A novel mice colitis model recapitulates human T cell and myeloid cell reconstitution to Support drug evaluation of inflammatory bowel disease 2258809

Abstract

Abstract Introduction Inflammatory bowel disease (IBD) is a chronic autoimmune disorder of the gastrointestinal tract with complex pathogenesis. Conventional IBD animal models primarily rely on the activation of the murine immune system, which limits their translational relevance and the in vivo evaluation of human-specific biologics. To address this gap, we developed a novel humanized colitis mouse model that combines a reconstituted human immune system with dextran sulfate sodium (DSS), better reflecting human IBD pathology. Methods Severe immunodeficient mice NCG-M/hIL15 were engrafted with human hematopoietic stem cells (huHSC), and allowed to reconstitute human immune cells for 12 weeks. Colitis was induced using 3% (DSS) administered for 10 days. The therapeutic efficacy of adalimumab was evaluated at the onset of DSS exposure. Results huHSC-NCG-M/hIL15 mice demonstrated robust human T and myeloid cell subpopulations 12 weeks after engraftment of HSCs. Following DSS challenge, humanized mice exhibited significant changes in body weight, colon length, and mouse survival, along with disrupted colonic epithelial integrity, compared with untreated controls. Treatment with adalimumab ameliorated disease activity index (DAI), mortality, and histopathological scores, while reducing human TNF mRNA expression relative to the DSS control group. Conclusion The DSS-induced huHSC-NCG-M/hIL15 mouse model successfully recapitulates key immunopathological features of human IBD, including human T and myeloid cell responses. This model provides a valuable in vivo platform for assessing the efficacy of human antibodies and novel therapies in IBD research and drug development. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)