Scientific Abstract

Proposal No. IBD-0281
Principal Investigator:  Joel V. Weinstock, M.D.
Applicant Organization:  Tufts Medical Center (Boston, Massachusetts, U.S.A.)
Project Title:  Helminth induction of distinct regulatory T cell subsets that control murine inflammatory bowel disease
Period of Award:  August 1, 2009 - February 29, 2012

A dysregulated mucosal immune response to normal intestinal bacteria may lead to human IBD. These diseases have increased substantially in industrialized regions over the last 75 years, and now are increasing quickly in developing countries. Unrecognized environmental factors clearly influence susceptibility for IBD. Our major hypothesis is that living in an exceedingly clean environment negatively effects immune development and predisposes to IBD. Moreover, we proposed that the modern day absence of exposure to intestinal helminths resulting from this hygiene is an important environmental factor contributing to IBD in industrialized societies. Helminths regulate their host’s immune system and prevent excessive immune responses. Until the present era, nearly all children and adults harbored intestinal helminths. Substantial epidemiological data, and human and animal studies support this hypothesis. Others and we showed that helminths prevent or reverse intestinal inflammation in various animal models of IBD. This proposal will focus on worm induction and control of regulatory-type T cells in colitic mice, since this likely is a major portal through which helminths control IBD. The major hypothesis of this application is that within the gut helminths induce expression of several distinct regulatory T cell subsets that work in concert to limit disease potential and antigen-specific mucosal responses. The project will use a Rag-IL10 transfer murine model of IBD characterized in our laboratory and substantiate findings using the CD25- T cell Rag transfer model. The experiments will use various “reporter” mice and other transgenic animals, in vitro cell culture, adoptive cell transfer, cytokine inhibitors and various molecular and immunological techniques. Also employed will be Heligmosomoides polygyrus, an intestinal helminth of mice. Aim I will characterize the regulatory T cell phenotypes induced in the gut following helminth infection. This aim will test the hypothesis that helminths promote the appearance of various, distinct regulatory-type T cell subsets in the intestines that act locally in the gut to limit the function of the local effector T cells. Aim II will study the capacity of worm-induced, regulatory T cells to restrict effector T cell function in colitis. This aim will test the hypothesis that helminths promote the appearance of regulatory-type T cell subsets in the intestines that inhibit the antigen-driven effector T cells that drive the inflammation. This investigation may provide fresh insight into the pathogenesis of IBD and lead to better treatment.