Lay Summary

Proposal No.   IBD-0211
Principal Investigator: Lee A. Denson, M.D.
Applicant Organization:  Cincinnati Children's Hospital Medical Center (Ohio, U.S.A.)
Project Title: GM-CSF bioactivity and IBD phenotype
Period of Award:  October 1, 2007 - September 30, 2009

It is likely that there are several immunogenetic forms of inflammatory bowel disease (IBD), with Crohn’s disease (CD) and ulcerative colitis (UC) representing the broadest clinical classifications. We have sought to define fundamental features of the abnormal immune system amenable to targeted therapies in specific subsets of patients with IBD. Our preliminary studies have defined a novel basis for immune system dysfunction in some CD patients, due to naturally occurring antibodies against the immune system protein, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF). GM-CSF is needed for the body to fight off infections. We have found that naturally occurring antibodies against GM-CSF (anti-GM-CSF) specifically reduce the part of the immune system involved in controlling bacterial infections, and that high levels of these antibodies are associated with increased risk for early surgery in children with CD. Our proposed studies will examine the role of these anti-GM-CSF antibodies in reducing immune system function and promoting more aggressive disease requiring surgery in a large group of children and adults with IBD. The proposed studies are in line with the goals of the Broad Medical Research Program to support innovative projects that will improve the care of IBD patients in the near future. This will be the first study to investigate the role of a naturally occurring antibody (anti-GM-CSF) which regulates the immune system in IBD. It will likely provide significant new insights into the causes of IBD, and the role that combined defects in the immune system due to anti-GM-CSF antibodies and CD genes may play in promoting more aggressive small bowel disease. The anti-GM-CSF lab test will also for the first time provide a novel diagnostic test which may allow doctors to define whether an individual patient may benefit from a medication to regulate GM-CSF activity in the body. The anti-GM-CSF assay is currently completing the processes to be offered as an approved clinical laboratory test at Cincinnati Children’s Hospital Medical Center (CCHMC). It is quite likely that it will be available as a diagnostic test for IBD patients in the near future, following validation in a large group of pediatric and adult patients as proposed. Ultimately, the anti-GM-CSF level will identify patients with symptoms driven by specific inflammatory pathways, and may predict the likelihood of response with a given therapy. For example, CD patients with high anti-GM-CSF levels may be offered GM-CSF therapy in upcoming clinical trials. If the studies supported by the BMRP confirm the potential utility of the anti-GM-CSF assay in this regard, we will apply to NIH for longer term funding to both develop the clinical diagnostic assay, and to perform further mechanistic studies concerning how anti-GM-CSF regulates the immune system in IBD. Collectively, these studies will provide a significant advance towards achieving targeted therapy for clinically important sub-groups of IBD patients.