Oxazolone Colitis, a Th2 Colitis Model Resembling Ulcerative Colitis, Is Mediated by IL-13-Producing NK-T Cells (original) (raw)
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Journal of Experimental Medicine, 1998
In this study we describe oxazolone colitis, a new form of experimental colitis. This model is induced in SJL/J mice by the rectal instillation of the haptenating agent, oxazolone, and is characterized by a rapidly developing colitis confined to the distal half of the colon; it consists of a mixed neutrophil/lymphocyte infiltration limited to the superficial layer of the mucosa which is associated with ulceration. Oxazolone colitis is a T helper cell type 2 (Th2)-mediated process since stimulated T cells from lesional tissue produce markedly increased amounts of interleukin (IL)-4 and IL-5; in addition, anti–IL-4 administration leads to a striking amelioration of disease, whereas anti–IL-12 administration either has no effect or exacerbates disease. Finally, this proinflammatory Th2 cytokine response is counterbalanced by a massive transforming growth factor-β (TGF-β) response which limits both the extent and duration of disease: lesional (distal) T cells manifest a 20–30-fold incre...
Immunology, 2014
Interleukin-4 (IL-4) and IL-13 are critical drivers of immune activation and inflammation in ulcerative colitis, asthma and other diseases. Because these cytokines may have redundant function, dual targeting holds promise for achieving greater efficacy. We have recently described a bifunctional therapeutic targeting IL-4 and IL-13 developed on a novel protein scaffold, generated by combining specific binding domains in an optimal configuration using appropriate linker regions. In the current study, the bifunctional IL-4/IL-13 antagonist was evaluated in the murine oxazoloneinduced colitis model, which produces disease with features of ulcerative colitis. The bifunctional IL-4/IL-13 antagonist reduced body weight loss throughout the 7-day course of the model, and ameliorated the increased colon weight and decreased colon length that accompany disease. Colon tissue gene expression was modulated in accordance with the treatment effect. Concentrations of serum amyloid P were elevated in proportion to disease severity, making it an effective biomarker. Serum concentrations of the bifunctional IL-4/IL-13 antagonist were inversely proportional to disease severity, colon tissue expression of pro-inflammatory genes, and serum amyloid P concentration. Taken together, these results define a panel of biomarkers signifying engagement of the IL-4/IL-13 pathway, confirm the T helper type 2 nature of disease in this model, and demonstrate the effectiveness of dual cytokine blockade.
Non-lymphoid and lymphoid cells in acute, chronic and relapsing experimental colitis
Clinical & Experimental Immunology, 2008
In rodents, intracolonic administration of ethanol 30% induces an acute colitis, while administration of 2,4,6-trinitrobenzene sulphonic acid (TNBS) in ethanol induces a longer lasting colitis. In the acute and chronic stages of experimental colitis, lymphoid and non-lymphoid cells were studied in the colon by immunohistochemistry. During the acute inflammation a high damage score of the colon was observed, which was related to an increase in the number of macrophages and granulocytes. Also a change in distributional patterns of macrophage subpopulations was found. The chronic stage of TNBS-ethanol-induced colitis was characterized by an increase in the number of lymphocytes, especially T cells. These data suggest that macrophages and granulocytes are important in the acute phase of experimental colitis, while lymphocytes play a pivotal role in the chronic stage. As most inflammatory bowel disease (IBD) patients have relapses during the chronic disease, we attempted to induce a relapse during experimental colitis by giving a second i.p. or s.c. dose of TNBS. This resulted in increased damage scores of the colon, new areas of ulceration and a further increase in macrophage numbers. No effect on the number of granulocytes was seen. These results indicate that it is possible to mimic relapses in experimental colitis by a second administration of TNBS, and suggest that the rats had been sensitized by the first dose of TNBS, given into the colon.
