Lay Summary

Proposal No.   IBD-0042
Principal Investigator:  Rodney Newberry, M.D.
Applicant Organization:  Washington University (St. Louis, Missouri, U.S.A.)
Project Title:  Post-gestational lymphotoxin/lymphotoxin beta receptor interactions essential to the intestinal immune response
Period of Award:  January 1, 2003 – March 31, 2005

Inflammatory bowel diseases (IBD) are chronic inflammatory conditions affecting the large and/or small intestines.  The precise causes of these diseases are not known, but our current understanding suggests that these diseases result from an inappropriate immune response to stimuli, such as normal bacteria that reside in the intestine.  Despite our lack of knowledge as to how these inflammatory conditions arise, we have gained significant insight into these diseases by studying the mechanisms of some of the successful therapies.

In previous studies, blocking the function of a tumor necrosis factor receptor family member, the lymphotoxin beta receptor (LTβR), prevented intestinal inflammation.  The mechanism of action of this therapy is unclear, but we feel it is related to the function of the LTβR in cells intrinsic to the intestine, intestinal stromal cells.  We have recently identified a role for intestinal stromal cells in directing the composition of immune cells in the intestine through the function of the LTβR.  We propose to use our observations, and the observations of others regarding the efficacy of LTβR blockade in preventing intestinal inflammation, to focus our studies on the role intestinal stromal cells play in intestinal inflammatory responses.  We propose to identify the LTβR expressing stromal cells within the intestine, and the factors these cells produce, which contribute to the propagation of chronic inflammation in the intestine.  These stromal cells are intrinsic and potentially unique to the intestine, and therefore these cells and the inflammatory processes they participate in are attractive targets for specific therapies for IBD.