Crohns Disease A Failure of Mucosal Immunoregulation

Implicit in the function of the mucosal immune system is the ability to mount an immune response to pathogens whilst maintaining tolerance to the vast array of luminal antigens derived from food and commensal bacteria. The fact that many animal models of Crohn's disease remain disease-free if reared in germ free conditions suggest that luminal bacteria are involved in either the initiation or prolongation of intestinal inflammation. Further evidence for this hypothesis is provided by clinical studies showing that diversion of the faecal stream from an area of active inflammation via a defunctioning split ileostomy induces remission in 65-70% of patients with Crohn's disease, the majority of whom will relapse after the reintroduction of ileal effluent.21,22 A lack of tolerance to intestinal bacteria is probable, as the activity of the ileal effluent is lost after sterilization through a 0.22 ^m filter. Furthermore, mucosal mononuclear cells isolated from areas of active Crohn's disease proliferate in response to autologous intestinal bacteria, whereas mononuclear cells harvested from noninflamed intestine show no response to autologous bacteria, but will proliferate in response to heterologous intestinal flora.5 It is possible that this lack of tolerance is mediated by a failure in the generation or function of similar regulatory T lymphocytes that have been demonstrated to prevent disease in the CD4+CDRBhigh transfer model of colitis discussed above.

Crohn Disease Progression Model

Figure 4. Antigen specific regulatory T cells. The transfer of CD45RBhigh T cells into a C.B17 SCID mouse leads to a Th1 T-cell driven colitis that is dependent on the presence of luminal antigen. Cotransfer of regulatory T cell clones (Tr1) expressing a transgenic T-cell receptor specific to ovalbumin are able to suppress the CD45RBhigh colitis by secreting IL-10 and TGF-|. However, this regulatory effect will only occur in mice that are fed ovalbumin in their drinking water.

Figure 4. Antigen specific regulatory T cells. The transfer of CD45RBhigh T cells into a C.B17 SCID mouse leads to a Th1 T-cell driven colitis that is dependent on the presence of luminal antigen. Cotransfer of regulatory T cell clones (Tr1) expressing a transgenic T-cell receptor specific to ovalbumin are able to suppress the CD45RBhigh colitis by secreting IL-10 and TGF-|. However, this regulatory effect will only occur in mice that are fed ovalbumin in their drinking water.

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