| Chemical agents |
Dextran Sodium Sulfate (DSS) Colitis Model. |
Administration: DSS in different concentrations is dissolved in drinking water; depending upon the dosing conditions, a mouse can develop acute or chronic colitis Pathophysiology: induction of indirect intestinal inflammation due to epithelial injury limited to the gut mucosa—disruption of the epithelial monolayer lining causes the entry of gut microbiome and antigens followed by immune cell activation in the underlying tissues. Disease manifestations: weight loss, bloody diarrhea, colon shortening, crypt abscesses are formed; symptoms in the large intestines are more pronounced than in the small intestines Immune cells: lesions infiltrated by immune cells such as neutrophils and macrophages near the damaged segment; switches from Th1-Th17-mediated acute inflammation to Th2-mediated in chronic colitis exhibiting Th1/Th2 cytokine profile changes Cytokine and Chemokines: increased TNFα, IL-6, IL-17, and Keratinocyte Chemoattractant (KC) in the acute state; increase in IL-4, IL-10, and concomitant decrease in TNFα, IL-6, IL-17; increase in myeloperoxidase activity.
|
Chronic colitis induced by DSS resembles the clinical course of human U—features such as cryptitis and crypt abscesses due to transepithelial neutrophil migration. miRNA commonly dysregulated: miR-223 (↨) *, miR-21 (↨), miR-31 (↑), miR-146a (↑), miR-155 (↑), miR-196a (↓), miR-142-5p (↑), miR-133b (↨), miR-135b (↓), miR-124 (↓).
|
[43,44,45,46,47,48,49] |
| Chemical agents |
Trinitrobenzenesulfonic acid (TNBS). |
Administration: TNBS (haptenating agent) is dissolved in ethanol at different concentrations and delivered rectally; depending upon the dosing conditions, a mouse can develop acute or chronic colitis Pathophysiology: ethanol disrupts the epithelial barrier enabling the interaction with haptenating TNBS, rendering proteins immunogenic, causing acute cell-mediated immune response by acute Th1 inflammation characterized by infiltration of CD4+ T cells. Disease manifestations: dramatic weight loss, inconsistent stool, occult or bloody diarrhea, reduction in colon length, mucosal edema, distorted crypts, formation of abscesses, diffused colonic inflammation Immune cells: T cell tolerance to the microbiota is disrupted, exhibits heightened Th1-Th17 response Cytokines and Chemokines: increased IL-12, IL-23, and IL-17; increased IFNϒ.
|
The NOD2 gene is involved in both TNBS-induced colitis as well as human CD. The transmural nature of colitis and edema induced by TNBS is similar to human CD. miRNA commonly dysregulated: miR-223 (↑), miR-196a (↓), miR-10b (↓), miR-21 (↑), miR-133b (↨), miR-135b (↓), miR-142-3p (↑), miR-124 (↓).
|
[43,47,49,50,51] |
| Chemical agents |
Oxazolone |
Administration: intrarectal administration of oxazolone dissolved in ethanol (haptenating agent) Pathophysiology: the haptenating agent induces inflammation in the mucosal layers of mainly the distal colon and is primarily characterized by Th2 cytokine response Disease manifestations: striking drop in body temperature, colon tissue damage, loss of enterocytes and goblet cells, edema, and dense immune cell infiltration Immune cells: higher proportion of CD3+ Ly49c+ and CD4+ natural killer T (NKT) cells, infiltration of neutrophils and monocytes Cytokines and Chemokines: Th2-mediated responses, IL-4, IL-13 (may be induced by IL-33 from damaged epithelial cells or through IL-25), IL-9 (produced because of IL-13 stimulation and TGF-β).
|
|
[43,52,53] |
| Spontaneous colitis |
SAMP1/YitFcsJ mouse strain |
Derivation: selective and continuous brother-sister mating of parental AKR/J mice that developed skin lesions and ileitis formed the SAMP1/Yit colony, which upon constant inbreeding led to SAMP1/YitFc sub strain. Pathophysiology: spontaneous ileitis without genetic, chemical, or immunological manipulation; IFNϒ production at four weeks of age followed by ileitis at ten weeks of age; host-microbial interactions amplify disease severity. Disease manifestations: inflammatory changes are transmural and discontinuous, crypt elongation, villous blunting, infiltration by polymorphonuclear and mononuclear cells in the submucosa, cryptitis, crypt micro abscess formation as the disease progresses. Thickening of the bowel wall characterizes later stages of the disease. Secretory cells outnumber the epithelial/absorptive cells as the disease progresses. Immune cells: Th1 predominant in the early/inductive phase of the disease and changes to a Th1/Th2 chronic phase phenotype as severity progresses. Cytokines and Chemokines: chronic ileitis shows Th1 CD4+ cells that produce higher levels of TNFα and IFNϒ and a higher number of CD8 + α+T-cell receptor T cells.
