Lay Summary

Proposal No.   IBD-0056
Principal Investigator:  Andrew W. Stadnyk, Ph.D.
Applicant Organization:  Dalhousie University (Halifax, Nova Scotia, Canada)
Project Title: Targeting neutrophil transepithelial migration as a means of controlling inflammation
Period of Award:  June 1, 2003 - May 31, 2004

Crohn's disease and ulcerative colitis (inflammatory bowel disease – IBD) are chronic intestinal inflammatory diseases of unknown causes.  Recent successes with the biological agent, “anti-TNF monoclonal antibody,” has demonstrated that understanding the events of the inflammatory response can lead to new strategies to treat the disease.

It is presently understood that IBD is due in part to an overactive inflammatory response, possibly including reacting to the bacteria in our intestines.  One feature of the inflammation is the presence of neutrophils, one type of white blood cell, in the intestinal tissues.  Neutrophils are normally found in the blood, but are recruited to sites of injury to battle invading pathogens.  In the absence of pathogens, these cells aggressively attack the normal tissues in the intestine.  In the intestines, neutrophils also migrate straight across the tissue and into the lumen, resulting in damage to the cells lining the gut.  It is believed that this damage makes the inflammation worse and so stopping the neutrophils from reaching the lumen may help reduce the inflammation.  We are studying how the neutrophils cross the lining cells (the epithelium) with a goal of discovering how to prevent it.

We have made progress in understanding what draws the neutrophils out of the blood in the first place.  It seems that the epithelial cells make chemicals that attract neutrophils as a result of the first insult to the intestines.  In fact, evidence gathered from experimental intestinal inflammatory diseases suggest the epithelial cells can initiate the inflammatory response, but this has not been proven in humans with IBD.  The recruitment of neutrophils may be making the inflammation worse by provoking further production of inflammatory chemicals by the epithelium.

We are studying how neutrophils stick to the epithelium when crossing it.  The epithelium is a formidable barrier to a cell determined to reach the lumen and the neutrophils must stick to, and push their way between, adjacent cells.  We can imitate these events using cells in the laboratory.  We already work with neutrophils from IBD patients, in case there are things going on in the blood of the patient that make their neutrophils behave differently than a healthy person's cells might behave.  The limitation in the present experimental system is that human cancer cells are used instead of normal epithelial cells.  These cancer cells do not resemble normal epithelium.  Therefore, the goal of this project is to learn to use newly isolated human intestinal epithelial cells from surgery patients, for further studies with patient neutrophils.  This would represent a substantial improvement in making the experimental system better resemble the events in the diseased human intestine.  Ultimately, information regarding neutrophil interactions with fresh epithelial cells and with epithelial cells from IBD patients is needed in order to formulate therapies intended to block this event as a treatment for inflammatory bowel disease.