Final Progress Report

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

Lay Summary

Inflammatory bowel disease (IBD) is a chronic disorder characterized by an inappropriate intestinal immune response to unidentified luminal antigens.  This inappropriate immune response results in damage to the intestine; manifested by ulceration, bleeding, malabsorption of nutrients, stricture formation, fistula formation, and an increased risk for the development of cancer.  It is well accepted that T-lymphocytes are the primary cell types mediating this inappropriate immune response through the production of inflammatory cytokines.  The goal of this study was to examine inflammatory pathways that are activated during intestinal inflammation and that function to recruit these pathogenic T-lymphocytes into the intestine.

Lymphotoxin (LT) and its receptor, the LT beta receptor (LTβR), play crucial roles in the formation of lymph nodes during embryogenesis.  The interaction of LT with the LTβR results in the production of a number of small molecules, which act to recruit lymphocytes to the sites of lymph node formation.  LT and the LTβR are highly expressed in the adult intestine, however, the function of LT and the LTβR in the adult intestine at baseline and during inflammatory responses is unknown.

The interactions of LT with the LTβR can be disrupted in recently developed biologic therapies.   Studies have demonstrated that the LTβR blockade is effective at preventing inflammatory responses in a variety of organs in various animal models.  This agent has proven to be safe in nonhuman primates, and is currently being evaluated for the treatment of autoimmune/inflammatory conditions outside the gastrointestinal tract.   We propose that LT and LTβR may play analogous roles in the adult and fetal intestine, functioning to recruit T-lymphocytes into the adult intestine, and this effect may be augmented during inflammatory responses, such as those seen in IBD.  Accordingly, we believe that blockade of the LTβR may be an attractive therapy to prevent the recruitment T-lymphocytes into the intestine and to ameliorate the pathogenic T-lymphocyte responses seen in IBD. 

To explore the potential utility of LTβR blockade as a means to ameliorate intestinal inflammatory responses, we examined the cellular sources of LT and LTβR in the adult intestine, we examined LT and LTβR expression in active IBD and in the normal intestine, and we examined the factors produced following LTβR activation in the intestine.  We found elevated expression of LT and LTβR in the intestine of individuals with IBD.  We identified fibroblasts and macrophages as cellular sources of the LTβR in the intestine of individuals with IBD.  We identified several factors that are produced following LTβR activation, and whose expression is elevated in the intestine in the setting of IBD; these factors include chemokines, which act to recruit lymphocytes into the intestine during inflammation.  We observed that a primary function of LT and LTβR in the adult intestine is to drive the accumulation of lymphocytes into organized aggregates.  Notably, these aggregates have been proposed to harbor the earliest manifestations of Crohn’s disease.  These findings identify critical roles for LT and the LTβR in intestinal inflammatory responses and suggest that blockade of the LTβR or blockade of mediators produced downstream of the LTβR will be effective strategies to ameliorate pathogenic inflammatory responses seen in IBD.