|
CD-like ileitis, pathogenesis resembles chronic intestinal inflammation; useful for studying pathways that precede the clinical phenotype. Common features to human CD include disease location, the incidence of extra-intestinal manifestations, perianal disease and fibrostenotic strictures (hallmark features of human CD), and response to conventional therapies.
|
[54,55] |
| Spontaneous colitis |
C3H/HeJBirLtJ mouse strain |
Derivation: selective breeding of the severely affected C3H/HeJ mice with perianal ulcerations resulted in a substrain C3H/HeJBir with a high incidence of perianal ulceration and soft feces. Pathophysiology: mice develop a spontaneous and heritable form of idiopathic IBD, developing defective mucosal immune regulation allowing the activation of pathogenic T cells against gut bacterial antigens Disease manifestations: perianal ulcers occur between 4–7 weeks and once healed, do not recur. Intestinal lesions are present primarily in the cecum, and right colon, characterized by acute and chronic inflammation, ulceration, crypt abscesses, regenerative hyperplasia, and submucosal scarring; less than 10% of cases develop occult blood, soft feces, and large perianal ulcers. Immune cells: CD4+ T cells are quickly activated to produce a Th1-type response, increased IgM B+ cells in Peyer’s patches, increased intestinal S-IgA levels, higher level of activation markers such as CD45RB and CD44 than those from C3H/HeJ, elevated α4β7peripheral blood lymphocytes and in colon intraepithelial lymphocytes when compared to parental levels. Cytokines and Chemokines: CD4+ T cell in response to bacterial antigens produce predominantly IL-2 and IFNϒ.
|
A valuable resource for genetic and immunological studies of the disease. Mice develop an idiopathic chronic inflammatory bowel illness that is heritable. Acute and chronic inflammation, submucosal scarring, regenerative hyperplasia, crypt abscesses, and ulcerations are found in histopathology investigations of cecum and proximal colon lesions.
|
[56,57] |
| Gene knockout (KO) |
B6.129P2-Il10tm1Cgn/J
(IL-10 KO) |
Derivation: targeted deletion of IL-10 in mice leads to the development of spontaneous inflammation; deletion of IL-10 from Foxp3+ Treg cells also results in spontaneous colitis. Pathophysiology: immune cell stimulation by gut bacteria is critical for colitis development in this model; the aberrant response of CD4+ Th1-like T cells. Disease manifestations: inflammatory infiltration by lymphocytes, macrophages, and neutrophils. Immune cells: initial inflammation is pro-inflammatory Th1 T cell-driven, progressive increase in Th2 cytokines; excessive inflammatory response may also be due to loss of p100δ induction. Cytokines and Chemokines: after increasing Th1 T cell response (IL-12, IL-17, and IFNϒ), there is a reduction in its production and increased Th2 cytokines IL-4 and IL-13.
|
IL-10 locus polymorphism has been shown to increase the risk for development of both UC and CD. Colon histopathology shows similarities to human IBD samples. miRNAs commonly dysregulated: miR-223 (↑), miR-101 (↑), miR-155 (↑), miR-31 (↑), miR-142-5p (↑), miR-21 (↑), miR-146a (↑).
|
[43,49,58,59] |
| Reconstitution of immunodeficient mice with CD4+ T-cells |
Adoptive transfer colitis |
Derivation: pancolitis and small bowel inflammation is induced 5–8 weeks after adoptive transfer of naïve CD4 + CD45RB (high) T cells from healthy wild type mice into syngeneic mice (such as RAG KO) that lack T and B cells. Pathophysiology: disruption of T cell homeostasis; good model for examining the early onset of disease inflammation and perpetuation; naïve T cells are susceptible to gut antigens, activating colitogenic T cells secreting cytokines leading to small and large intestinal inflammation. Disease manifestations: transmural inflammation, dense immune infiltration by neutrophils, crypt abscesses; varied degree of weight loss, diarrhea, and loose stools depending on the donor and recipient mouse strain.
|
This model shows both colitis and small bowel inflammation, which is similar to Crohn’s disease. Disease manifestations, including epithelial cell hyperplasia and cell erosion, transmural inflammation, significant infiltration of leukocytes, and crypt abscesses are similar to those seen in human IBD. Delineates the immunological mechanisms in the induction and regulation of chronic inflammation. miRNAs commonly dysregulated: miR-223(↑), miR-146a (↑), miR-146b (↑), miR-142-5p (↑), miR-21 (↑), miR-203 (↓).
|
[43,58,60,61] |
