Biocytogen has developed DSS-induced, TNBS-induced, and T cell transfer IBD disease models, along with various IBD-related target humanized mice, such as B-hTL1A mice, for preclinical drug evaluation.
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Inflammatory bowel disease (IBD) refers tochronic inflammatory disease of the colon or gastrointestinal tract, including ulcerative colitis (UC) and Crohn's disease (CD) Clinical symptoms of IBD include recurrent diarrhea, abdominal pain, intestinal bleeding/hematochezia, fever, and weight loss. The pathogenesis of IBD is not clear, and studies have shown that various factors such as genes, immune system, external environment and intestinal microorganisms are associated with the occurrence of disease. A variety of preclinical mouse models are currently used to study IBD, and disease models derived based on different induction methods have specific uses. The mouse enteritis model induced by dextran sulfate sodium (DSS) is the most widely used chemically-induced mouse IBD model. Acute ulcerative enteritis or chronic colitis isinduced by dissolving DSS in drinking water, which destroys intestinal epithelial cells in mice, releases cytokines by non-specific immune cells, and finally results in disruption of the integrity of the mucosal barrier. Animals experience significant weight loss, loose stools, hematochezia, and granulocyte infiltration, symptoms that are extremely similar to human ulcerative colitis in clinical symptoms and pathological features.
A stable DSS-induced IBD disease model protocol was established in C57BL/6 mice by Biocytogen, which can be used for preclinical studies and pharmacodynamic evaluation of inflammatory enteritis.
| Mice strains |
| B-hCXCR2 |
| B-hTL1A |
| B-hTL1A/IL23A/IL12B |
| Readout | ||
| Included tests | Clinical scores | Body weight |
| DAI score | ||
| Colon | Colon length | |
| Colon weight | ||
| Histopathology | H&E | |
| Optional tests | Tissue homogenate | Cytokines test |
| Tissue histopathology | IHC | |
Efficacy Validation on IBD(wild-type C57BL/6) Mouse Models for CsA (cyclosporin A). C57BL/6 mice were provided drinking water containing DSS for 7 consecutive days, and body weight changes were recorded throughout and scored clinically(A-D) at study endpoint, the colon weight and colon length were recorded. Two way-ANOVA (A-D) or one way ANOVA (E-F) followed by multiple comparison. Values are expressed as mean ± SEM. ****p<0.0001, ***p<0.001 , **p<0.01 , *p<0.05.
Photomicrographs of histopathological score and H&E staining cross-sections (10x and 40x magnification). Values are expressed as mean ± SEM. ****p<0.0001, ***p<0.001 , **p<0.01 , *p<0.05
Effects of anti-IL12/23p40 on DSS-induced acute colitis.
C57BL/6 mice received 3% DSS in drinking water for 5 days, CsA was injected to mice every day from day0 to day7, anti-IL12/23P40 was administered to mice on day2, day 6 and day 8 (A). Body weight and excreta were recorded every day(B, C). At the end, colon was collected for H&E staining, colon length (D) and weight (E) were recorded. CsA and anti-IL12/23p40 alleviated 3% DSS induced ulcerative colitis in this experiment. Two way-ANOVA followed by multiple comparison. Values are expressed as mean ± SEM. ****p<0.0001, ***p<0.001 , **p<0.01 , *p<0.05.
Clinical score of IBD
Efficacy Validation on IBD(B-hCXCR2 mice) Mouse Models
C57BL/6 mice and B-hCXCR2 mice were provided drinking water containing DSS for 7 consecutive days, after which normal drinking water resumed. Body weight changes and clinical scores ( Weight loss score, stool hardness score, blood in stool score as well as total DAI score) were recorded throughout. Two way-ANOVA followed by multiple comparison, all group compared with G3. Values are expressed as mean ± SEM. ****p<0.0001, ***p<0.001 , **p<0.01 , *p<0.05.
Gross Sampling and Colon Evaluation
Histologic Assessment of the colon of IBD mouse model
C57BL/6 mice and B-hCXCR2 mice were provided drinking water containing DSS for 7 consecutive days, after which normal drinking water resumed. At study endpoint, colon length and colon weight were measured (left). And colon tissue were used for H&E staining (right). One-way ANOVA followed by multiple comparison, all group compared with G3. Values are expressed as mean ± SEM.
Body Weights and body Weight Changes
Clinical score of IBD
C57BL/6 mice and B-hTL1A/IL23A/IL12B mice were provided drinking water containing different concentration of DSS for 7 consecutive days. Body weight changes and clinical scores ( Weight loss score, stool hardness score, blood in stool score as well as total DAI score) were recorded throughout. Two way-ANOVA followed by multiple comparison, all group compared with G1. Values are expressed as mean ± SEM. ****p<0.0001, ***p<0.001 , **p<0.01 , *p<0.05.
