New IBD Model: C3Bir.129P2(B6) -Il10tm1Cgn/Lt
JAX® NOTES Issue 502, Summer 2006
Inflammatory bowel disease (IBD) is a complex heterogeneous group of gastrointestinal diseases that affect children and adults. Its two most common forms are Crohn's disease and ulcerative colitis. Though it 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 result in the immune system's inability to suppress inflammatory responses to normal enteric flora. IBD susceptibility loci have been identified on at least 10 different human chromosomes (Farmer et al. 2001). The Jackson Laboratory has recently developed a promising new model of spontaneously induced chronic IBD: congenic mouse strain C3Bir.129P2(B6)-Il10tm1Cgn/Lt (004326).
C3Bir.129P2(B6)-Il10tm1Cgn/Lt has a targeted mutation of the interleukin 10 (Il10) gene (on Chr 1), one of several genes whose disruption induces IBD. Its encoded cytokine, IL10, is secreted by T cells, B lymphocytes, macrophages, and dendritic cells. It is essential for maintaining intestinal homeostasis by suppressing the production of proinflammatory cytokines (particularly IL12, IL1, and TNF) by macrophages, dendritic cells, and neutrophils in response to enteric flora antigens (Farmer et al. 2001; Mahler and Leiter 2002).
Evidence from several studies using mouse models indicates that the ability of IL10-deficiency to induce IBD depends on at least two factors: 1) strain-dependent modifier genes and as yet undefined and 2) possibly strain-unique enteric flora. Evidence for strain-dependent modifier genes is substantial: several studies have either revealed or confirmed that whereas IBD-susceptibility in Il10-deficient C57BL/6J mice is mild, it is severe in Il10-deficient 129SvEv, BALB/cJ, and C3H/HeJBir mice (Berg et al. 1996; Bristol et al. 1997, 2000; Mahler and Leiter 2002). The differential susceptibility between Il10-deficient C57BL/6J and Il10-deficient C3H/HeJBir mice has been attributed to six QTLs (Beckwith et al. 2005). Although the enteric flora necessary to induce IBD in Il10-deficient mice (and in other mouse models and humans) have not been identified, evidence that they exist and contribute to susceptibility is also substantial. For example, C3Bir.129P2(B6)-Il10tm1Cgn/LtJ mutants (003968, now cryopreserved) are identical to C3Bir.129P2(B6)-Il10tm1Cgn/Lt mice. 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 enteric flora, they apparently indicate their presence or are associated with them.
We maintain our colony of C3Bir.129P2(B6)-Il10tm1Cgn/Lt mice at JAX West, in isolators that harbor Helicobacter and other as yet undefined enteric flora necessary to induce IBD. Under these conditions, they develop the following phenotype:
- stable inflammatory lesions in the cecum and colon in both sexes by six to seven weeks of age;
- outward signs (perianal ulceration, diarrhea) of IBD in the majority by three to four months of age;
- a near-normal and stable body weight, making them amenable to therapeutic interventions; and
- colitis that can be assessed by measuring either circulating neutrophil numbers or elevated blood serum amyloid A (SAA) levels.
In addition to the C3Bir.129P2(B6)-Il10tm1Cgn/Lt strain, several other JAX® Mice strains may be used to research IBD. Our In Vivo Research Services can use either dextran sodium sulfate (DSS) to induce IBD in C3H/HeJ males or trinitrobenzene sulfonic acid (TNBS) to induce it in C57BL/6J males or BALB/cJ females. These models all have unique IBD phenotypes (Table 1) and can be used to research various aspects of IBD. Alternatively, some investigators have used Il10-deficient mice on a C57BL/6J background (B6.129P2-Il10tm1Cgn/J, 002251). Elliott et al. (2004) maintained such mice in SPF conditions (where they are colitis-free) and treated them with piroxicam to induce colitis; Hale et al. (2005) maintained them in conventional mouse rooms (where they normally develop colitis by six to seven months of age) and treated them with piroxicam to accelerate the development of colitis.
