Gut models

Preclinical CRO Services

for Inflammatory Diseases of the Gut

 

Acute and chronic inflammatory diseases of the gastro-intestinal tract can be triggered by several causes such as food intolerance, immunotherapies or immune dysregulation. Rodent models of gut inflammations, available as CRO services, are helpful to decipher mechanisms of disease triggering or sustaining observed in patients.

Oncodesign Services offers access several preclinical models addressing a variety of gut diseases, and provides CRO support for de novo development of new gut inflammation models recently described in literature.

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Typical readouts for gut inflammation

  • Clinical score aka “Disease Activity Index (DAI)”
  • Histopathology of swiss-rolled colon,
    – Hematoxylin/Phloxin stain for inflammation
    – AB-PAS stain for Goblet cell mucus production
  • Body weight
  • Stool consistency
  • Blood in stool
  • Gene expression in colon, by qPCR/dPCR
  • Biomarker / drug monitoring

Discover Oncodesign Services offers for gut inflammation diseases

  • In Vivo Models
    • DSS-induced acute colitis
    • DSS-induced acute colitis in CD34+ humanized mice
    • DSS + anti-CTLA4 antibody-induced chronic colitis
    • Repeated DSS cycles-induced chronic colitis
    • Anti-CD40-induced mild colitis in C57b6 RAG2-/- mice
    • Spontaneous colitis in IL-10 -/- mice

Humanized models

Oncodesign services has a strong experience with mouse humanization as a support for cancer research. Those techniques have also been deployed to other therapeutic areas. BRGSF-HIS (“Human immune system”) mice are super-immunodeficient animals (no T/B/NK cells) that have been humanized with CD34+ human hematopoietic stem cells and have an FLT3L-boostable human dendritic cell compartment.

The DSS-induced colitis BRGSF-HIS model causes similar cytokine and chemokine gene expression patterns in both syandard and humanized mice, with increases in TNFa, CCl2, CXCl2, CCl3, CCl4, CXCl10, IL-12 and IL-17f over seven days of treatment.

Integrated Drug Discovery Services by Oncodesign

Case studies for gut inflammation diseases

#1 DSS-induced Acute Colitis

DSS is added to drinking water, over a 7-day treatment protocol.  Tacrolimus (FK-506 immuno-suppressor) partially limits the evolution of the disease, as seen by DAI. Untreated animals display increased spleen size and weight at D7, and also colon shortening.

Tacrolimus limits spleen inflammatory cell accumulation. Cytokine expression can be measured by qPCR, and a classic inflammatory profile is typically observed, with elevated IL-1a, IL-1b and IL-6.

 

Score Body weight loss (%) Stool consistency Blood in feces
0 0 Normal Absence
1 1-5 Soft Hemoccult +
2 6-10 Very soft Hemoccult ++
3 11-15 Diarrhea Bloody
4 >15 Severe diarrhea
Gut - DSS colitis model graph Tacrolimus
Gut - Cytokine expression colon qPCR DSS colitis model

#2: DSS + Anti-CTLA4 Antibody-induced Chronic Colitis Model

Immuno-oncology approaches are promising new cancer treatments, but a number of unfortunate side effects need to be managed clinically.  These typically result from hyper-activation of the immune system, which can affect the gut, skin, liver or endocrine glands.  Over 1/3 of patients receiving the anti-CTLA4 antibody Ipilimumab report colitis symptoms, for example.

This same antibody is used by Oncodesign-Services to create a chronic colitis model by combining the antibody with DSS as a standard colitis inducer. Mice typically recover from the DSS-induced colitis after DSS removal on D7, but anti-CTLA4 treatment delays the recovery phase,mimicking chronic colitis.

 

Gut - DSS CTLA4 chronic colitis model BW graph