Mechanisms of allergen-specific immunotherapy: Multiple suppressor factors at work in immune tolerance to allergens

doi:10.1016/j.jaci.2013.12.1088

Journal of Allergy and Clinical Immunology

Volume 133, Issue 3, March 2014, Pages 621-631

https://doi.org/10.1016/j.jaci.2013.12.1088 Get rights and content

Allergen-specific immunotherapy (AIT) has been used for more than 100 years as a desensitizing therapy for IgE-mediated allergic diseases and represents a potentially curative way of treatment. The mechanisms of action of AIT include the induction of very early desensitization of mast cells and basophils; generation of regulatory T and regulatory B (Breg) cell responses; regulation of IgE and IgG₄; decreases in numbers and activity of eosinophils and mast cells in mucosal allergic tissues; and decreases in the activity of basophils in circulation. Skewing of allergen-specific effector T and effector B cells to a regulatory phenotype appears as a key event in the course of AIT and normal immune response to allergens. Recently, inducible IL-10–secreting Breg cells were also demonstrated to contribute to allergen tolerance through suppression of effector T cells and selective induction of IgG₄ isotype antibodies. Allergen-specific regulatory T and Breg cells orchestrate a general immunoregulatory activity, which can be summarized as suppression of cytokines from inflammatory dendritic cells; suppression of effector T_H1, T_H2, and T_H17 cells; suppression of allergen-specific IgE and induction of IgG₄; and suppression of migration of mast cells, basophils, eosinophils, and effector T cells to tissues. A detailed knowledge of the mechanisms of AIT is not only important in designing the prevention and treatment of allergic diseases but might also find applications in the treatment of autoimmune diseases, organ transplantation, chronic infection, and cancer.

Section snippets

Mechanisms of AIT

Cellular and molecular events that take place during the course of AIT can be classified into 4 groups (Fig 1). Although there is significant variation between donors and protocols, decreases in mast cell and basophil activity and degranulation and the tendency for systemic anaphylaxis start to take place within hours when natural allergens are used. The second group of events are generation of allergen-specific Treg and regulatory B (Breg) cells and suppression of allergen-specific effector

Rapid desensitization of mast cells and basophils by allergens

Several mechanisms have been proposed to explain why mast cells and basophils become unresponsive to environmental proteins, even in the presence of specific IgE. Notably, after the first injection of AIT, very early decreases in the susceptibility of mast cells and basophils to degranulation and in systemic anaphylaxis can be observed, even though all the treated subjects have high quantities of specific IgE. This effect occurs when 3-dimensional structure-intact allergens are used. Although

Treg and Breg cells in AIT

It is now generally appreciated that peripheral T-cell tolerance is essential for a normal immune response and successful immunotherapy of allergic disorders (Fig 2).²³ Although multiple factors contribute, the tolerant state of specific cells essentially results from increased IL-10 secretion.24, 25, 26 Suppressor capacity for allergen/antigen-stimulated T cells is particularly confined to IL-10 but not its other family members, such as IL-19, IL-20, IL-22, IL-24, and IL-26.²⁷ IL-10

AIT and Treg and Breg cells influence allergen-specific antibody responses

Natural exposure to a relevant allergen is often associated with an increase in IgE synthesis. Similarly, AIT often induces a transient increase in serum specific IgE levels, followed by a gradual decrease over months or years of continued treatment.34, 35, 36 In pollen-sensitive patients desensitization prevents increases in serum specific IgE titers during the pollen season.37, 38 However, the changes in IgE levels cannot account for the diminished responsiveness to specific allergen caused

Suppression of late-phase responses of effector cells during AIT

Long-term AIT is associated with a significant reduction in the immediate response to allergen provocation and the late-phase response (LPR) in the nasal and bronchial mucosa or the skin. The mechanism of LPRs is different from that of mast cell–mediated immediate reactions and involves the recruitment, activation, and persistence of eosinophils and activation of T cells at sites of allergen exposure. The immunopathologic changes seen in mucosal tissues of subjects chronically exposed to

Treg and Breg cells and other cells of immune regulation

More than 30 years ago, it was postulated that CD8⁺ suppressor cells limit ongoing immune responses and might prevent autoimmune disease.⁵⁸ The recent phenotypic and functional characterization of suppressive Treg cells has led to a renaissance of interest in their therapeutic application in a number of immune-mediated diseases. Two broad subsets of CD3⁺CD4⁺ Treg cells have been described: constitutive or naturally occurring Treg cells and adaptive or inducible Treg cells. It has been recently

