Transcriptional analysis in TNFdeltaARE mice to study progression of Crohn's-ileitis and assess relative benefits of global TNF blockade versus TNFR1 targeted modulation

Background and Aims: Crohn’s disease is a debilitating chronic inflammatory disorder of the mammalian gastrointestinal tract. While current therapeutic interventions using anti-TNF biologics show long-term benefit in up to half of the patients, broadly effective approaches are still needed. This study focused on the role of the TNF receptor 1 (TNFR1) in disease pathogenesis in a TNF-driven model of ileitis, and the relative benefits of global TNF blockade versus TNFR1-targeted modulation.
Methods: We studied genetically engineered TNFDAU-rich element (ARE)/+ (TNFdARE) mice, which develop progressive ileitis, with similarities to Crohn’s ileitis in humans. Histopathological analysis and gene expression profiling was used to characterize the progression of disease in 5 to 16-week old TNFdARE mice. In addition, we studied mice with TNFR1 hemizygosity (TNFdARE/R1het) to assess gene dosage effects on disease pathogenesis. Transcriptional profiling, at various ages, established inflection poi...

研究背景与目的：克罗恩病（Crohn’s disease）是一种致残性哺乳动物胃肠道慢性炎症性疾病。当前采用抗TNF生物制剂的治疗手段虽可使约半数患者获得长期获益，但仍亟需广谱有效的治疗方案。本研究聚焦于TNF受体1（TNF receptor 1, TNFR1）在TNF驱动的进行性回肠炎模型中的疾病发病机制作用，以及全局TNF阻断与TNFR1靶向调控的相对获益。
研究方法：本研究使用经基因工程改造的TNFΔAU富集元件（AU-rich element, ARE）/+（TNFΔARE）小鼠，该模型可发生进行性回肠炎，其表型与人类克罗恩回肠炎高度相似。本研究采用组织病理学分析与基因表达谱分析，对5至16周龄TNFΔARE小鼠的疾病进展进行表征。此外，本研究还针对TNFR1半合子小鼠（TNFΔARE/R1het）开展实验，以评估基因剂量效应对疾病发病机制的影响。通过在不同年龄阶段进行转录组谱分析，本研究确立了疾病进展的拐点……