Novel mechanisms in immune tolerance to allergens during natural allergen exposure and allergen-specific immunotherapy

•Allergen-specific immunotherapy is effective in reducing symptoms of allergic asthma and rhinitis as well as venom-allergy with the possibility of clinical cure.•Multiple mechanisms and receptors play a role in allergen tolerance, such as IL-10, TGF-β, histamine receptor 2, PD-1 and CTLA-4.•Recently, roles for innate lymphoid cells have been demonstrated in allergy development and allergen tolerance.•Similar cellular and molecular mechanisms are apparently utilized in prevention of allergic disease. Allergen-specific immunotherapy (AIT) has been used for more than 100 years as a clinical tolerance-inducing and immune tolerance-inducing therapy for allergic diseases and represents a potentially curative method of treatment. AIT functions through multiple mechanisms including early desensitization of basophils and mast cells, regulating T-cell and B-cell responses, changing antibody isotypes, and decreasing activation, mediator release and affected tissue migration of eosinophils, basophils, and mast cells. Similar molecular and cellular mechanisms have been observed in subcutaneous AIT, sublingual AIT and peptide immunotherapy as well as natural tolerance to high doses of allergen exposure in beekeepers and cat owners.