Acute colitis

Abstract: Inflammatory bowel diseases (IBDs) result in diarrhea and abdominal pain with further potential complications such as tissue fibrosis and stenosis Animal models help in understanding the immunopathogenesis of IBDs and in the design of novel therapeutic concepts Here we present an updated version of a protocol we published in 2007 for key models of acute and chronic forms of colitis induced by 2,4,6-trinitro-benzene sulfonic acid (TNBS), oxazolone and dextran sulfate sodium (DSS) This protocol update describes an adaptation of the existing protocol that modifies the technique This protocol has been used to generate improved mouse models that better reflect the nature of IBDs in humans In TNBS and oxazolone colitis models, topical administration of hapten reagents results in T-cell-mediated immunity against haptenized proteins and luminal antigens By contrast, to generate DSS colitis models, mice orally receive DSS, causing death of epithelial cells, compromising barrier function and causing subsequent inflammation The analysis of the acute colitis models can be performed within 1-2 weeks, whereas that of the chronic models may take 2-4 months The strengths of the acute models are that they are based on the analysis of short-lasting barrier alterations, innate immune effects and flares The advantages of the chronic models are that they may offer better insight into adaptive immunity and complications such as neoplasia and tissue fibrosis The protocol requires basic skills in laboratory animal research

Abstract: Expression of IL-22 is induced in several human inflammatory conditions, including inflammatory bowel disease (IBD). Expression of the IL-22 receptor is restricted to innate immune cells; however, the role of IL-22 in colitis has not yet been defined. We developed what we believe to be a novel microinjection-based local gene-delivery system that is capable of targeting the inflamed intestine. Using this approach, we demonstrated a therapeutic potency for IL-22-mediated activation of the innate immune pathway in a mouse model of Th2-mediated colitis that induces disease with characteristics similar to that of IBD ulcerative colitis (UC). IL-22 gene delivery enhanced STAT3 activation specifically within colonic epithelial cells and induced both STAT3-dependent expression of mucus-associated molecules and restitution of mucus-producing goblet cells. Importantly, IL-22 gene delivery led to rapid amelioration of local intestinal inflammation. The amelioration of disease by IL-22 was mediated by enhanced mucus production. In addition, local gene delivery was used to inhibit IL-22 activity through overexpression of IL-22-binding protein. Treatment with IL-22-binding protein suppressed goblet cell restitution during the recovery phase of a dextran sulfate sodium-induced model of acute colitis. These data demonstrate what we believe to be a novel function for IL-22 in the intestine and suggest the potency of a local IL-22 gene-delivery system for treating UC.