Histologic Assessment of the colon of IBD mouse model
Gross Sampling and Colon Evaluation
C57BL/6 mice and B-hTL1A/IL23A/IL12B mice were provided drinking water containing different concentration of DSS for 7 consecutive days. At study endpoint, colon length and colon weight were measured. And colon tissue were used for H&E staining. One way ANOVA followed by multiple comparison compared to G1. Values are expressed as mean ± SEM. ****p<0.0001, ***p<0.001 , **p<0.01 , *p<0.05.
| Mice strains |
| B-hTL1A |
| Readout | ||
| Included tests | Clinical scores | Body weight |
| DAI score | ||
| Colon | Colon length | |
| Colon weight | ||
| Histopathology | HE | |
| Sirius Red staining | ||
| Optional tests | Tissue homogenate | Cytokines test |
| Tissue histopathology | IHC | |
Histologic Assessment of the colon of chronic colitis
DSS induced chronic colitis. Mice were repeatedly exposed to 4 cycles of DSS. Each cycle contained 2% DSS for 5 days, followed by water for the next 2 days (A). Body weight (B). colon weight and length were recorded, Histopathological sstaining H&E and Sirius Red. Colon was collected for histology analysis. Mice received DSS showed lower body weight (B) ,higher colon weight and shorter colon length than mice received water. Multiple T-test. Mean ±SEM, n=5, ****p<0.0001, ***p<0.001 , **p<0.01 , *p<0.05.
| Mice strains |
| B-hTL1A |
| Readout | ||
| Included tests | Clinical scores | Body weight |
| Colon | Colon length | |
| Colon weight | ||
| Histopathology | HE | |
| Optional tests | Tissue homogenate | Cytokines test |
| Tissue histopathology | IHC | |
Effects of CD4-GK1.5-mlgG2a on TNBS-induced acute intestinal inflammation. Animals were presensitizated with TNBS solution on shaved skin area on day 0, and then received TNBS intrarectal administration on day 7. Body weight (A) and body weight change (B) were recoded every day, CD4-GK1.5-mlgG2a (3, 10 mg/kg, i.p.) were administered on day 6. Mice were sacrificed on day 10 and colon length (C) and weight (D) were recorded. Two-way ANOVA or One-way ANOVE followed with Dunnett multiple comparisons, all groups compared with each other. Values are expressed as mean ± SEM. ****p<0.0001, ***p<0.001, **p<0.01 , *p<0.05.
Efficacy of PF06480605 on TNBS-induced acute IBD on B-hTL1A mice. Animals received TNBS intrarectal administration on day 0. For TA administration, 10 of 25 mg/Kg PF06480605 were administered on day -1, day 2 and day 5. Schematic diagram of the scheme(A). Survival rates (B) were calculated and body weight (C-D) were recorded every day. Two-way ANOVA followed with Dunnett multiple comparisons, all groups compared G2. Values expressed as mean ± SEM. ****p<0.0001, ***p<0.001, **p<0.01 , *p<0.05.
Gross Sampling and Colon Evaluation
Histologic Assessment of the colon of IBD mouse model
Animals received TNBS intrarectal administration on day 0. Body weight were recorded every day and survival rates were calculated. For TA administration, 10 of 25 mg/Kg PF06480605 were administered on day -1, day 2 and day 5. On day 7, mice were sacrificed and colon length and weight were recorded. Colone tissue was later used for H&E staining. One-way ANOVA followed with multiple comparisons, all groups compared with G2. Values expressed as mean ± SEM. ****p<0.0001, ***p<0.001, **p<0.01 , *p<0.05.
| Mice strains |
| B-hPSGL1(spleen donor) |
| Readout | ||
| Included tests | Clinical scores | Body weight |
| DAI score | ||
| Colon | Colon length | |
| Colon weight | ||
| Histopathology | H&E | |
| Optional tests | Tissue homogenate | Cytokines test |
| Tissue histopathology | IHC | |
| Histopathology | Sirius Red staining | |
Efficacy of T cell transfer inducing IBD.
The spleens of Balb/c mice were used to obtain CD4+CD25- T cells or CD4+ T cells using commercial kits. Animals in G2 received 3×105 CD4+ T cells injection while animals G3-G5 received same quantity of CD4+CD25- T cells. For treatment, animals in G4 received weekly administration of 10 mg/kg anti-TNFα and animal in G5 received weekly administration of 10 mg/kg anti-CD4. Two-way ANOVA or One-way ANOVA followed with multiple comparison, every group compared with G3. Values expressed as mean±SEM. ****p<0.0001, ***p<0.001 , **p<0.01 , *p<0.05.
