Cow's milk allergy; immune modulation by dietary intervention

In developed countries 3% of infants exhibit cow’s milk allergy (CMA). Although most infants outgrow CMA, immunoglobulin (Ig)E-mediated CMA may predispose for development of other allergies and asthma later in life. Clinical symptoms may involve the skin, respiratory tract and gastrointestinal tract, and can even lead to a systemic anaphylactic reaction. Both whey and casein allergic mice exhibited systemic acute allergic symptoms as reflected by an increase in ear swelling upon intradermal challenge. However striking differences were observed between the sensitizing capacities of whey and casein. Whey sensitized mice revealed enhanced serum levels of whey- specific IgE, the classical allergic marker whereas casein sensitized mice had allergic symptoms in the absence of casein-specific IgE. However, immunoglobulin free light chain (Ig-fLC) antagonist (F991) abrogated the development of allergic symptoms in the casein sensitized mice only. The relevance for Ig-fLC in human allergic disease was confirmed in infants at risk for allergy. Serum Ig-fLC concentrations were enhanced in infants that had developed atopic dermatitis (AD). In order to investigate the preventive effect of dietary short-chain galacto-(scGOS) and long-chain fructo-oligosaccharides (lcFOS) and/or Bifidobacterium breve M-16V mice were fed the diets during oral whey sensitization. The scGOS/lcFOS (ratio 9:1) mixture (Immunofortis) contains non-digestible carbohydrates that selectively stimulate the growth of bacteria which supports host health. These prebiotics mimick non-digestible carbohydrates such as present in breast milk. The synbiotic mixture containing both the prebiotics and Bifidobacterium breve M-16V was most effective in diminishing the acute allergic skin and anaphylactic response upon allergen challenge hence protecting against development of CMA symptoms. In order to examine the contribution of regulatory T-cells (Treg) in the protective effect of prebiotics, in vivo Treg depletion and adoptive transfer studies were performed. In these studies pectin-derived acidic-oligosaccharides (pAOS) were added to the scGOS/lcFOS mixture. The in vivo depletion studies revealed CD4+CD25+Foxp3+ Treg to play a crucial role in the preventive effects of the scGOS/lcFOS/pAOS. In the adoptive transfer studies it was shown that protection against allergic symptoms generated by the diet could be transferred using spleen cells. Depletion of Treg-cells abrogated this. Furthermore these results showed that the protective effect of the prebiotic diet was antigen specific. Another potentially important regulatory cell type in allergy is the invariant Natural Killer T (iNKT)-cell. Stimulation with ? -galactosylceramide (? GalCer), a specific iNKT-cell agonist, almost completely depleted the iNKT-cells from the liver and worsened the acute allergic skin response, which was most pronounced in whey sensitized mice. Hence, these data suggested iNKT-cells to have immunomodulatory capacities, in particular relevant in mice orally sensitized with whey. In conclusion, induction of cow’s milk allergy in mice via oral sensitization revealed IgE dependent allergic symptoms in whey sensitized mice while casein allergic symptoms were caused by immunoglobulin free light chain. Dietary intervention studies with in particular synbiotics, combining both specific non-digestible carbohydrates and Bifidobacterium breve M-16V most effectively prevented the occurrence of cow’s milk allergic symptoms in mice. The induction of allergen specific regulatory T-cells was involved in the mechanism underlying the protective effect of prebiotics.