Experimental Models of Inflammatory Bowel Diseases

Abstract

The understanding of the intestinal inflammation occurring in the inflammatory bowel diseases (IBD) has been immeasurably advanced by the development of the now numerous murine models of intestinal inflammation. The usefulness of this research tool in IBD studies has been enabled by our improved knowledge of mucosal immunity and thus our improved ability to interpret the complex responses of mice with various causes of colitis; in addition, it has been powered by the availability of models in which the mice have specific genetic and/or immunologic defects that can be related to the origin of the inflammation. Finally, and more recently, it has been enhanced by our newly acquired ability to define the intestinal microbiome under various conditions and thus to understand how intestinal microorganisms impact on inflammation. In this brief review of murine models of intestinal inflammation we focus mainly on the most often used models that are, not incidentally, also the models that have yielded major insights into IBD pathogenesis.

Keywords: Cell Transfer Colitis; DSS Colitis; IL-10 Deficiency; Murine colitis models; NKT Cells; Oxazolone Colitis; TNBS Colitis; Th1 Cells; Th17 Cells; Tregs.

Figure 1

Mechanism of dextran sulfate sodium (DSS) colitis. DSS colitis is most essentially a colitis due to loss of epithelial barrier function and entry of luminal organisms or their products into the lamina propria. Such entry results in stimulation of innate and adaptive lymphoid elements and secretion of proinflammatory cytokines and chemokines. In addition, it results in the influx of cells with cytotoxic potential such as neutrophils and inflammatory macrophages.

Figure 2

Mechanism of oxazolone colitis. Oxazolone colitis is driven by natural killer T (NKT) cells that originate in the cytokine milieu of epithelial cells subjected to damage by oxazolone as well as hematopoietic cells in the lamina propria. As shown in the figure, the NKT cells are activated by glycolipids presented to them in the context of CD1 and then mediate toxicity via their direct cytotoxic activity directed at target epithelial cells bearing glycolipid antigen. Alternatively, the NKT cells mediate tissue damage via their production of interleukin-13, a cytokine that has been shown to affect tight junction proteins and to thereby affect epithelial barrier function.

Figure 3

The cell transfer colitis model. Cell transfer colitis is initiated in lymphopenic (SCID or Rag^−/−) mice that are the recipients of naïve CD45RB^high T cells, a cell population that cannot be induced to generate regulatory T cells in a timely fashion to prevent the expansion of effector T cells that mediate inflammation. However, if the naïve T cells are transferred in the company of mature CD45RB^low T cells that already contain regulatory T cells, the latter prevent the development of inflammation. This model thus provides a way of isolating the function of effector cells and regulatory cells.

Figure 4

The five experimental models of inflammation discussed in the text are grouped here in relation to their varying inducing conditions. To the right of the individual mouse models are the major mucosal immune functions/therapies/diseases that are best addressed using these respective models.