Orally-Induced Intestinal CD4+ CD25+ FoxP3+ Treg Controlled Undesired Responses towards Oral Antigens and Effectively Dampened Food Allergic Reactions

Abstract

The induction of peripheral tolerance may constitute a disease-modifying treatment for allergic patients. We studied how oral immunotherapy (OIT) with milk proteins controlled allergy in sensitized mice (cholera toxin plus milk proteins) upon exposure to the allergen. Symptoms were alleviated, skin test was negativized, serum specific IgE and IgG1 were abrogated, a substantial reduction in the secretion of IL-5 and IL-13 by antigen-stimulated spleen cells was observed, while IL-13 gene expression in jejunum was down-regulated, and IL-10 and TGF-β were increased. In addition, we observed an induction of CD4+CD25+FoxP3+ cells and IL-10- and TGF-β-producing regulatory T cells in the lamina propria. Finally, transfer experiments confirmed the central role of these cells in tolerance induction. We demonstrated that the oral administration of milk proteins pre- or post-sensitization controlled the Th2-immune response through the elicitation of mucosal IL-10- and TGF-β-producing Tregs that inhibited hypersensitivity symptoms and the allergic response.

Molecular and cellular mechanisms of food allergy and food tolerance

“…The induction of peripheral T cell tolerance is a crucial step induced by IT, and in different models various changes in Ag specific T cell populations correlated with tolerance, including increased Tregs, 169 decreased Th2 cells, 170 and increased anergic T cells. 171 The proportion of allergen-specific T cell subsets and the change in the dominant subset may skew towards allergy vs. tolerance.…”

“…169 In a cholera toxin induced mouse model of milk allergy, treatment with milk OIT increased levels of IL-10 and TGF-β in the jejunum, likely produced by Tregs within the gut. 170 Using allergen-MHC tetramers to track allergen-specific T cells during the course of wasp-venom immunotherapy, clinical tolerance was associated with a loss of IL-4-producing T cells and increased IL-10-producing Foxp3 + Ag-specific T cells that might share a common precursor with IL-4-producing T cells specific for the same epitope. 171 Recently, we used peanut-MHC dextramers to sort peanut-specific T cells from subjects with peanut allergy and analyzed changes in gene expression of individual CD4 + T cells during the course of OIT.…”

B‐FAHF‐2 plus oral immunotherapy (OIT) is safer and more effective than OIT alone in a murine model of concurrent peanut/tree nut allergy

“…Smaldini et al reported induction of CD4+CD25+FoxP3 Tregs localized to gut lamina propria after prolonged antigen desensitization. [52] Additionally, in a recent study by Tordesillas et al, LAP+ CD25-FoxP3- Tregs generated via epicutaneous desensitization localized to the gut but not spleen and inhibited mast cell activity and anaphylaxis in a murine food allergy model. [53] Treg activity in the Smaldini study was associated with tissue elevation of IL-10 and TGF-β and the Tordesillas study implicated a role for TGF-β.…”

Oral Immunotherapy for Food Allergies

“…In mouse models of food allergy, in conjunction with improved tolerance of the food, OIT resulted in an increase in CD4+CD25+FoxP3+ cells and IL-10-and TGF-β-producing Tregs in the lamina propria [19] . The increase in Tregs with OIT may be attributed to a replacement with polyclonal T cells, rather than to a 'reeducation' of existing T cells [20] .…”