Oxazolone Colitis: A Murine Model of  T Helper Cell Type 2 Colitis Treatable with Antibodies to Interleukin 4

Abstract

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 increase in TGF-β production, whereas nonlesional (proximal) T cells manifest an even greater 40–50-fold increase. In addition, anti–TGF-β administration leads to more severe inflammation which now involves the entire colon. The histologic features and distribution of oxazolone colitis have characteristics that resemble ulcerative colitis (UC) and thus sharply distinguish this model from most other models, which usually resemble Crohn's disease. This feature of oxazolone colitis as well as its cytokine profile have important implications to the pathogenesis and treatment of UC.

FTY720 Ameliorates Th1-Mediated Colitis in Mice by Directly Affecting the Functional Activity of CD4+CD25+ Regulatory T Cells

“…For histological examination, a sample of colon tissue located precisely 3 cm above the anal canal was obtained from the mice of all treatment groups. Tissues were graded semiquantitatively from 0 to 5 (0: no changes to 5: marked transmural inflammation with severe ulceration and loss of intestinal glands) in a blinded fashion according to previously described criteria (37,38).…”

An important regulatory role for CD4+CD8αα T cells in the intestinal epithelial layer in the prevention of inflammatory bowel disease

“…Interestingly, cotransfer of CD45RB low cells with CD45RB high cells to scid mice prevented initiation and progression of colitis, suggesting a suppressive effect of CD45RB low cells on CD45RB high cells during the pathogenesis of IBD (2). However, it is unlikely that these CD45RB low cells are prototypical Th2 cells, because Th2 cells can also induce colitis, as shown in human ulcerative colitis and in the trinitro benzene sulfonic acid-induced colitis model (4)(5)(6)(7). Furthermore, IL-4 has been shown to cause aggravation of intestinal inflammation (8).…”

Predominant T helper type 2‐inflammatory responses promote murine colon cancers

“…In this model, a Th2 type cytokine, interleukin (IL)-13 was the major effector cytokine. 21,22 Further, transfer of Th2-dominant T cells to T cell-deficient recipient mice resulted in ileal villus atrophy and goblet cell metaplasia, 23 while transfer of Th1 dominant T cells induced erosive gastritis with enhanced surface epithelial cell apoptosis. 24 These results suggest that a predominance of either Th1-or Th2-type cytokines in inflammatory responses has a major influence on the pathology and tissue remodeling in the chronic inflammation, and eventually affects controlling epithelial cell differentiation, as well as their turnover.…”