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The Immunotoxicology group

Monday 22 October 2012

Dr. Raymond Pieters
The Immunotoxicology group, Institute for Risk Assessment Sciences, Faculty of Veterinary Sciences

The Immunotoxicology group examines fundamental processes involved in immunosensitization and inflammatory responses by various agents, including drugs, environmental chemicals/pollutants and food components. Knowledge obtained will help to define early indicators of immunosensitizing potential of compounds (e.g. pharmaceuticals or new foods) that can be included in new and existing predictive models. In addition, this knowledge also contributes to development of prophylactic measures or therapies. Ongoing projects:

- Therapeutic approaches for food allergy
Food allergy results from an abnormal immune response to food and this allergic reaction can sometimes cause serious illness and death. To date, there is no cure or therapy for food allergies and there are no models to predict the allergenic potential of novel foods. In established food allergy models in mice, we investigate the role of various immune cells (such as (regulatory) T cells, intraepithelial lymphocytes cells and dendritic cells in the initiation and maintenance of food allergy. Studying the interaction of these cells with intestinal epithelial cell enables to determine processes that are responsible for the balance between oral tolerance en sensitization to food proteins. The influence of environmental substances such as AhR ligands (e.g. TCDD) , drugs (NSAIDs) and probiotics on this balance is examined as well. Knowledge on these fundamental mechanisms will be translated to therapies and risk assessment approaches.
Research in this project is done in collaboration with TNO, UMC and UIPS in the Utrecht Centre for Food Allergy, the University of Applied Sciences (HU) and with the department of Immunobiology, King’s College London.

- Mechanisms of drug hypersensitivity and immune-mediated liver injury
Adverse drug reactions related to hepatotoxicity, blood dyscrasias and drug hypersensitivity are responsible for the top 3 of drug withdrawals due to toxicity. This research project aims to assess how pharmaceutical drugs that induce these adverse effects interfere with immunological processes at the interface between innate with adaptive immune responses. Focus is on the interplay between neutrophils, dendritic cells, NK cells, and immunoregulatory T cells in the liver and spleen. Mechanisms are studied in mouse models that enable to study the effect of innate immune activation in relation to systemic sensitization. Ultimate goal of this project is to translate the immunological mechanisms underlying drug hypersensitivity and immune-mediated hepatotoxicity into predictive in vitro and in vivo models.
This research is currently sponsored by an Innovative Medicines Initiative (IMI) project called MIP-DILI (Drug Induced Liver Injury).

Current group members:
Raymond Pieters (Associate professor, Group Leader)
Marianne Bol-Schoenmakers (Scientist)
Joost Smit (Scientist)
Lydia Kwast (PhD student)
Veronica Schulz (PhD student)
Rob Bleumink (Technician)
Manon van Roest (Technician)
Laura Kruijssen (Technician)

Key papers:
Schulz VJ, Smit JJ, Bol-Schoenmakers M, Duursen MB, van den Berg M, Pieters RH. Activation of the aryl hydrocarbon receptor reduces the number of precursor and effector T cells, but preserves thymic CD4(+)CD25(+)Foxp3(+) regulatory T cells. Toxicol Lett. 2012 in press.

Smit JJ, Willemsen K, Hassing I, Fiechter D, Storm G, van Bloois L, Leusen JH, Pennings M, Zaiss D, Pieters RH. Contribution of classic and alternative effector pathways in peanut-induced anaphylactic responses. PLoS One. 2011. 6:e28917.

Smit JJ, Bol-Schoenmakers M, Hassing I, Fiechter D, Boon L, Bleumink R, Pieters RH.
The role of intestinal dendritic cells subsets in the establishment of food allergy. Clin Exp Allergy. 2011. 41: 890-8.

Kwast LM, Fiechter D, Hassing I, Bleumink R, Boon L, Ludwig IS, Pieters RH.
Oral exposure to drugs with immune-adjuvant potential induces hypersensitivity responses to the reporter antigen TNP-OVA. Toxicol Sci. 2011 Jun;121:312-9.

Marcondes Rezende M, Hassing I, Bol-Schoenmakers M, Bleumink R, Boon L, van Bilsen J, Pieters R.
CD4(+) CD25(+) T regulatory cells do not transfer oral tolerance to peanut allergens in a mouse model of peanut allergy.
Clin Exp Allergy. 2011 41:1324-33

Bol-Schoenmakers M, Marcondes Rezende M, Bleumink R, Boon L, Man S, Hassing I, Fiechter D, Pieters R, Smit JJ. Regulation by intestinal γδ T cells during establishment of food allergic sensitization in mice. Allergy. 2010. 66:331-40

Bol-Schoenmakers M, Bleumink R, Marcondes Rezende M, Mouser E, Hassing I, Ludwig I, Smit JJ, Pieters RH. Diclofenac enhances allergic responses in a mouse peanut allergy model. Clin Exp Allergy. 2010. 41:424-33