Therapy of birch pollen-related food allergy

Birch pollen is one of the most common causes of rhinoconjunctivitis and allergic asthma in Northern and Central Europe and North America. In addition to respiratory symptoms, more than 70% of birch pollen-allergic patients develop allergic reactions to plant foods, most commonly apples, which often occur perennially. This birch pollen- related food allergy (BPRFA) is a consequence of immunological cross-reactivity between the major birch pollen allergen Bet v 1 and structurally-related proteins in foods, e.g. Mal d 1 in apple. Although resulting from immunological cross-reactivity with birch pollen allergens, BPRFA cannot be effectively treated by specific immunotherapy (SIT) with birch pollen extract. We have previously found that the limited therapeutic efficacy of birch pollen SIT on BPRFA is associated with a limited modulation of the food allergen-specific immune response. Whereas successful birch pollen SIT induced tolerance and immune deviation of Bet v 1-specific T cells and Bet v 1-specific "blocking" IgG4 antibodies, only modest alterations of the food allergen-specific cellular and humoral responses were observed. Therefore, we hypothesize that a vaccine designed to effectively treat BPRFA should contain the disease-eliciting food allergen. In a pilot study, we aim to analyse the clinical and immunological effects of sublingual administration of recombinant (r) Mal d 1, a main trigger of BPRFA, to birch pollen-allergic patients with associated apple allergy. Treatment with rMal d 1 will be compared with sublingual administration of rBet v 1 and placebo. Clinical effects on food and pollen-induced allergic reactions will be evaluated by employing objective and subjective parameters of oral provocation tests with rMal d 1 and on the basis of symptom/medication scores during the birch pollen seasons before and after treatment. In addition, Mal d 1- and Bet v 1-specific antibody and T cell responses before, during and after sublingual treatment will be analysed in detail. Although often regarded as non-severe allergic disease, BPRFA is highly prevalent and often perennial. This situation calls for effective treatment strategies which at present do not exist. Our pilot study will provide the proof-of-concept of treating BPRFA with the involved food allergens and pave the way for the future design of standardized vaccines to efficiently treat this allergic disorder. In addition, this study will gain further insights into cellular and humoral immune responses to highly homologous allergens and will improve the understanding of the relevance of cross-reactivity between allergens for disease development and therapy.

Birch pollen-related allergy to apple is the most frequent food allergy in adolescent/adult individuals. From our previous scientific work we have learnt that this birch pollen-related food allergy mainly results from sensitization to the major birch pollen allergen Bet v 1 and subsequent cross-reaction with the apple protein Mal d 1. Seasonal birch pollen allergy can successfully be treated by allergen-specific immunotherapy with birch pollen. However, in many patients this therapy fails to improve the associated food allergy. Thus, at present no efficient therapy for birch pollen-related food allergy exists. Our detailed investigation of the immune response to Bet v 1 and Mal d 1 provided evidence that birch pollen-related apple allergy should be treated with the apple allergen. To proof this, we conducted a single centre, double-blind clinical study including 60 birch pollen-allergic patients with apple allergy randomized to sublingual application of placebo (n=20) or daily 25 g of recombinant Mal d 1 (n=20) or recombinant Bet v 1 (n=20) for 16 weeks. Apple allergy was monitored by sublingual challenges with standardized doses of the recombinant apple allergen. Moreover, skin prick testing with recombinant allergens were performed before and after treatment. To assess possible effects on the Mal d 1-specific immune response we collected samples to analyse different immunological parameters. Sublingual administration of recombinant Mal d 1 induced a substantial reduction of apple-induced symptoms which significantly differed from the two other groups and was accompanied by significantly reduced skin reactivity to rMal d 1. Moreover, an alteration of the Mal d 1-specific immune response was detected. For the first time SLIT with a recombinant food allergen was tested for clinical efficacy as determined by standardized challenges. We succeeded in developing a novel concept for safe and effective treatment of birch pollen-related apple allergy. Sublingual administration of Mal d 1 induced an impressive improvement of apple allergy, was well tolerated and can be done at home. In summary, this study is a positive example for successful translation of basic research data from bench-to-bedside. Further studies are planned to investigate the immune processes induced by sublingual treatment with Mal d 1. The results from these investigations will markedly contribute to the development of an effective treatment for birch pollen-related food allergy.