Lay Summary

Proposal No. IBD-0193R
Principal Investigator: Anthony W. Segal, M.D., Ph.D., D.Sc.
Applicant Organization: University College London (United Kingdom)
Project Title: Impaired innate immunity and the pathogenesis of Crohn’s disease
Period of Award: March 1, 2007 – February 29, 2008

Until now, Crohn’s disease (CD) treatments have focused on suppressing an overactive immune response, with varying degrees of success. However, recent research suggests that CD begins as what is essentially an under-activity of the immune system.

Macrophages are immune cells that act as the first line of defense against bacteria. They are stimulated by bacteria to produce chemicals called cytokines, which attract other immune cells. One of these, interleukin-8, is important because it attracts key cells called neutrophils to help clear bacteria and start healing in a process known as acute inflammation. Without enough neutrophils, bacteria clearance is impaired and other types of immune cells then have to be recruited – but this leads to persistent (‘chronic’) inflammation and damage, rather than healing. Microscopic examination of bowel specimens in CD show exactly this picture – a mix of immune cells trying to wall-off the bacterial threat in chronic inflammation – and it is just what one would expect if our ‘bacterial persistence’ hypothesis were true.

We have shown that fewer neutrophils are attracted to sites of experimental injury in the bowel wall and skin of patients with CD. Furthermore, macrophages from patients with CD produce less IL-8 in response to experimental stimulation by bacterial components. In addition, blood-flow to sites of experimental bacterial inoculation is reduced in patients with CD (in the forearm). All these experiments were carried out with the help of patients with CD. What we therefore have is strong, but circumstantial evidence to support the fact that patients with CD might be less able to remove bacteria and that this might lead to disease.

We therefore propose to directly study the clearance of bacteria from sites of experimental skin inoculation in patients with CD and healthy control subjects. Bacteria will be labeled with a safe amount of radioactive tracer that can be measured with a specialized camera-counter over several hours. If this proves true, it will give us a clear insight into how CD actually begins. We also aim to study both neutrophils and macrophages from patients with CD more closely as part of this proposal.

These experiments will help validate our theory as to how CD actually starts and will also highlight avenues for further study and therapeutic intervention – with direct benefit for patients with CD.