Scientific Abstract
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
The etiology of inflammatory bowel disease (IBD) is unknown. Based upon our current understanding, IBD is due to a dysregulated adaptive immune response to luminal antigens. Despite our insufficient knowledge regarding the genetic defects and environmental stimuli relevant to the pathogenesis of IBD, we have gained valuable insight into the downstream pathways responsible for disease pathogenesis from the success of biologic therapies.
Drawing from this experience, we wish to examine the mechanism of a biologic therapy directed at a tumor necrosis factor (TNF) receptor family member, the lymphotoxin beta receptor (LTβR). Others have demonstrated that LTβR blockade is successful at preventing disease in animal models of intestinal inflammation; however, the relevant mechanism of this therapy remains unclear. We have recently identified a role for LTβR sufficient intestinal stromal cells in directing the composition of intestinal lymphocytes. Based upon the role of LTβR sufficient stromal cells in directing the composition and segregation of lymphocytes in other tissues, we propose that intestinal lamina propria (LP) stromal cells produce chemokines in an LTβR-dependent fashion, thus directing the composition of LP lymphocytes. Chemokines, and the cells and pathways resulting in their production, are attractive targets for immunomodulatory therapies, as chemokines may be produced in a tissue restricted fashion and may recruit specific subsets of immunologically relevant cell types.
We wish to combine our observations with the observations of others demonstrating the efficacy of LTβR blockade, to focus our studies and identify target molecules produced in an LTbR dependent manner by LP stromal cells. We believe that the efficacy of LTβR blockade in animal models of intestinal inflammation results in part from the prevention of LTbR dependent chemokine production by LP stromal cells.
The goal of this proposal is to identify the chemokines produced in a LTβR fashion by these stromal cells. We believe that identification of these chemokines will give important insight into the regulation of lymphocyte trafficking in the intestinal LP, and will provide more precise targets for pharmacological manipulation of intestinal inflammatory responses. The outlined proposal is unique in that little is known about the expression of LTβR in the intestinal LP or the mechanism by which LTβR expressing stromal cells direct the lymphocyte composition in the adult intestine. In this proposal, we will identify the LTβR expressing LP stromal cells within the intestine, and develop clonal cell lines for further in vitro studies. In addition, we will identify the relevant disease modifying molecules produced by LP stromal cells in a LTβR dependent fashion. Completion of the aims outlined in this study will broaden our understanding of the intestinal immune system in the basal state and in the state of inflammation. These studies may yield new targets for the therapy of IBD, and specifically targets which are intrinsic and potentially unique to the intestine.