2nd Annual BMRP Investigator Meeting - Abstract

Post-gestational Lymphotoxin/Lymphotoxin Beta Receptor Interactions Essential to the Intestinal Immune Response

Rodney D. Newberry

Department of Internal Medicine, Washington University School of Medicine (St. Louis, Missouri, U.S.A.)

Lymphotoxin beta receptor (LTbR), a tumor necrosis factor receptor superfamily member, has been demonstrated to play a crucial role in the development and organization of lymphoid tissues.  Ligation of the LTbR mediates these effects via the production of chemokines and adhesion molecules.  The role of the LTbR in other tissues, including the intestine, is not well understood.  Blockade of the LTbR with a soluble chimeric protein consisting of the extracellular domain of the LTbR fused with the immunoglobulin constant region (LTbR-Ig) is currently being tested as a treatment for human inflammatory diseases.  To better understand the role of LTbR blockade in ameliorating intestinal inflammatory responses, we examined the ability of LTbR-Ig to ameliorate disease in the splenocyte transfer model of intestinal inflammation and we examined the expression of the LTbR, its ligands, and downstream targets in biopsies from human inflammatory bowel disease (IBD).

We have observed that the LTbR is expressed in the adult murine and human intestine.  We observed that administration of LTbR-Ig prevented weight loss and intestinal inflammation in the splenocyte transfer model of intestinal inflammation.  Analysis of chemokine expression revealed that lamina propria cells from human-Ig (control) treated splenocyte recipients over-expressed multiple chemokines when compared with LTbR-Ig treated recipients.  To confirm the dependence of LTbR ligation upon the production of these chemokines, we examined the expression of chemokines by murine embryo fibroblasts following LTbR ligation by recombinant lymphotoxin (LT).  We identified RANTES, MIP-3a, and MIG as being chemokines whose expression is altered by administration of LTbR-Ig and whose expression is induced following LTbR ligation.  We observed increased expression of LTbR, LT, and LIGHT (a ligand for LTbR) in biopsies from human IBD.  We are currently examining the expression of these target chemokines in these biopsies.  Together, this data suggest that LTbR expression in the intestine contributes to inflammatory responses and that the efficacy of LTbR blockade in aborting intestinal inflammation may be mediated through decreased production of these three chemokines.