IDDF2024-ABS-0394 A mouse model for inflammatory bowel disease based on DSS-induced NCG-m mice reconstituted with human hematopoietic stem cells

Background

For the past 20 years, numerous murine models of colitis have been developed to study human Inflammatory Bowel Disease (IBD). However, these neither reflect the heterogeneous symptoms observed in the IBD-affected population nor can be used to test the efficacy of clinical drugs which show no cross-reactivity with murine targets. In an attempt to overcome these problems, we have developed a colitis mouse model that relies on DSS-induced NCG-M mice reconstituted with human hematopoietic stem cells (HSCs) from healthy individuals. We observed a significant pharmacodynamic effect of Mesalazine and a small molecular inhibitor in this colitis model.

Methods

Six-week-old NCG-M mice, the immune deficiency mice transgenically engineered to express granulocyte/macrophage colony-stimulating factor 2 (GM-CSF, also known as CSF2), interleukin-3 (IL-3), and stem cell factor (SCF, also known as KITLG), were engrafted with human HSCs to reconstitute the human immune system. HSC-NCG-M mice were given drinking water containing 3% DSS for 10 days after 10-14 weeks of engraftment along with or without Mesalazine or small molecular inhibitor treatment. Assessment of DAI scores and weight loss were performed daily. Mice were killed on day 11 after DSS induction to measure the length of the colon and do HE staining to analyze the pathological changes.

Results

T cells, B cells, myeloid cells, NK cells, monocytes, and DC cells were detected in the peripheral blood of NCG-M mice 10-14 weeks after engraftment with human HSCs. Administrated with DSS to HSC-NCG-M mice induced colitis symptoms, such as weight loss, increased DAI scores, thinner fecal, and bloody stool. The histological study also showed increased inflammatory cell infiltration, especially the CD3+ T cell, and epithelial structure damage in the colon in HSC-NCG-M with induction of DSS. Significant amelioration of weight loss and DAI score were achieved by Mesalazine or small molecular inhibitor treatment.

Conclusions

We developed an IBD model induced in human immune system reconstituted mice to provide a better-matched model for preclinical pharmacodynamic evaluation of IBD-related drugs, especially antibodies against human targets, and explore potential therapeutic interventions.