IBD hu-mouse model

Inflammatory Bowel Diseases (IBD) is mediated by bowel epithelium cells and by immune cells such as infiltrating T lymphocytes and macrophages known to be key components of the disease progression via the secretion of inflammatory human cytokines like human-TNFα. Classical Inflammatory Bowel Diseases murine models do not offer the possibility to assess human-specific drugs targeting human-specific immune cells or human cytokines such as human-TNFα. However, reconstitution of a fully functional human immune system in hu-mice with both lymphoid and myeloid lineages reconstitution is ideal for the profiling of human specific drug targets such as mAb against h-TNFα.
Acute and/or chronic IBD can be induced in hu-mice by addition of Dextran Sulfate Sodium (DSS) in the drinking water or TNBS in the colon. A clinical global scoring and specific scales have been developed to determine the severity of the Inflammatory Bowel Diseases either related to progression or regression. Body weight, stool consistency, rectal bleeding and mortality have been scored and are presented. We are also applying colonoscopy imaging tools for non-invasive assessment of the early disease onset.

 

 

Induction of chronic/acute Colitis and Evaluation in hu-IBD 

Human Mediated Inflammation

Infiltration of Human Immune Cells

  • Human leukocyte infiltration in the hu-mouse colon
  • Co-localization of ALU staining and huTNF-α

Ulceration And Damage Of The Mucosa

  • DSS induced colitis
  • Ulceration and extensive damage of the mucosa
  • Scoring by Anapathophysiologist

Implication Of Human TNF-alpha

  • Anti-TNF-α decreased DSS induced chronic colitis severity
  • Implication of human cytokines in DSS induced chronic colitis

Infiltration of Human Lymphocytes

  • DSS induced colitis
  • hCD3 infiltration in inflamed colon

Implication of T-Cells in DSS Induced Colitis

  • Cyclosporine-A decreased DSS induced chronic colitis severity
  • Implication of T-cells in DSS induced chronic colitis

Readouts

Histopathology hu-IBD Colitis Scales and Scores

Ulceration and extensive damage of the mucosa 

Clinical hu-IBD Colitis Scales and Scores

Endoscopic index of Colitis Severity

Advantages:

detailed description of colonic mucosa

mucosal lesion follow-up over time

early and accurate appearance of colitis compared to the

clinical score alone. (cf. graph.)

real time treatment efficacy on evolution of the lesions

after drug treatment

good correlation with histological analysis

reveal optimal therapeutic window for single or combo

therapies

Strengths of IBD hu-mouse model

  • Acute and chronic models
  • Infiltration of human leukocytes in inflamed colon
  • Lymphoid and Myeloid compartments implicated
  • Efficacy evaluation and bioequivalence of human specific monoclonal antibodies (anti-hTNFa)

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