Allergen-Specific Immunotherapies for Food Allergy

Abstract

With rising prevalence of food allergy (FA), allergen-specific immunotherapy (AIT) for FA has become an active area of research in recent years. In AIT, incrementally increasing doses of inciting allergen are given with the goal to increase tolerance, initially through desensitization, which relies on regular exposure to allergen. With prolonged therapy in some subjects, AIT may induce sustained unresponsiveness, in which tolerance is retained after a period of allergen avoidance. Methods of AIT currently under study in humans include oral, sublingual, epicutaneous, and subcutaneous delivery of modified allergenic protein, as well as via DNA-based vaccines encoding allergen with lysosomal-associated membrane protein I. The balance of safety and efficacy varies by type of AIT, as well as by targeted allergen. Age, degree of sensitization, and other comorbidities may affect this balance within an individual patient. More recently, AIT with modified proteins or combined with immunomodulatory therapies has shown promise in making AIT safer and/or more effective. Though methods of AIT are neither currently advised by experts (oral immunotherapy [OIT]) nor widely available, AIT is likely to become a part of recommended management of FA in the coming years. Here, we review and compare methods of AIT currently under study in humans to prepare the practitioner for an exciting new phase in the care of food allergic patients in which improved tolerance to inciting foods will be a real possibility.

Keywords: Food allergy; epicutaneous immunotherapy; oral immunotherapy; subcutaneous immunotherapy; sublingual immunotherapy.

Fig. 1. Putative mechanisms of tolerance induction in allergen-specific immunotherapy. In allergen-specific immunotherapy (AIT), native or modified allergen is taken up by dendritic cells which migrate to regional lymph nodes, where they induce naïve T cells to regulatory T cell phenotype, through presentation of the allergen in context of MHC, secretion of cytokines such as TGF-β, generation of retinoic acid and indoleamine 2,3-dioxygenase, and other mechanisms. Secretion of cytokines IL-10 and TGF-β suppress T_H2 immunity and mast cell reactivity, reduce sIgE synthesis, and may increase sIgG and sIgA synthesis. AIT, particularly with LAMP-DNA vaccines, may also enhance tolerance through increased T_H1 immunity: presentation of allergen by dendritic cells in context of MHC to naïve T cell may induce T_H1 commitment particularly in presence of costimulators; production of IFN-γ by T_H1 cells suppresses T_H2 responses and reduces class switch to IgE. Other mechanisms of AIT may include increased anergy and apoptosis of T_H2 cells through persistent antigenic stimulation.

Fig. 2. Putative mechanisms of oral tolerance induction in the gut. On passage through the epithelial barrier, food protein allergen is captured by the dendritic cell (DC). The DC migrates to the nearby mesenteric lymph nodes and produces TGF-β, IL-10, and IL-27, which induce T regulatory cells (Tregs) and promote secretion of IgA and IgG4 by B cells. Tregs express surface receptors CCR9 and α4β7 integrin, which direct migration to the gut. Tregs secrete immunosuppressive cytokines IL-10 and TGF-β, which reinforce tolerance. Reprinted from Journal of Allergy and Clinical Immunology: In Practice (Volume 5), Gernez Y and Nowak-Wegrzyn A, “Immunotherapy for Food Allergy: Are we there yet?”, Page 253, 2017, with permission from Elsevier.

Fig. 3. Typical protocol for oral and sublingual immunotherapy. Initial doses of OIT and SLIT are generally given under medical supervision. Initial dose escalation day(s) starting at subthreshold dose with increasing doses given every 30 minutes over several hours is more common for OIT than for SLIT. Highest tolerated dose given under observation is then continued daily at home, and increased every 1 to 2 weeks under supervision during the build-up phase. The dose achieved at the end of the build-up is continued daily during a maintenance phase. After a few months or years of maintenance, double-blind placebo-controlled food challenge (DBPCFC) to the food is performed to assess for desensitization. Daily dosing may then be discontinued for a period of 4–12 weeks and reintroduced during DBPCFC, to assess sustained tolerance (SU). Reprinted from Journal of Allergy and Clinical Immunology: In Practice (Volume 5), Gernez Y and Nowak-Wegrzyn A, “Immunotherapy for Food Allergy: Are we there yet?”, Page 253, 2017, with permission from Elsevier.