Scientific Abstract

Proposal No.   IBD-0201R
Principal Investigator:  Dirk Föll, M.D.
Applicant Organization:  University Hospital of Münster (Germany)
Project Title: Functional characterization of GM-CSF induced monocyte subsets and analysis of their relevance in Crohn's disease
Period of Award:  September 1, 2007 - August 31, 2010

There is little doubt that innate immune mechanisms are among the most important factors which initiate and perpetuate inflammation in Crohn’s disease (CD). On the other hand, monocytes and macrophages also have a clearing function and are enormously important for the resolution of inflammation as well as tissue regeneration. In this context, it is remarkable that the most innovative therapies used or anticipated today (e.g., anti-TNF or GM-CSF) are mainly targeting monocytes and macrophages or their products, respectively.

It is still not clear how GM-CSF exerts its beneficial activities in CD. While it is hypothesized that augmenting innate immune mechanisms is a key function, a phenotype switch of target cells bearing the GM-CSF receptor towards more mature phagocytes eventually functioning as anti-inflammatory cells is also conceivable. The reported long-lasting induction of remission in IBD patients treated with GM-CSF could be better explained by a complex modulation of immune mechanisms than simply by a transitory amplification of innate immunity. However, it is not known whether the resolution of inflammation requires alternative activation of resting macrophages or if freshly recruited monocytes have the capacity to differentiate towards anti-inflammatory phenotypes.

In previous studies, we found that monocytes – as opposed to common belief – were not generally suppressed by steroid treatment. In contrast, our gene expression analyses revealed that there are more genes up- than down-regulated. Functional studies confirmed that steroids induced an anti-inflammatory monocyte phenotype. We will now compare the response of monocytes from healthy donors to GM-CSF with monocytes obtained from well characterized CD patients with NOD2/CARD15 mutations, either having active disease or inactive disease without medication. We will also investigate whether the expression of GM-CSF and the GM-CSF receptor differs between healthy intestinal tissue and CD tissue. We have also included exploratory experiments on GM-CSF effects on T-cells and primary endothelial cells isolated from human intestine. In addition, we will analyze how GM-CSF influences the cross-talk between innate and immune mechanisms.

The overall aim of this project is to reveal novel insights into the pathogenesis of IBD, and to identify mechanisms by which modulation of innate immunity alters the natural history of this disease. Understanding the roles of distinct monocyte and macrophage subsets in IBD may suggest other novel treatment options for IBD.