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Role of a mast cell secreted cytokine in local immune suppression

Friday 12 February 2010

Dr Alice Sijts

Project
Autoimmune diseases, allergies and asthma are steadily increasing within the human population and also form a major health problem in different animal species or breeds. At this time, there is no treatment that could prevent or cure atopic diseases.

Most interestingly, chronic helminth (worm) infections and the accompanying type II immune responses have been associated with protection against allergies and autoimmune diseases. Experimental worm infections of patients have successfully been tested in clinical trials, as cure for autoimmune diseases. As the underlying mechanism, mast cell-mediated responses and regulatory T-cell function have been suggested, however, a clear explanation for the observed therapeutic effects is still missing.

We have shown, (Zaiss et al. Science 2006) that an EGF-like growth factor, Amphiregulin (AREG) is a type II cytokine, secreted by activated Th2 and mast cells. Recently, we found, in addition, a link between mast cell-derived AREG and local immune suppression.

Based on our data, we argue that the observed immune suppressive function of chronic worm infections is AREG mediated. We will use a variety of in vitro and in vivo experiments, such as a murine asthma model, in which asthma development is ameliorated by a synchronous chronic worm infection, to test this hypothesis. This research might potentially open new opportunities to treat and even cure atopic (allergic) and autoimmune diseases.

Techniques
Mice: Reconstitution of mast cell deficient mice with mast cells, T-cell transfer, worm infections, Induction of experimental asthma (under supervision).
Ex vivo analysis: Quantitative analysis of T cell responses, flowcytometry, Preparation of lungs and histological analysis
Cell culture: Maintaining, differentiating and propagating mammalian cells
Molecular biology: plasmid preps, bacterial transformation, DNA digestion, ligation, PCR

Duration
9 months

Contact
Dr Dietmar Zaiss, D.Zaiss@uu.nl, 030 - 253 4345

References:
Amphiregulin, a TH2 cytokine enhancing resistance to nematodes. (2006) Zaiss DM, Yang L, Shah PR, Kobie JJ, Urban JF, Mosmann TR. Science.314(5806):1746.

Protective effect of Schistosoma mansoni infection on allergic airway inflammation depends on the intensity and chronicity of infection. (2007) Smits HH, Hammad H, van Nimwegen M, Soullie T, Willart MA, Lievers E, Kadouch J, Kool M, Kos-van Oosterhoud J, Deelder AM, Lambrecht BN, Yazdanbakhsh M. J Allergy Clin Immunol. 120(4):932-40

Allergy, parasites, and the hygiene hypothesis. (2002) Yazdanbakhsh M, Kremsner PG, van Ree R. Science.296(5567):490-4.

Suppression of allergic airway inflammation by helminth-induced regulatory T cells. (2005) Wilson MS, Taylor MD, Balic A, Finney CA, Lamb JR, Maizels RM. J Exp Med. 202(9):1199-212.

Expansion and activation of CD4(+)CD25(+) regulatory T cells in Heligmosomoides polygyrus infection. (2007) Finney CA, Taylor MD, Wilson MS, Maizels RM. Eur J Immunol. 37(7):1874-86.

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