The future of biologics: applications for food allergy

Abstract

Allergic diseases affect millions worldwide, with growing evidence of an increase in allergy occurrence over the past few decades. Current treatments for allergy include corticosteroids to reduce inflammation and allergen immunotherapy; however, some subjects experience treatment-resistant inflammation or adverse reactions to these treatments, and there are currently no approved therapeutics for the treatment of food allergy. There is a dire need for new therapeutic approaches for patients with poorly controlled atopic diseases and a need to improve the safety and effectiveness of allergen immunotherapy. Improved understanding of allergy through animal models and clinical trials has unveiled potential targets for new therapies, leading to the development of several biologics to treat allergic diseases. This review focuses on the mechanisms that contribute to allergy, with an emphasis on future targets for biologics for the treatment of food allergy. These biologics include immunotherapy with novel anti-IgE antibodies and analogs, small-molecule inhibitors of cell signaling, anti-type 2 cytokine mAbs, and TH1-promoting adjuvants.

Keywords: Food allergy; allergen sensitization; anaphylaxis; anti-IgE; biologics; immunotherapy; oral tolerance.

Figure 1. Oral tolerance

In oral tolerance, antigen is recognized by the immune system, but does not induce adverse immune reactions. Dendritic cells (DC) sample luminal contents, recognize antigen and traffic to lymph nodes. Activated tolerogenic DCs and macrophages secrete regulatory mediators like IL-10, TGF-β, and retinoic acid. Tolerogenic DCs migrate to the lymph node to present antigens to naive T lymphocytes (Th0) and promote differentiation of regulatory T (Treg) cells. Tregs secrete IL-10 and reduce effector CD4⁺ and CD8⁺ T cell responses.

Figure 2. Breakdown of tolerance

Allergy is associated with a breakdown in tolerance that promotes antigen sensitization. Increased epithelial cell permeability permits access of allergens to the underlying mucosa. Epithelial cells produce cytokines like TSLP, IL-33, and IL-25 that skew dendritic cell (DC) phenotype, activate innate lymphoid cells, and promote type 2 (Th2) immunity. DCs recognize food antigen and migrate to the lymph node, where they present allergens to naive T lymphocytes (Th0) in the presence of Th2-polarizing mediators (like IL-4) to promote the development of Th2 lymphocytes. Th2 lymphocytes secrete additional type 2 cytokines (IL-4, IL-5 and IL-13) and promote B cell isotype switching and IgE production. IgE binds to FcεRI/II receptors expressed by cells like mast cells and basophils to promote inflammatory allergic responses.

Figure 3. Early and late phase anaphylaxis

Anaphylactic reactions to allergens occur as an early and a late phase. In the early phase, IgE -allergen complexes are recognized by FcεRI/II expressed by cells like mast cells and basophils. Activation through FcεRI/II promotes the release of preformed mediators such as platelet activating factor (PAF), histamine, cytokines and chemokines, leukotrienes and proteases. These mediators induce immediate anaphylactic symptoms, including vasodilation, vascular permeability, and bronchoconstriction, and promote leukocyte recruitment from circulation. During the late phase reaction, recruited leukocytes, including basophils, eosinophils, T lymphocytes and monocytes/macrophages produce inflammatory cytokines, proteases and cytotoxic mediators that can damage tissue and induce anaphylactic symptoms.