Lay Summary
Proposal No. IBD-0234R
Principal Investigator: Irma van Die, Ph.D.
Applicant Organization: VU University Medical Center (Amsterdam, The Netherlands)
Project Title: Protection against inflammatory bowel disease by glycan antigens
Period of Award: November 1, 2008 - July 31, 2011
IBD can be treated by administration of eggs from the pig helminth Trichuris suis, which develop into adult worms in the intestines. Worms have the capacity to suppress inflammatory responses which enables them to survive in their hosts as part of their life cycle. It is this capacity that leads to the beneficial reduction of chronic inflammation in the intestines of IBD patients and the use of worms seems to be an attractive alternative to current treatments.
The aim of this proposal is to identify which components in the worm cause the anti-inflammatory effects, unravel their mode of action and use this knowledge to develop a new, safe and effective therapy against IBD.
Based on our previous studies we hypothesize that specific carbohydrate structures, glycans, expressed on the worms are responsible for the anti-inflammatory effects. These glycans suppress immune responses mediated by T lymphocytes and are promising candidates for use as therapeutic molecules.
Our approach will be based on the purification of anti-inflammatory glycan components from total helminth worms using several biochemical fractionation methods. These fractions will be studied for functionality in several assays with an emphasis on how the function of dendritic cells is affected by these components. Dendritic cells are central to initiate any type of immune response and are the cells that present antigen and activate T lymphocytes. This makes them the best targets to study the effects of immuno-suppression. We will study how the various glycans can suppress dendritic cells in their ability to produce pro-inflammatory cytokines, signaling molecules that enhance inflammation, and look for possible switching to anti-inflammatory cytokine production. Recently we have shown that total extracts from the helminth Schistosoma mansoni completely suppress the capacity of DCs to induce inflammation, and that this effect is glycan-dependent.
Having identified the glycan components that confer such functions it will be important to study the mechanisms of suppression. We will study whether T lymphocyte activity is affected and what the cellular processes are that lead to the changes of the dendritic cells. In addition we will analyze the effect of the purified glycans using immune cells derived from patients with Crohn’s disease. This will help us to better design therapeutic components. In this stage of the research it will be important to test putative therapeutic components in a disease model. Therefore we will use mouse models of bowel inflammation to study the effects of the components in a complex system.