Scientific Abstract

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

Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) reduces disease activity in CD, suggesting that alterations in GM-CSF bioactivity may contribute to pathogenesis in a sub-set of patients.  GM-CSF is required for priming of monocyte/macrophage and neutrophil antimicrobial functions.  Based upon our recent studies, we hypothesize that anti-GM-CSF auto-antibodies regulate IBD phenotype and behavior by reducing GM-CSF bioactivity and mucosal barrier function.  We will test this hypothesis in the following Aims: Aim 1.  Characterize anti-GM-CSF antibody regulation of monocyte/neutrophil function and IBD phenotype.  Hypothesis:  Endogenous anti-GM-CSF antibodies regulate monocyte/neutrophil function and IBD phenotype.  The serum concentration of neutralizing anti-GM-CSF antibodies will be determined and related to alterations in monocyte/neutrophil function and IBD phenotype in patients with both pediatric and adult onset disease.  The CARD15 genotype and titers of ASCA, pANCA, OmpC, I2, CBir1, and EndoCAb antibodies will be determined and related to anti-GM-CSF levels and IBD phenotype and behavior.  Aim 2.  Determine the effect of anti-GM-CSF antibodies and CARD15 deficiency upon mucosal barrier function.  Hypothesis: Anti-GM-CSF antibodies synergize with CARD15 deficiency to reduce ileal mucosal barrier function and increase susceptibility to intestinal inflammation.  The effect of a neutralizing anti-GM-CSF antibody upon mucosal injury due to TNBS or indomethecin administration will be determined in wild type (WT) and CARD15 deficient mice.  Differences in mucosal injury will be related to anti-GMCSF dependent alterations in intestinal permeability, macrophage/neutrophil function, and bacterial translocation.  Completion of the proposed studies will determine whether anti-GM-CSF auto-antibodies reduce GM-CSF bioactivity and mucosal barrier function and promote more aggressive small bowel CD.  Ultimately, determination of the anti-GM-CSF level in patients may guide therapy, in terms of whether modulation of GM-CSF bioactivity would be beneficial.