We are excited to introduce a new addition to our collection of genetically modified mice used in human disease modelling. We have now developed and characterized a proprietary Rag1KO/BMC mouse line that either alone or in combination with our collection of proprietary mouse lines allows us to offer a new series of anti-CD40 colitis mouse models that can serve as invaluable preclinical tools to better understand and treat the pathogenic mechanisms involved in the development and progression of Inflammatory Bowel Disease (IBD).

💉 The anti-CD40 model of colitis is a valuable model to study innate immune responses in colon inflammation and to evaluate the therapeutic effect of TNF, IFNγ or IL-12/IL-23 p40 inhibition 💊

What is the anti-CD40 induced colitis model?
Activation of CD40 by an agonistic anti-CD40 antibody in mice lacking T and B cells, as the Rag1 or Rag2 knockout mice, leads to the activation of innate immune responses, the excessive production of IL-23, IL-1β and IL-12 and the development of inflammation in the colon.
The anti-CD40 induced colitis pathology is characterized by body weight loss, increased levels of circulating cytokines, reduced colon length and increased colon weight,  accompanied by relevant histopathological signs of gut inflammation and extensive crypt destruction.

This newest addition in our collection of humanized mouse disease models integrates characteristics of the human Systemic Lupus Erythematosus complexity and develops a chronic multiorgan autoimmune disease marked by proteinuria, anti-dsDNA antibodies, severe inflammatory lesions in the skin and milder pathologies in the kidneys and lungs.

This novel model of lupus can prove to be an invaluable translational tool for studying the aetiopathogenic role of the IL23 cytokine in SLE and for use as a preclinical tool to assess the efficacy of novel  lupus  therapeutics.

Published in Arthritis Rheumatol. 2024 Feb 15. doi: 10.1002/art.42830.

Christodoulou-Vafeiadou E, Geka C, Iliopoulou L, Ntari L,  Denis MC, Karagianni N, Kollias G

Objective: Interleukin-23 (IL-23) is a crucial cytokine implicated in chronic inflammation and autoimmunity, associated with various diseases like psoriasis, psoriatic arthritis, and systemic lupus erythematosus (SLE). This study aimed to create and characterize a transgenic mouse model (TghIL23A) overexpressing human IL23A, providing a valuable tool for investigating the pathogenic role of hIL23A and evaluating the efficacy of anti-human-IL23A therapeutics.

Methods: TghIL23A mice were generated via microinjection of CBAxC57BL/6 zygotes with a fragment of the human IL23A gene, flanked by its 5′-regulatory sequences and the 3’UTR of human beta-globin. The TghIL23A pathology was assessed through hematological and biochemical analyses, cytokine and anti-nuclear antibody detection, histopathological examination of skin and renal tissues. The response to the anti-hIL23A therapeutic agent guselkumab, was evaluated in groups of 8 mixed-sex mice receiving subcutaneous treatment twice weekly for 10 weeks, using clinical, biomarker and histopathological readouts.

Results: TghIL23A mice exhibited interactions between hIL23A and mouse IL23/IL12p40, and developed a chronic multiorgan autoimmune disease marked by proteinuria, anti-dsDNA antibodies, severe inflammatory lesions in the skin, and milder phenotypes in the kidneys and lungs. The TghIL23A pathological features exhibited significant similarities to those observed in human SLE patients and they were reversed following guselkumab treatment.

Conclusions: We have generated and characterized a novel genetic mouse model of SLE, providing proof-of-concept for the etiopathogenic role of hIL-23A. This new model has a normal lifespan and integrates several characteristics of the human disease’s complexity and chronicity making it an attractive preclinical tool for studying IL23-dependent pathogenic mechanisms and assessing the efficacy of anti-hIL23A or modeled disease-related therapeutics.

Read the article here >