpha-Tg小鼠模型为开发靶向hTNFalpha蛋白的药物以及在体内评估其疗效和毒性提供了强大的临床前平台。
查看英文原文 English abstract
Rheumatoid arthritis (RA) is the most prevalent autoimmune arthropathy characterized by persistent inflammation, pain, swelling and progressive destruction of the synovial joints. Tumor necrosis factor alpha (TNFalpha) plays a central role in the autoimmune response leading to RA, as evidenced by the significant therapeutic benefits observed upon its inhibition. However, certain inhibitors targeting human TNFalpha (hTNFalpha), such as Infliximab, failed to cross-neutralize mouse TNFalpha (mTNFalpha). This limitation has impeded mechanistic and therapeutic investigations of hTNFalpha inhibitors in vivo , necessitating the development of humanized mouse models expressing hTNFalpha.Here, we developed an hTNFalpha transgenic mouse model (hTNFalpha-Tg) in C57BL/6 background, which carries the native promoter and coding sequences of the human TNFalpha gene, thereby driving robust overexpression of the human TNFalpha, as a relevant model for RA. By measuring serum hTNFalpha levels through ELISA following LPS stimulation, we confirmed significant overexpression of both hTNFalpha and endogenous mTNFalpha. Regarding the RA phenotype, macroscopic evaluation of arthritis revealed visible joint swelling in hTNFalpha-Tg mice compared to wild-type mice. Micro-CT imaging further confirmed prominent joint bone loss in hTNFalpha-Tg mice, validating their utility as an RA mouse model. To assess the in vivo therapeutic efficacy of hTNFalpha-targeted inhibitors, we administrated Infliximab to hTNFalpha-Tg mice and observed that Infliximab significantly reduced pathological scores of joint swelling and paw thickness, along with a significant increase in body weight gain. Concurrently, the treated mice exhibited amelioration of the joint space widening caused by bone destruction or inflammation, as well as phalangeal deformity.Overall, our hTNFalpha-Tg mouse model provides a powerful preclinical platform for the development of drugs targeting the hTNFalpha protein and for evaluating their efficacy and toxicity in vivo.
利益披露 Disclosure
Q. Qi,
Shanghai Model Organisms Center, Inc. Parent company.
S. Li,
Shanghai Model Organisms Center, Inc. Other, Parent Company.
X. Qiu,
Shanghai Model Organisms Center, Inc. Other, Parent Company.
Y. Li,
Shanghai Model Organisms Center, Inc. Other, Parent Company.
R. Sun,
Shanghai Model Organisms Center, Inc. Other, Parent Company.