The Disease
Inflammatory Bowel Disease (IBD) can be Crohn’s disease or ulcerative colitis – two serious, chronic diseases directly affecting the digestive system causing intestinal tissue to become inflamed, form sores, and bleed easily. The incidence of IBD is rising in developing countries around the world and approximately 5 million people worldwide are currently affected by a form of IBD.
This chronic condition is without a medical cure and commonly requires a lifetime of care. With the advent of monoclonal antibodies for use in IBD there has been a breakthrough in disease management while many more biologics are in the pipeline. Currently the global market is estimated at $16 billion and this is set to continue to rise.
Our Preclinical Testing Tools
Biomedcode offers services of preclinical drug efficacy evaluation of therapeutics using spontaneous and induced mouse models of inflammatory bowel disease (IBD).
Mouse TNF driven Crohn's like pathology
TNF ΔΑRE+/- is a mouse mutant with defective post transcriptional regulation of endogenous TNF. Deregulated TNF expression leads to the gradual development of spontaneous inflammatory polyarthritis and inflammatory bowel pathology closely resembling Crohn’s disease . TNF ΔΑRE+/- are crossed to hTNFR1KI mice to yield TNF ΔARE/hTNFR1KI, a mouse model expressing human TNFR1 and retaining all pathology features of the original model, offering thus the opportunity to test both anti TNF therapeutics and anti-hTNFR1 biologics.
Human TNF dependent DSS colitis
Administration of Dextran Sodium Sulfate (DSS) in drinking water induces intestinal inflammation probably due to the disruption of the intestinal epithelial monolayer lining, allowing the entry of luminal bacteria and associated antigens into the mucosa and leading to the dissemination of proinflammatory intestinal contents into underlying tissue causing a pathology closely resembling human Ulcerative Colitis.
αCD40 induced colitis
Activation of the CD40 pathway through the systemic administration of agonistic anti-CD40 antibodies to mice lacking T and B cells triggers a cascade of innate immune responses including upregulation of IL-23, IL-12 and IL-1β in myeloid cells, elevated proinflammatory serum cytokines, and inflammation of the distal colon leading to tissue damage with mild clinical symptoms similar to those of human IBD. αCD40 colitis is induced in Rag1KO mice crossed to lines expressing humanized therapeutic targets as the human TNF expressing Tg197 mice, the hTNFR1KI, hIL23AKI or combinations of them.
TNBS induced colitis
Intrarectal instillation of the haptenizing agent TNBS in an ethanol containing solution results in ethanol mediated disruption of the intestinal barrier and enabling of TNBS to reach and haptenize high molecular weight colonic autologous or microbiota proteins, rendering them immunogenic to the host immune system. Due to the TNBS administration method, inflammation tends to be more localized and is often concentrated in specific segments of the colon, affecting multiple layers of the colon wall, that may include the mucosa, submucosa, and muscularis, reproducing pathology features that resemble human Crohn’s disease.
Read-Out Parameters
Body weight change
Histopathological evaluation of ileum or colon sections
Ex vivo colon tissue culture and local cytokine levels measurement
Platform validation
TNFΔARE/+/hTNFR1KI mice are treated and monitored from 8 weeks of age for 4-8 weeks.
DSS colitis is an acute disease model of 2 weeks duration. Induced in hTNF transgenic mice, can be effectively treated with anti-TNF biologics..
αCD40 colitis is a model of colitis pathology induced in mice lacking T and B cells. The model is available in mice with humanized targets as the hTNFR1KI, hIL23AKI, hTL1aKI and their combinations crossed to our proprietary Rag1KO.
Competitive Advantage
TNFΔARE/+ mice reliably model human Crohn’s pathology and offer a unique combination of co-manifested pathologies including arthritis, IBD and heart valve pathology that share common aetiopathogenic mechanisms.
DSS colitis in hTNF transgenic mice offer a unique model of colitis pathology with significant TNF involvement.
The anti-CD40 colitis model is a rapid, reproducible, T and B cell-independent, innate immune-driven model of IBD, ideal for the preclinical evaluation of anti-TNF and anti-IL23 therapeutics.
