Oral Tolerance Induction to Newly Introduced Allergen is Favored by a Transforming Growth Factor-β-Enriched Formula

Abstract

Food allergies have become a major healthcare concern, hence preventive efforts to ensure oral tolerance induction to newly introduced antigens are particularly relevant. Given that transforming growth factor-β (TGF-β) plays a key role in immune tolerance, we tested whether an infant formula enriched with TGF-β would improve oral tolerance induction. A partially hydrolyzed whey protein-based formula was enriched with cow's-milk-derived TGF-β (TGF-β-enriched formula) by adding a specific whey protein isolate (WPI). The manufacturing process was optimized to achieve a concentration of TGF-β within the range of human breast milk concentrations. Protection from allergic sensitization and immune response was assessed in a mouse model. Adult mice received the TGF-β-enriched formula, a control non-enriched formula, or water ad libitum for 13 days before sensitization and suboptimal tolerization to ovalbumin (OVA). When compared to non-tolerized mice, suboptimally-tolerized mice supplemented with the TGF-β-enriched formula showed significantly lower levels of total immunoglobulin-E (IgE) and OVA-specific (IgG1). Mouse mast-cell protease-1 (mMCP-1) and cytokine levels were also significantly decreased in suboptimally-tolerized mice fed the TGF-β-enriched formula. In conclusion, oral supplementation with cow's-milk-derived TGF-β decreased allergic responses to newly introduced allergens and thus reduced the risk of developing food allergy.

Micellar Casein and Whey Powder Hold a TGF-β Activity and Regulate ID Genes In Vitro

“…The clinical relevance of the finding that micellar casein and whey powder, independent of the manufacturer, strongly increase TGF-β target genes and decrease ID1 and ID3 genes, remains unclear but leaves room for speculations. Considering that milk TGF-β can reduce the allergic reactions in ovalbumin-tolerized mice [ 3 ] and ameliorate tissue damage in colitis and endotoxemia murine models [ 4 ], some beneficial effects of the TGF-β in micellar casein and whey powder can also be assumed. Particularly in athletes, micellar casein and whey powder support muscle growth upon weight training [ 19 ].…”

“…Milk should not be restricted to its nutritional aspects being a rich source of the TGF-β [ 2 ]. Milk TGF-β is supposed to exert at least part of the beneficial activity of milk in vivo, for example to reduce the allergic reactions in ovalbumin-tolerized mice [ 3 ] and to ameliorate tissue damage and mortality in colitis and endotoxemia murine models [ 4 ]. In vitro, TGF-β activity is identified by its ability to regulate target genes, most notably interleukin11 (IL11), NADPH oxidase 4 (NOX4) and proteoglycan4 (PRG4) based on independent screening approaches [ 5 , 6 , 7 ], and some of TGF-β effects in vivo are mediated via IL11 [ 8 , 9 ] and NOX4 [ 10 ].…”

“…For example, the adsorption of bovine milk caseins on the tooth surface was proposed having a positive impact on the prevention of dental diseases by affecting the adhesion of early bacterial colonizers [ 25 , 26 , 27 ] and reducing demineralization of hydroxyapatite [ 28 , 29 ]. The possible role of TGF-β activity to contribute to oral health, however, remains at the hypothetic level that is based on findings of the gastrointestinal system [ 3 , 4 ]. It is particularly the mixing of toothpaste with lactoperoxidase that has entered the market of health care products [ 13 ].…”

“…Thus, there is a demand to better understand the influence of casein and whey on oral cells. Considering that regular infant formula holds a potent TGF-β activity [ 12 ] that reduces allergic reactions in ovalbumin-tolerized mice [ 3 ], it is likely that this is also true for the main ingredient’s casein and whey protein. If, however, casein and whey, similar to milk [ 14 ], activate cells of the epithelial cell lineage remains to be studied.…”

Fighting Food Allergy by Inducing Oral Tolerance: Facts and Fiction

“…When fed a TGF-β-enriched formula to mice with ovalbumin (OVA)-induced FA, allergenic responses were decreased when compared with the control group. IgE, IgG1, mMCP-1, and correlated cytokine levels all indicated decreased allergic responses [68]. Carrier et al [69] found that Th3 cells can act directly and induce Foxp3 + to act indirectly as the central mediator of peripheral immune tolerance using a transgenic mouse model of TGF-mice.…”