Abstract 1597: A spontaneous arthritis mouse model driven by TNF-α overexpression

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 α (TNFα) 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 TNFα (hTNFα), such as Infliximab, failed to cross-neutralize mouse TNFα (mTNFα). This limitation has impeded mechanistic and therapeutic investigations of hTNFα inhibitors in vivo, necessitating the development of humanized mouse models expressing hTNFα.Here, we developed an hTNFα transgenic mouse model (hTNFα-Tg) in C57BL/6 background, which carries the native promoter and coding sequences of the human TNFα gene, thereby driving robust overexpression of the human TNFα, as a relevant model for RA. By measuring serum hTNFα levels through ELISA following LPS stimulation, we confirmed significant overexpression of both hTNFα and endogenous mTNFα. Regarding the RA phenotype, macroscopic evaluation of arthritis revealed visible joint swelling in hTNFα-Tg mice compared to wild-type mice. Micro-CT imaging further confirmed prominent joint bone loss in hTNFα-Tg mice, validating their utility as an RA mouse model. To assess the in vivo therapeutic efficacy of hTNFα-targeted inhibitors, we administrated Infliximab to hTNFα-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 hTNFα-Tg mouse model provides a powerful preclinical platform for the development of drugs targeting the hTNFα protein and for evaluating their efficacy and toxicity in vivo. Citation Format: Qingqing Qi, Shuang Li, Xiaolei Qiu, Yi Li, Ruilin Sun, . A spontaneous arthritis mouse model driven by TNF-α overexpression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1597.