July 23, 2012

IBD Compound Efficacy Testing at JAX

Inflammatory bowel disease (IBD) is a chronic, relapsing and remitting (comes and goes) inflammatory condition characterized by two overlapping phenotypes – ulcerative colitis (UC) and Crohn’s disease (CD). Whereas UC primarily affects the colon, CD affects both the colon and the distal small intestine. Though IBD occurs worldwide, it is more common in the United States, the United Kingdom, and Scandinavia (Hendrickson et al. 2002). Its pathogenesis is likely due to a complex interaction of genetic and environmental factors that render the immune system unable to suppress inflammatory responses to normal gastrointestinal (GI) flora (Elson et al. 1998). Whether in humans or mouse models, IBD severity is greatly enhanced by the presence of that flora. We specialize in testing compound efficacy in IBD mouse models that harbor that flora.

IBD and GI flora

Although the GI flora that enhance IBD susceptibility have not been identified, evidence that they exist is substantial. For example, C3Bir.129P2(B6)-Il10tm1Cgn/LtJ mice (003968, now cryopreserved) are genetically identical to C3Bir.129P2(B6)-Il10tm1Cgn/Lt mice (004326). However, when they are maintained in full barrier, Helicobacter-free rooms, they do not spontaneously develop IBD. Although Helicobacter species are not known to be the colitogenic trigger in the GI flora, they apparently indicate their presence or are associated with them (JAX NOTES 2006).

Testing compound efficacy in IBD mouse models

All our IBD mouse models, except C3H/HeJ (000659), develop IBD more consistently and severely when they harbor the necessary GI flora. We maintain our colony of C3Bir.129P2(B6)-Il10tm1Cgn/Lt mice (004326) at our in vivo pharmacology services facility, in a room with natural flora, and we transfer that flora to all our IBD mouse models. We distribute and test compound efficacy in the following models:

Induction by dextran sodium sulfate (DSS) (acute)

Lab mouse C57 black 6, stock number 000664
C57BL/6J (000664) mouse used in DSS-induced acute and chronic models of IBD.
  • C57BL/6J (000664) mice are induced via DSS-laced drinking water for one 5- to 6-day cycle
  • Study lasts up to 14 days and can be extended to assess fibrosis
  • Disease severity can be controlled
  • Affects cecum and colon in two phases: primary acute phase is a mechanical insult; secondary acute phase is an innate immune response mediated by dendritic cells and macrophages
  • Histology: mucosal inflammation, ulceration, poor wound healing, fibrosis, mucosal hyperplasia, crypt abscesses
  • Reference compounds include sulfasalazine and glatiramer acetate
  • Measurements of compound efficacy: body weight, disease activity index (stool consistency, blood, rectal prolapse), colon and cecum histology

Induction by DSS (chronic)

  • C57BL/6J (000664) mice are induced via DSS-laced drinking water for three 5- to 6-day cycles, each separated by a week of standard drinking water
  • Study last 5 weeks
  • Disease severity can be controlled
  • Affects cecum and colon: acute phases (see above) progress to chronic phase, which is T cell-mediated and leads to fibrosis
  • Histology: mucosal inflammation, ulceration, poor wound healing, fibrosis, mucosal hyperplasia, crypt abscesses
  • Reference compounds include sulfasalazine and glatiramer acetate
  • Measurements of compound efficacy: body weight, disease activity index (stool consistency, blood, rectal prolapse), colon and cecum histology

Induction by trinitrobenzene sulfonic acid (TNBS) (acute)

Lab mouse BALB/c, stock number 000651
BALB/cJ (000651) mouse used in TNBS-induced model of acute IBD.
  • BALB/cJ (000651) mice are induced via rectally injected TNBS
  • Study lasts up to 14 days
  • Disease severity can be controlled
  • Affects distal colon: mechanical insult increases permeability and exposure of innate immune system to bacterial flora; innate immune system activates the Th1 response, leading to IFNG and IL2 secretion
  • Histology: transmural necrosis, acute necrosis and inflammation
  • Reference compounds include sulfasalazine and glatiramer acetate
  • Measurements of compound efficacy: body weight, disease activity index (stool consistency, blood, rectal prolapse), colon and cecum histology

Adoptive transfer of CD45HI cells – a T cell population depleted of regulatory T cells) (chronic)

Lab mouse BALB scid, stock number 001803
CBySmn.CB17-Prkdcscid/J (BALB scid, 001803) mouse used in adoptive transfer model of chronic IBD.
  • BALB/cByJ (001026)-derived CD45RBHI cells are injected IP or IV into CBySmn.CB17-Prkdcscid/J (BALB scid, 001803) mice
  • Study lasts 2-5 months
  • Most chronic model, with severe disease
  • Also a model of psoriasis
  • Affects colon: adaptive immune response; Th1/Th17-mediated disease (Th17 may be involved as a regulatory response)
  • Histology: poor wound healing, fibrosis, mucosal hyperplasia
  • Measurements of compound efficacy: body weight, disease activity index (stool consistency, blood, rectal prolapse), colon and cecum histology

As you can see, each model mimics different aspects of human IBD. Whereas the acute DSS and TNBS models develop IBD in a relatively short time, the adoptive transfer model develops IBD over a longer time period. Whereas the DSS models are used to initially screen the efficacy of novel compounds, the other models more strongly involve the types of dysregulated T cells typical of human IBD.

JAX® In Vivo Pharmacology Services for IBD

The JAX In Vivo team is outstandingly and singularly qualified to perform compound evaluation studies in IBD mouse models:

  • PhD-level directors oversee approximately 75 autoimmune and inflammatory disease studies each year
  • The team developed and characterized all the models described above
  • The team developed IBD severity scales and characterized many disease-stage phenotypes, including percentage body weight change, colon-to-weight ratios, colon histopathology, and sulfasalazine efficacy, for each model
  • JAX has a state-of-the-art mouse in vivo pharmacology services facility (including ABSL1 and ABSL2 rooms) that can house approximately 13,000 mice

For more details, including comparisons with human IBD, experimental timelines, and sample protocols, see our In Vivo Pharmacology Services website.

If you want compound evaluation studies performed by the people who pioneered and continually improve the best IBD models available, call our Customer Service Department at 1-800-422-6423 (US, Canada & Puerto Rico) or 1-207-288-5845 (from any location) and tell them you want our In Vivo team to conduct an IBD study for you.