Scientific Abstract

Proposal No. IBD-0290
Principal Investigator:  Susanne Hartmann, Ph.D.
Applicant Organization:  Humboldt University Berlin (Germany)
Project Title:  Treatment of inflammatory bowel disease with helminth immunomodulators
Period of Award:  March 1, 2010 - August 31, 2012

Parasitic worms have developed intricate mechanisms to manipulate their hosts’ immune system in order to suppress inflammatory responses directed against them. Epidemiological studies in humans (1, 2) and animal experiments (3, 4) indicate that immune regulation exerted by parasitic worms represents an important factor that correlates with the low incidence of IBD in developing areas of the globe, where nematode infections are common. Parasitic worms are known to directly counteract inflammatory diseases such as IBD. Recently, successful clinical trials have been performed indicating that short-term infections with parasitic nematodes represent an effective therapy for inflammatory bowel disease (5, 6, 7, 8). Therefore, parasitic nematodes may provide a basis for novel therapies, which are desperately needed in view of the high incidence of allergic and inflammatory diseases in industrial countries. However, the application of living nematodes has constraints, thus, characterization of active components of the parasites represent the alternative application for future use. 

We aim to evaluate the therapeutic capacity of recombinant immunomodulators produced in our laboratory to establish treatment of IBD in mouse models. In particular, the potential of two helminth molecules characterized by us will be studied in detail. Our initial data show that filarial cystatin (AvCyst) and filarial tropomyosin (AvTropo) are able to markedly ablate allergic lung pathology in mice. With respect to cystatin we could further show that the effect was due to the induction of IL-10-producing macrophages (9). Thus, the major aims in the proposed project are as follows: (I) Analyses of the capacity of AvCyst and AvTropo to interfere with the formation of inflammatory bowel disease. (II) Analyses of the mechanisms induced by helminth proteins that mediate amelioration of IBD with a particular focus on macrophages and regulatory Tcells (Treg). (III) Establishment of transgenic probiotic bacteria as therapeutic vehicle for helminth immunomodulators to downregulate inflammatory responses in the gut.

The influence of the helminth proteins will be investigated in two mouse models of colitis, namely transfer of CD45RBhi T cells in SCID mice and DSS-induced colitis. Beyond the examination of clinical parameters we will analyse underlying mechanisms. The emergence of suppressive macrophage populations after application of the helminth immunomodulators and their contribution to an anti-inflammatory environment as well as the appearance and suppressive activities of Treg cells in the draining lymph nodes will be studied. Hence, our study will give insights into mechanisms of immune suppression triggered by helminth immunomodulators and allow development of novel strategies to interfere with inflammatory responses in IBD with potential for development of new therapeutic drugs.