Introduction
Allergic diseases are becoming the focus of attention, as their incidences as well as severity are increasing worldwide.1–3 Among the responsible allergens, birch pollen were identified as the third most-diagnosed allergen for respiratory allergy,4 and around 70% of patients allergic to birch also develop a secondary food allergy.5–7 The symptoms of this so-called pollen-associated food allergy (PFA) range from nasal, ocular and oral pruritus and angioedema to severe allergic asthma and anaphylaxis,6,8–10 which has a comprehensive impact on personal quality of life, work or school performance and the socio-economic burden.4,11
In the pathogenesis of PFA, patients are first sensitized towards a pollen allergen, such as Bet v 1 (Bet), a birch pollen allergen belonging to the pathogenesis-related (PR)-10 protein family.12,13 PR-10 proteins share a high degree of amino acid sequence identity as well as structural homology and facilitate cross-reactivity of pollen-specific IgE antibodies and T cells with food allergens, which initiates the development of secondary food allergies.14–17 PR-10 proteins are found in different plant pollen and in edible plant parts like hazelnut (Cor a 1, Cor), apple (Mal d 1) and carrot (Dau c 1).7,18Interestingly, the hazelnut allergen isoform Cor a 1.04 is more similiar to the birch pollen isoallergen Bet v 1.0101 than to the hazel pollen isoallergen Cor a 1.01.19
In contrast to the ongoing spread of allergic diseases due to cross-reactivities, the selection of efficient and long-lasting therapies that improve pollen and cross-reactive food allergies together are sparse. The only disease-modifying therapy available is allergen-specific immunotherapy (AIT), which might achieve a 20-50% reduction of combined symptom and medication scores.20–22 But several years of therapy are needed to maintain the therapeutic success23,24 and placebo-controlled studies showed that pollen AIT have little to no clinical effect on the associated food allergy.25–28Therefore, the current state of the art regarding treatment of PFA remains unsatisfying and novel therapeutic strategies have to be explored.
Autologous tolerogenic dendritic cells (tolDC) are promising candidates for cell-based immunomodulatory therapies, as they can be differentiated from peripheral blood cells of patients ex vivo based on standardized protocols.29–31 After loading with the desired antigen, they are reintroduced into the patients, where they are generally well tolerated without any severe side effects.32–34 In our group, we found that Interleukin (IL) 10-modulated DC (IL-10 DC) are exceptionally suited for tolerance-inducing therapies, as they displayed a stable, tolerogenic phenotype, with strong migratory and suppressive functions.30,35–37 Induced Treg (iTreg) primed by these IL-10 DC exhibited a suppressive phenotype resulting in highly efficient antigen-specific regulatory functions.38,39In this study, we combined our expertise in IL-10 DC and iTreg biology demonstrating the capacity of IL-10 DC as inducers of iTreg which facilitated allergen-specific and cross-reactive tolerance in birch pollen allergic patients with associated hazelnut allergy in vitro and in a humanized mouse model of allergy in vivo .