Interleukin 13-mediated colitis in the absence of IL-4Rα signalling
Gut, 2017
Table 1: Disease activity in oxazolone treated gene-deficient or transgenic BALB/c mice. Groups Body weight a Distress Score b Colon length (cm) Colitis Score c Previously published BALB/c etoh 98.19±1.6 3.33±0.2 8.23±0.5 2.78±0.5 BALB/c [2] BALB/c oxa 91.66±1.8 * 9.38±0.9 *** 6.81±0.4 * 8.33±0.8*** BALB/c [2] BALB/c IL-4-/-89.85±1.4 ** 9.34±1.2 **
IL-33 Signaling Protects from Murine Oxazolone Colitis by Supporting Intestinal Epithelial Function
Inflammatory Bowel Diseases, 2015
Background-IL-33, a member of the IL-1 cytokine family that signals through ST2, is upregulated in ulcerative colitis (UC); however, the role of IL-33 in colitis remains unclear. IL-33 augments type 2 immune responses, which have been implicated in UC pathogenesis. We sought to determine the role of IL-33 signaling in oxazolone (OXA) colitis, a type 2 cytokine-mediated murine model of UC. Methods-Colon mucosal IL-33 expression was compared between pediatric and adult UC and non-IBD patients using immunohistochemistry and real-time PCR. OXA colitis was induced in
Gut, 2014
The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, a non exclusive (work performed as a US government employee) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if accepted) to be published in Gut editions and any other BMJPGL products to exploit all subsidiary rights, as set out in our license. No authors have competing interests but, declare the issuance of a patent broadly relevant to this work to Drs. Fuss and Strober, for the use of inhibitors of IL-13 in the treatment of ulcerative colitis.
Mediators of Inflammation, 2020
A hallmark of ulcerative colitis is the chronic colonic inflammation, which is the result of a dysregulated intestinal mucosal immune response. Epithelial barrier disruption which allows the entry of microorganisms eventually leads to more aggressive inflammation and potentially the removal of the colon. We have previously shown that the T helper- (Th-) type 2 cytokines, Interleukin- (IL-) 4 and IL-13, mediate CD4+ T cell- or B cell-driven inflammation in the oxazolone-induced mouse model of ulcerative colitis. In contrast, mice deficient in the shared receptor of IL-4 and IL-13, IL-4 receptor-alpha (IL-4Rα), on all cells develop an exacerbated disease phenotype. This suggests that a regulatory role of IL-4Rα is required to protect against severe colitis. However, the cell populations responsible for regulating the severity of disease onset through IL-4Rα in colitis are yet to be identified. By deleting IL-4Rα on specific cell subsets shown to play a role in mediating colitis, we de...
Inflammatory Bowel Diseases, 2005
Background and Aims: V␣14 natural killer T (NKT) cells seem to play important roles in the development of various autoimmune diseases. However, the pathophysiologic role of NKT cells in inflammatory bowel disease remains unclear. To clarify the mechanism by which the activation of NKT cells mediates protection against intestinal inflammation, we investigated the antiinflammatory role of specifically activated V␣14 NKT cells by glycolipids in a mouse experimental model of colitis induced by dextran sulfate sodium (DSS). Methods: Colitis was induced in C57BL/6 mice by the oral administration of 1.5% DSS for 9 days. A single dose of OCH or ␣-galactosylceramide, a ligand for NKT cells, was administered on day 3 after the induction of colitis. Body weights and colonic mucosal injury were assessed in each glycolipid-treated group. Interferon-␥ and interleukin-4 levels in the supernatants from colonic lamina propria lymphocytes (LPLs) were measured by enzyme-linked immunosorbent assay. Results: The administration of a single dose of OCH attenuated colonic inflammation, as defined by body weights and histologic injury. The protective effects of OCH could not be observed in V␣14 NKT cell-deficient mice. In vivo treatment with OCH had improved the interferon-␥/interleukin-4 ratio from colonic LPLs on day 9 after DSS treatment. Conclusion: The present data indicated that the activation of V␣14 NKT cells by OCH plays a pivotal role in mediating intestinal inflammation via altered mucosal T-helper type 1/type 2 responses. Therapeutic strategies that are designed to activate specifically V␣14 NKT cells may prove to be beneficial in treating intestinal inflammation.