The broad, long-term objective of this application is to understand causes of intestinal inflammatory pathology induced during infection with the opportunistic protozoan pathogen Toxoplasma gondii. Ultimately, this will enable development of rational treatment strategies for inflammatory bowel diseases caused by dysregulated mucosal immunity in humans. Oral infection of C57BL/6 strain mice with Toxoplasma rapidly triggers a Crohn's disease-like pathology, characterized by overproduction of Type 1 cytokines leading to extensive necrosis in the small intestinal epithelium. Pathogenic populations of CD4+ T cells are believed to be mediators of disease. Studies in other model systems also suggest involvement of CD8+ T lymphocytes. Intraepithelial lymphocytes (IEL) are a major subset of T cells in the intestinal mucosa, the majority of which express the CD8 molecule. The hypothesis underlying this proposal is that dysregulated IEL responses play an important role in disease pathogenesis triggered by Toxoplasma and in human disease. To test this hypothesis, the specific aims are to isolate IEL and their subpopulations from T. gondii-infected mice and evaluate their ability to produce pro- and anti-inflammatory cytokines, as well as determining their cytotoxic activity on infected and noninfected target cells. Another aim is to determine if IEL from infected mice transfer pathology to infected and noninfected recipients, and if so whether this is dependent upon IEL cytokine production or cytotoxic activity. We will also determine if IEL are sufficient to cause pathology themselves, or if they act by triggering pathogenic lamina propria CD4+ T cells. Achieving these aims can be expected to contribute to a deeper understanding of IBD pathogenesis triggered by experimental infection, as well as during clinical disease.
Chronic inflammatory bowel disease is a widespread and serious condition with increasing incidence in developed countries. Factors involved in disease pathogenesis are not well understood. We expect to gain insight into immunological causes of disease in humans by using Toxoplasma gondii infection as a trigger. The ultimate goal is to develop improved treatments for disease.
