REGULATION OF MUCOSAL IMMUNE-RESPONSES - THE MISSING LINK IN IBD

Although the etiology of inflammatory bowel disease (IBD) remains unkn own, a major working hypothesis is that it represents a dysregulated i mmune response to common enteric bacterial antigens. Until recently th ere has been relative death of experimental models to study this hypot hesis. However, exciting developments in experimental models of coliti s, including spontaneous, transgenic and knockout mice now allow this and other hypotheses to be tested. The regulation of mucosal immune re sponses is not well understood in the normal animal, much less in thos e with chronic intestinal inflammation. Clearly the CD4 Th1 and Th2 pa thways are important in the host response to microbial pathogens, and recent data indicate that the intestinal mucosa seems to be a site of preferential Th2 responses toward exogenous antigens. Deletion of cert ain cytokine genes involved in maintaining this Th1/Th2 balance (inter leukin [IL]-2, IL-10) resulted in colitis, although deletion of others (IL-4, interferon-gamma) that are also involved did not. Whether thes e cytokine gene deletions cause a dysregulation of the mucosal immune response has yet to be shown. However, the importance of regulation ca n be demonstrated in a model in which a normal CD4(+) T cell subset (C D45Rb(high)) is transferred into syngeneic severe combined immunodefic iency syndrome recipients. This results in a striking colitis over the ensuing weeks with chronic diarrhea and wasting of the animals. If th e reciprocal CD4(+) subset (CD45Rb(low)) is co-transferred of if whole CD4(+) T cells are transferred no colitis ensues. Therefore, T cells capable of causing colitis are present in normal animals but are preve nted from doing so by immunoregulatory mechanisms. The antigens that d rive the colitis in several of these models (IL-2 knockout mouse, huma n leukocyte antigen B27/beta 2M transgenic rat) appear to be those of the normal enteric bacterial flora because germ-free animals do not ge t the disease. Spontaneously colitic C3Y/HeJBir mice also show promine nt reactivity to enteric bacterial antigens. There are major differenc es among inbred mouse strains in susceptibility to colitis. The genes involved are not yet identified, but newly available technologies show allow that. In summary, these new models provide an experimental foun dation to one of the major hypotheses on the cause of IBD, and will al low dissection of the genetic, environmental and immune components con tributing to chronic colitis.