The adaptive immune response to cow's milk proteins in allergy and tolerance

Abstract

Cow's milk (CM) and related products are an important source of protein in the diet. Unfortunately, cow's milk proteins (CMPs) can also be allergenic. IgE-mediated cow's milk allergy (CMA) occurs in 1.5% of infants, as well as in 0.3% of older children and adults. Insight into the immune response towards CMP in CMA, as well as in tolerant individuals, may provide targets for therapeutic strategies. CMP-specific T cells recognize small fragments of CMPs, known as T cell epitopes. T cells from children with CMA and tolerant children were observed to recognize essentially the same T cell epitopes in alfa-s1-casein, the most abundant CMP. This indicates that CMA is not caused by differential recognition of selective epitopes. The human leucocyte antigen (HLA) genes determine which CMP fragments are presented to T cells. No major differences were found in allele frequencies of HLA genes between subjects with CMA and tolerant individuals, suggesting that these genes do not contribute significantly to the genetic predisposition underlying CMA. CMP-induced production of interleukin-10 (IL-10) by peripheral blood mononuclear cells (PBMCs), as well as plasma levels of CMP-specific IgG4, were higher in adults sensitized to CM but without CMA, than in non-atopic adults. The upregulation of the immunoregulatory cytokine IL-10 may be needed to balance the CMP-specific immune response in an atopic environment, and may play a role in tolerance to CM in sensitized adults without CMA by counter-regulating specific IgE and IgG4. In line with this hypothesis, it was observed that CMP-specific IgG4 was also higher in atopic children and adults without CMA or sensitization to CM, as compared to non-atopic individuals. Specific IgG for the causative allergen is higher in CMA than in peanut allergy (PA) and birch bollen allergy (BPA), whereas specific IgE levels are comparable. Allergen-specific IgG in CMA appears to reduce the binding of allergen-Ig complexes to B cells, and may hereby inhibit IgE-facilitated allergen presentation (IgE-FAP) to specific T cells. Feedback enhancement of the specific Th2 response by IgE-FAP may therefore be less prominent in CMA than in allergies characterized by low specific IgG, such as BPA. Lastly, a possible prophylactic treatment for atopic disease was investigated. A hypo-allergenic whey formula was supplemented with a prebiotic oligosaccharide mixture (GOS/FOS) and fed to infants at risk for development of atopic disease. GOS/FOS supplementation appeared to specifically modulate the immune response towards food antigens, while leaving the response to pathogens intact. The decreased CMP-specific IgG1 response in treated infants suggests a suppression of the immune response to CMP, which may decrease the risk for development of CMA. The balance between specific IgE and IgG appears to be decisive for the development of CMA or tolerance. Peptides spanning immunodominant sequences in alfa-s1-casein and other major CM allergens could be a good candidate for application in tolerance-inducing therapy in CMA. This may induce an immune response comparable to that observed in atopic subjects without CMA, which is characterized by high IL-10 production by CMP-specific T cells, associated with low specific IgE and high IgG4.