Immunomodulation by specific HMOS and the relevance in allergy management: Towards advanced human in vitro mucosal immune models

Early life is considered an essential period in life for the maturation of the immune system. Flawed immune maturation predisposes for immunological abnormalities later in life such as the development of disorders including autoimmunity and allergic diseases. In light of the increasing prevalence and incidence of allergic diseases observed in the past decades, an urgent need for preventive strategies is identified. The development of immune homeostasis and therefore potential prevention of allergic sensitization in infants is supported by breastfeeding. Human milk contains many biological active components, which may contribute to the allergy preventive effects. Using several in vitro and in vivo approaches, this thesis aims to investigate the immunomodulatory effects of a unique group of human milk components: the human milk oligosaccharides. The development of novel advanced in vitro human mucosal immune models to improve our understanding of allergic sensitization upon allergen exposure and predict sensitizing allergenicity risk is described in this thesis. These models were used to reveal the ability of specific fucosylated and sialylated human milk oligosaccharides to affect crosstalk between epithelial and immune cells during allergic inflammation in intestinal and airway mucosal settings. Specific human milk oligosaccharides were found to differentially support mucosal immune responses during allergic inflammation in vitro, these findings were supported by preclinical models for food allergy and allergic asthma. This thesis provides building blocks, novel insights and potential options for interventions to understand and build preventive strategies for allergy development in early life.