Immunological mechanisms of allergen-specific immunotherapy

Key Points Allergen-specific immunotherapy (SIT) for allergic diseases is the oldest form of antigen-specific disease-modifying therapy. Administration of allergen by injection or mucosal (sublingual) application leads to amelioration of clinical symptoms and has lasting effects that exceed the period of treatment. Immunological changes that are associated with SIT include the induction of allergen-specific antibodies (mainly IgG but also IgA) that block the interaction of allergen with IgE, preventing the activation of mast cells and basophils and reducing the IgE-dependent uptake of allergen by antigen-presenting cells (APCs). SIT induces anergy in T cells, induces functional allergen-specific regulatory T-cell populations, and is associated with increased production of interleukin-10 (as well as transforming growth factor-β in some studies) by T cells and APCs. Novel approaches towards SIT include the use of adjuvants to antagonize T-helper-2-cell responses and the use of modified allergen preparations, including recombinant allergens, genetically engineered hypoallergenic allergens, peptides corresponding to T-cell or B-cell epitopes, and allergen fusionproteins. Improved understanding of the mechanisms that are involved in successful SIT will inform the development of novel treatments for other chronic diseases, such as autoimmune and transplantation-related conditions. Allergen-specific immunotherapy can ameliorate the symptoms of allergic diseases and has shown long-lasting benefits. Recent work discussed in this Review indicates that the beneficial effects result from immunomodulation, including a switch to IgG responses and induction of regulatory T cells. Allergen-specific immunotherapy has been carried out for almost a century and remains one of the few antigen-specific treatments for inflammatory diseases. The mechanisms by which allergen-specific immunotherapy exerts its effects include the modulation of both T-cell and B-cell responses to allergen. There is a strong rationale for improving the efficacy of allergen-specific immunotherapy by reducing the incidence and severity of adverse reactions mediated by IgE. Approaches to address this problem include the use of modified allergens, novel adjuvants and alternative routes of administration. This article reviews the development of allergen-specific immunotherapy, our current understanding of its mechanisms of action and its future prospects.