The frequency of Crohn's disease (CD) has increased substantially in industrialized countries over the last 40 years. CD is an overly exuberant Th1 response probably directed at normal constituents of the intestinal flora. Helminthes live within the human gut interacting with the mucosal immune system. The host mounts a mucosal Th2-type reaction to limit helminthic colonization. Helminthic worms and their eggs are potent stimulators of mucosal Th2 and suppressors of Th1 responses. Th2-type reaction to a helminth can modulate the immune response to other concomitant parasitic, bacterial and viral infections. Many people live in increasingly hygienic environments and acquire fewer helminthes. The major hypothesis of this proposal is that helminthic colonization conditions our mucosal immune system to appropriately respond to stimuli without excessive release of strong tissue-destructive, Th1 cytokines. Failure to undergo helminthic colonization and to experience this mucosal conditioning predisposes people to Crohn's disease, which is an overly exuberant Th1 reaction. To test this hypothesis, the investigator is using normal mice exposed to TNBS and IL-10 mutant mice that develop IBD spontaneously to show if exposure to a murine intestinal helminth affords protection against the subsequent aberrant intestinal Th1-type inflammation. The project has three specific aims.
Aim 1 will determine if helminthes protect mice from acute TNBS colitis and determine the role of T cells and cytokine pathways in mediating this protective process.
Aim 2 will evaluate the effect of helminthic conditioning on the natural development of chronic mucosal inflammation in the IL-10-/- mouse. The investigator will determine if exposure to helminthes can prevent or down-modulate ongoing spontaneous Th1-type colitis. Also, the investigator will identify mechanisms through which this exposure affords protection.
Aim 3 will determine if immune dysregulation or various agents used to treat IBD alter the host/helminth interaction. These experiments are important, since it must determined how patients with dysregulated immunity may respond to docile live helminthes used as therapy. This investigation could provide new insight into the pathogenesis of CD. The results may lead to novel therapies for disease prevention and treatment.
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