Interleukin 10-modulated dendritic cells induce tolerance in patients with birch pollen and associated hazelnut allergies
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Abstract
Birch pollen allergy is one of the most prevalent type 1 allergic diseases in Northern Europe. Among birch pollen allergic individuals approximately 70% experience secondary food allergies, which are then classified as pollen-associated food allergies. These patients are first sensitized towards a birch pollen allergen (Bet v 1, [Bet]) and subsequently develop an allergy towards a homologous food allergen such as hazelnut (Cor a 1, [Cor]). However, the only disease-modifying therapy for type 1 allergies called allergen immunotherapy (AIT) has little to no effect on secondary food allergies.
In this study, allergen-loaded IL-10-modulated dendritic cells (IL-10 DC) were investigated in regard to their potential to induce allergen-specific and cross-reactive tolerance in the context of pollen-associated food allergies. Therefore CD4+ T cells from birch pollen (Bet)-allergic donors with associated hazelnut (Cor) allergies were primed by Bet-loaded IL-10 DC to obtain Bet-specific iTreg. The T cell response was evaluated during priming and after restimulation by analysis of cytokine concentration, phenotype and proliferation. The suppressive capacity of iTreg was analysed in vitro and in vivo.
This study revealed that Bet-specific iTreg were anergic during priming, but proliferated vigorously after Bet- and Cor-induced restimulation. They displayed a high capacity to suppress allergen-specific and cross-reactive immune responses: in vitro they reduced the proliferation of Bet- and Cor-specifically stimulated responder T cells which was accompanied by a reduction of the allergy-related TH2 cytokine IL-13 and a profound increase in IL-10 secretion. Flow cytometric analysis also revealed a highly activated and suppressive phenotype of Bet-specific iTreg. In a humanised mouse model of allergic intestinal and airway inflammation, Bet-specific iTreg were able to ameliorate birch pollen- and hazelnut-induced symptoms and to reduce Bet-specific IgE. Compared to non-specific iTreg, Bet-specific iTregBet showed a significantly increased capacity to suppress allergen-specific and cross-reactive T cell responses in vitro, indicating that allergen-specific priming does have a beneficial effect and that IL-10 DC-induced Treg do not only facilitate a general immunosuppression.
These pieces of evidence combined strongly suggest that iTreg which were primed by allergen-loaded IL-10 DC are able to facilitate highly allergen-specific as well as cross-reactive tolerance to both pollen and associated food allergens. IL-10 DC should therefore be considered as top candidates for cellular tolerance-inducing therapies in pollen-associated food allergies.