GENETICALLY-ENGINEERED MODELS OF INFLAMMATORY BOWEL-DISEASE

Recent advances in genetic engineering techniques have made possible n ew and exciting approaches to generating models of inflammatory bowel disease in mice and rats. Several recent studies have demonstrated tha t targeted deletions of genes encoding for interleukin-2, interleukin- 10, or certain T-cell receptor proteins produce mice that spontaneousl y develop chronic intestinal inflammation similar to human inflammator y bowel disease. In addition, it has been demonstrated that the introd uction of HLA-B27 and human beta2-microglobulin genes into rats produc es transgenic animals that spontaneously develop chronic gastrointesti nal inflammation. Data derived from these studies suggest that T cells play an important role in regulating B-cell activity, such that an un restrained or unregulated B-cell response to normal luminal antigens o r bacterial products promotes chronic gut inflammation. In addition, t hese studies demonstrate that endogenous luminal bacteria are importan t in promoting or exacerbating chronic gut inflammation. Indeed, these studies indicate that the production of very different defects in the immune system leads, in many cases, only to gut mucosal inflammation, suggesting that the gut mucosa is subjected to substantially more ant igenic ''stress'' than are other tissues. Thus, these new models offer new and exciting avenues of research for the study of the pathogenesi s of inflammatory bowel disease as well as providing new and possibly more appropriate models for the development and testing of new therape utic agents for the treatment of these diseases.