Mechanisms of allergen-specific immunotherapy and immune tolerance to allergens

Abstract

Substantial progress in understanding mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumors, organ transplantation and chronic infections has led to a variety of targeted therapeutic approaches. Allergen-specific immunotherapy (AIT) has been used for 100 years as a desensitizing therapy for allergic diseases and represents the potentially curative and specific way of treatment. The mechanisms by which allergen-AIT has its mechanisms of action include the very early desensitization effects, modulation of T- and B-cell responses and related antibody isotypes as well as inhibition of migration of eosinophils, basophils and mast cells to tissues and release of their mediators. Regulatory T cells (Treg) have been identified as key regulators of immunological processes in peripheral tolerance to allergens. Skewing of allergen-specific effector T cells to a regulatory phenotype appears as a key event in the development of healthy immune response to allergens and successful outcome in AIT. Naturally occurring FoxP3(+) CD4(+)CD25(+) Treg cells and inducible type 1 Treg (Tr1) cells contribute to the control of allergen-specific immune responses in several major ways, which can be summarized as suppression of dendritic cells that support the generation of effector T cells; suppression of effector Th1, Th2 and Th17 cells; suppression of allergen-specific IgE, and induction of IgG4; suppression of mast cells, basophils and eosinophils and suppression of effector T cell migration to tissues. New strategies for immune intervention will likely include targeting of the molecular mechanisms of allergen tolerance and reciprocal regulation of effector and regulatory T cell subsets.

Figure 1

Immunologic changes during the course of AIT. Starting with the first injection, decreases in mast cell and basophil activity, degranulation and tendency for systemic anaphylaxis degranulation takes place within the first hours. This is followed by generation of allergen-specific Treg and Breg cells and suppression of allergen-specific Th1 and Th2 cells. Specific IgE shows an early increase and decreases relatively late. These events are in parallel to increases of IgG4 that continuously increases as long as the treatment continues. After several months, the allergen-specific IgE/IgG4 ratio decreases. After a few months, decreases in tissue mast cells and eosinophils and release of their mediators and skin late phase response occurs. A significant decrease in type I skin test reactivity is also observed relatively late in the course. It has to be noted that there is significant variation between donors and protocols.

Figure 2

Role of Treg and Breg cells in the suppression of allergic inflammation. The balance between Th2 cells and Treg cells is decisive for the development or suppression of allergic inflammation. Treg cells and their cytokines suppress Th2 type immune responses and contribute to the control of allergic diseases in several major ways. Red arrows indicate the regulatory and suppressive effects of Treg cells, which exert their regulatory functions directly or indirectly on B cells by inducing IgG4 and IgA and suppressing IgE; on vascular endothelium by suppressing Th2 cell homing to tissues; on mast cells, basophils and eosinophils via direct and indirect suppressive effects; and on directly and indirectly suppression of epithelial cell activation and proinflammatory properties. In addition, B reg cells also suppress effector T cells and contribute to IgG4 synthesis.