Abstract
Hypoallergenic cow’s milk (HA) formulas play an important role in the prevention of cow’s milk allergy in high risk children as well as in treatment strategies. This thesis describes the development of a murine model for cow’s milk allergy to analyze the residual allergenicity and sensitizing capacities of cow’s milk
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protein hydrolysates, as present in HA infant formulas. Safety testing of new HA infant formulas in animal models is indispensable to confirm the absence of allergenic peptides in the HA infant formulas. Prevention of cow’s milk allergy with hydrolysed proteins is mainly based on avoidance of the allergen but can also be a result of oral tolerance induction. Therefore, the potency of these hydrolysates to induce oral tolerance and the mechanisms behind these protective effects were topic of investigation described in this thesis. In newborns the mucosal barrier is still immature for optimal absorption of nutrients provided by breastfeeding. The immature status of the immune system combined with a “leaky” immature gut is considered a risk factor to develop immune reactivity to food antigens when introduced too early in life. On the other hand, antigens provided via the oral route are important for the maturation and training of the mucosal immune system. Hence, a delicate balance occurs between avoidance of proteins to prevent early sensitization and the need for proteins to develop oral tolerance. In this thesis we positioned the whey based mouse model for cow’s milk allergy, as a new in vivo model, for safety testing of HA infant formulas. We started to validate the mouse model in a ring trial with four independent research facilities. Using this model, the studies described in this thesis have shown that a partial WH with limited sensitizing capacities was capable to induce oral tolerance to whey proteins in mice and that this protective effect can be enhanced using non-digestible oligosaccharides. Most likely CD11c+CD103+ and Foxp3+ regulatory T-cells contribute to these protective effects. The partial WH induced protection could be adoptively transferred using MLN cells of tolerized mice when provided to naﶥ recipient mice prior to whey sensitization. This indicates the importance of MLN in the transfer of local to systemic tolerance. It was observed that sensitization with cow’s milk proteins can result in IgLC-dependent acute allergic and intestinal hypersensitivity responses indicating that IgLC is a promising new biomarker for food allergy. Besides its role in the induction of cow’s milk allergy it was demonstrated that IgLC might contribute in the oral tolerance induction to whey proteins as well
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