| Inbred C57BL/6 mice develop an acute necrotizing ileitis following oral infection with Toxoplasma gondii that is associated with massive inflammatory infiltrates and morphologic tissue changes consistent with human Crohn's disease. In the course of the infection, the parasite interacts with both the innate and adaptive arms of the immune system. TLR9-dependant mechanisms, triggered by the parasite, induce Crp release in the lumen. Our results indicate that T. gondii induces Crp-3/-5 production and release by PCs via a TLR9-dependant production of type I IFN. Cryptdins have a limited direct effect against the parasite, but may affect the early control of T. gondii invasiveness by promoting the initiation of a protective Th1 response against the parasite. We also examined the ability of CD4+CD25+FoxP3+ T regulatory cells (Treg) to control T. gondii-induced ileitis. To determine whether the Treg cells generated during infection were suppressive, we adoptively transferred Treg from naive or T. gondii infected mice to naive animals, which were in turn infected. Mice that received T reg from infected mice showed reduced morbidity and improved small intestine pathology. Our results demonstrate that pathogen-experienced Treg are superior to naive Treg in control of T. gondii --induced ileitis. Finally, we investigated leukocyte cell trafficking to the intestine and CNS. Treatment with an analogue inhibitor of sphingosine-1-phosphate (S1P) reduced clinical and inflammatory changes in the small intestine. The brain parasite burden of treated mice was reduced indicating that S1P is required for both lymphocyte and parasite trafficking to the intestine and CNS following oral infection by T. gondii. Taken together, the studies presented herein demonstrate several potential targets for the treatment of inflammatory bowel disease. |
