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Research project


Status: Start date: 09-05-2017 End date: March 2022

This project aims at understanding the mechanisms of the development of cow’s milk allergy in order to find solutions to treat and eventually prevent CMA.

What we do

About our project

Cow’s milk allergy (CMA) is the most common food allergy in young children, with prevalence rates estimated in the range of 2.0% of all children. The form in which milk proteins are delivered to CMA children determines the induction of allergic symptoms or tolerance (“outgrowing” the allergy), with spontaneous tolerance development in about half the CMA children. Processing of cow’s milk determines the immunogenic and allergenic properties of the milk proteins and is therefore implicated in induction of allergy as well as the induction of tolerance. Literature analysis indicates that there are variable effects of processing of milk on allergenicity and/or immunogenicity.

Aims of the project: 
Create an understanding of how processing affects the immunogenicity and allergenicity of cow’s milk proteins. This will establish a scientific basis for the development of processing methods to prepare infant nutrition with lower immunogenicity of its proteins to prevent the development of CMA. These changes are based on studying the effect of heat processing of CM proteins on the formation of inflammation-inducing aggregates and MRPs and their effects on immunogenicity as well as allergenicity in vitro, as well comparing this to CM-proteins that have been processed via a lower thermal load, e.g. via microfiltration.

Societal objectives, relevance & impact:
The overall beneficial effects  of treating and/or preventing CMA on quality of life and health economics,  will be
Reducing the number of children that develops CMA
Developing diagnostic markers and methods to estimate efficacy of treatment of CMA
Lowering  the medical costs in children caused by their CMA e.g. doctors’ visits, hydrolysed formula diet
Preventing the child form entering the “allergic march”, reducing healthcare costs and improving quality of life on the short term as well as on the long term.

Our research focus

Research focus:
To allow detailed mechanistic studies, and acquire essential mechanistic insight into the immunogenicity-determining molecular events, a proper description of molecular changes to milk proteins that are the consequence of their processing, is imperative. The aim is therefore to characterize the physical-chemical changes in milk proteins of the above mentioned three protein types (unheated proteins: UP, heated proteins: HP, and glycated GP). The main effects of heating are denaturation, aggregation and glycation of milk proteins. The physical-chemical changes of UP, HP and GP proteins will be analysed in detail, as they are relevant to explain the differences in the response of the immune system.

Clinical study:
Children with CMA will be included according to the latest developed Dutch National Guidelines. Inclusion comprehends: questionnaires on history, SPT’s and blood sample analysis. In the first phase of the study, the child will be treated as according to the national guidelines which means: CM-free diet and administration of eHF in case of failure of breastfeeding.
Randomization and Intervention:
The 2nd phase of intervention starts with DBPCFC with HP and GP and the children will be randomized according to their tolerance status. (see flow chart). Each group will receive small amounts (1.3 gram packages) of the product developed in WP3 to be added to their daily eHF product.

Follow-up and tolerance measurement:
The follow- up comprises half year visits in which DBPCFC’s, SPT and blood sample analysis will be performed to measure tolerance and the child will most likely be placed in another group, either from placebo to verum, or from GP to HP or UP according to their tolerance status. In the 3rd phase of intervention this system will be continued, unless, the patient appears to be tolerant. UP tolerant children will finally undergo an open CM challenge and this will be repeated after 1 month and after 3 months to measure sustained tolerance.

Funds & Grants

This work is part of the research program iAGE/TTW with project number 14536, which is (partly) financed by the Netherlands Organization for Scientific Research (NWO).


Internal collaborations:

Paediatric allergology, Sofia Children’s hospital
Laboratory of Immunology; Erasmus MC Rotterdam

External collaborations:

WUR, Food and Biobased research Wageningen
UMCG, Groningen
Martinie, Groningen
Deventer Hospital
Alkmaar Medical Centre
Elkerliek Hospital, Helmond
Canisius Wilhelmina Hospital, Nijmegen
Reinier de Graaf Group, Delft
OLVG West, Amsterdam
Zuiderland medical centre, Heerlen
Catharina hospital, Eindhoven


Nutrients. 2019 Jun 25;11(6). pii: E1432. doi: 10.3390/nu11061432. Differential Effects of Dry vs. Wet Heating of β-Lactoglobulin on Formation of sRAGE Binding Ligands and sIgE Epitope Recognition.
Zenker HE, Ewaz A, Deng Y, Savelkoul HFJ, van Neerven RJJ, De Jong NW, Wichers HJ, Hettinga KA, Teodorowicz M.

Our team

Dr. Nicolette .W. de Jong; n.w.dejong@erasmusmc.nl
Dr. K.A. Hettinga; kasper.hettinga@wur.nl
Prof. dr. H. Wichers; Harry.wichers@wur.nl
Prof. dr. H.F.J. Savelkoul; Huub.savelkoul@wur.nl
Prof. dr. J. van Neerven; Joost.van neerven@wur.nl
Prof. R. Gerth van Wijk; r.gerthvanwijk@erasmusmc.nl
Dr A.B. Sprikkelman; a.sprikkelman@umcg.nl