Counter-regulation in the mucosal immune system and the mechanism of mucosal inflammation

摘要

In recent years a large number of murine models of mucosal inflammation have appeared which, in aggregate, are adding immeasurably to our understanding of how immune responses are regulated in the mucosal immune system in normal animals and how dysregulation of such responses leads to human inflammatory bowel disease (IBD). In general, the mucosal inflammation occurring in these models is due to exaggerated or excessive Th1 T cell responses or, less commonly, to exaggerated or excessive Th2 T cell responses; alternatively, they are due to insufficient counter-regulatory responses that ordinarily control (suppress) Thl and Th2 T cell responses in the mucosal immune system (Fig. 1 and Table 1). A clear example of an experimental inflammation caused by an exaggerated response is provided by mice who bear a transgene for STAT-4, the intracellular signalling molecule that transduces IL-12 signals and thus is necessary for Thl T cell responses (Fig. 2). In these transgenic mice the STAT-4 transgene is under the control of a CMV promoter; thus when it is activated by systemic administration of DNP-KLH (an antigen capable of inducing cross-reactive responses to gut antigens) unregulated STAT-4 signalling occurs which leads to a colitis characterized by excessive production of IFN-gamma and TNF-alpha. In addition, if spleen and colonic T cells from mice bearing this STAT-4 transgene are activated in vitro by intestinal microflora and then are adoptively transferred to SCID mice they induce colitis in the latter. These results, taken together, indicate that the intestinal microflora can conceivably be a driving force of an excessive Thl T cell response leading to colonic inflammation.