| Table 1. IBD phenotypes and three JAX Mice IBD models.1 | |||||
|
Characteristics |
Humans |
Mouse Models | |||
|
C3Bir.129P2(B6)-Il10tm1Cgn/Lt |
C3H/HeJ (males) |
C57BL/6J (males) | |||
|
Disease |
Crohn's disease |
ulcerative colitis |
spontaneous IBD |
DSS-induced2 IBD |
TNS-induced3 IBD |
|
Age of onset |
teen-adult |
teen-adult |
3-6 weeks |
2-3 weeks |
1-2 weeks |
|
Areas involved |
ileum |
|
|
|
|
|
cecum |
|
|
cecum |
| |
|
colon |
colon |
colon |
colon |
distal colon | |
|
|
rectum |
rectum |
|
| |
|
Histology |
transmural |
mucosal |
mucosal |
mucosal |
transmural |
|
ulceration |
ulceration |
ulceration |
ulceration |
ulceration | |
|
submucosal fibrosis |
loss of goblet cells |
wound healing, |
wound healing, |
Acute necrosis | |
|
|
crypt abcesses |
crypt abcesses |
crypt distortion |
| |
|
Weight loss |
sometimes |
sometimes |
no |
severe |
severe |
1 Information complied from Crohn's and Colitis Foundation of America Web site (www.ccfa.org) and references cited throughout the text.
2 DSS: dextran sodium sulfate. Typically, mice are given 3.5% DSS in drinking water for five days.
3 TNBS: trinitrobenzene sulfonic acid. Typically, mice are given an enema of 3.75 mg TNBS in ethanol.
Although you can generally order up to 20 C3Bir.129P2(B6)-Il10tm1Cgn/Lt (004326) mice of mixed gender per month, you can order more by making arrangements with JAX Services.
If your facility does not allow you to import C3Bir.129P2(B6)-Il10tm1Cgn/Lt mice because of their health status, our In Vivo Research Services experts at JAX West can conduct a study for you. We can dose the mice with prophylactic or therapeutic compounds (IP, IV, SC, PO, and other routes), harvest cecum and colon tissue, and determine lesion severity using a scale developed by Jackson Laboratory scientist Dr. John Sundberg and his colleagues.
To order or inquire about the availability of any of our IBD models, call us at 800-422-MICE (6423) or e-mail jaxservices@jax.org.
References
Beckwith J, Cong Y, Sundberg JP, Elson CO, Leiter EH. 2005. Cdcs1, a major colitogenic locus in mice, regulates innate and adaptive immune response to enteric bacterial antigens. Gastroenterology 129:1473?84.
Berg DJ, Davidson N, Kuhn R, Muller W, Menon S, Holland G, Thompson-Snipes L, Leach MW, Rennick D. 1996. Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. J Clin Invest 98:1010-20.
Bristol IJ, Farmer MA, Cong Y, Zheng XX, Strom TB, Elson CO, Sundberg JP, Leiter EH, 2000. Heritable susceptibility for colitis in mice induced by IL-10 deficiency. Inflamm Bowel Dis 6:290-302.
Bristol IJ, Mahler M, Leiter EH, Sundberg JP. 1997. Il10tm1Cgn, an Interleukin-10 gene targeted mutation. JAX NOTES 471:2-4.
Elliott DE, Setiawan T, Metwali A, Blum A, Urban JF Jr, Weinstock JV. 2004. Heligmosomoides polygyrus inhibits established colitis in IL-10-deficient mice. Eur J Immunol 34:2690-8.
Farmer MA, Sundberg JP, Bristol IJ, Churchill GA, Li R, Elson CO, Leiter EH. 2001. A major quantitative trait locus on chromosome 3 controls colitis severity in IL-10-deficient mice. Proc Natl Acad Sci U S A 98:13820-5.
Hale LP, Greer PK, Trinh CT, Gottfried MR. 2005. Treatment with oral bromelain decreases colonic inflammation in the IL-10-deficient murine model of inflammatory bowel disease. Clin Immunol 116:135-42.
Hendrickson BA, Gokhale R, Cho JH, 2002. Clinical aspects and pathophysiology of inflammatory bowel disease. Clin Microbiol Rev 15:79-94.
Mahler M, Leiter EH, 2002. Genetic and environmental context determines the course of colitis developing in IL-10-deficient mice. Inflamm Bowel Dis 8:347-55.