TGF-β, IL-10, and immune tolerance

TGF-β is a potent regulatory cytokine produced by a wide range of cell types playing a pivotal role in maintaining tolerance, particularly oral tolerance, within the immune system (Table II).⁸⁸ TGF-β inhibits the proliferation, differentiation, and survival of both B and T lymphocytes. Given its broad functions, the effects of TGF-β in patients with allergic disease are complex, with evidence of both disease inhibition and promotion. TGF-β is involved in (1) a negative feedback mechanism to

HR2 as a major player in peripheral tolerance

A small-molecular-weight monoamine that binds to 4 different G protein–coupled receptors, histamine regulates several essential events in the immune response.⁹⁴ HR2 is coupled to adenylate cyclase, and studies in animal models and human cells indicate that HR2 inhibits characteristic features of cells primarily through cyclic AMP formation.⁹⁵ During AIT with high allergen doses, histamine released from mast cells and basophils interferes with the peripheral tolerance induced in several pathways.

Immune tolerance induced in SLIT

SLIT has a well-established safety profile, with more than several hundred million doses administered to human subjects, and is considered an alternative to subcutaneous AIT.100, 101 The immunologic mechanisms of SLIT are less well established than those for subcutaneous immunotherapy (Table III). Meta-analyses concluded that IgG₄ levels increase but IgE levels remain stable in adults.100, 101 In addition, allergen-specific IgA is induced.¹⁰² There are conflicting data concerning

Conclusion

Immune tolerance to allergens is essential to develop a healthy immune response to allergens in highly exposed subjects. Allergen-specific tolerance involves a deviation in T-cell response to T_R1 cells, B-cell response to IL-10–secreting B_R1 cells, increased IgG₄ isotype specific antibody response, and decreased activation of effector cells, such as basophils, mast cells, and eosinophils. Multiple mechanisms and receptors play a role in this, such as IL-10, TGF-β, CTLA-4, PD-1, and HR2. These

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: Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, and William T. Shearer, MD, PhD

The authors' laboratories are supported by the Swiss National Foundation grants 320030_140772 and 320030_132899 and the Christine Kühne Center for Allergy Research and Education (CK-CARE), European 7th frame work projects MeDALL: Mechanisms of the Development of Allergy (no. 261357), and PREDICTA: Post-Infectious Immune Reprogramming and Its Association with Persistence and Chronicity of Respiratory Allergic Diseases (no. 260895).

Disclosure of potential conflict of interest: M. Akdis has received grants from the Swiss National Science Foundation, EF7 MeDALL, and EF7 Predicta. C. A. Akdis has consultant arrangements with Actellion, Aventis, Stallergenes, Allergopharma, and Circacia; is employed by the Swiss Institute of Allergy and Asthma Research, University of Zurich; and has received grants from Novartis, PREDICTA, the Swiss National Science Foundation, MeDALL, and the Christine Kühne Center for Allergy Research and Education Research.

: Terms in boldface and italics are defined in the glossary on page 622.

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Reviews and feature articleMechanisms of allergen-specific immunotherapy: Multiple suppressor factors at work in immune tolerance to allergens

Section snippets

Mechanisms of AIT

Rapid desensitization of mast cells and basophils by allergens

Treg and Breg cells in AIT

AIT and Treg and Breg cells influence allergen-specific antibody responses

Suppression of late-phase responses of effector cells during AIT

Treg and Breg cells and other cells of immune regulation

TGF-β, IL-10, and immune tolerance

HR2 as a major player in peripheral tolerance

Immune tolerance induced in SLIT

Conclusion

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Curr Opin Immunol

Allergol Int

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Cell Immunol

J Allergy Clin Immunol

Immunity

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Microbes Infect

J Allergy Clin Immunol

Mol Immunol

J Allergy Clin Immunol

Int Immunopharmacol

Allergen immunotherapy: a new semantic framework from the European Academy of Allergy and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL consensus report

Allergy

Sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: a systematic review

JAMA

Therapies for allergic inflammation: refining strategies to induce tolerance

Nat Med

Immune tolerance

Long-term clinical efficacy in grass pollen-induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet

J Allergy Clin Immunol

Therapeutic manipulation of immune tolerance in allergic disease

Nat Rev Drug Discov

In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure

J Exp Med

Allergens and their role in the allergic immune response

Immunol Rev

TH17 and TH22 cells: a confusion of antimicrobial response with tissue inflammation versus protection

J Allergy Clin Immunol

Interleukins, from 1 to 37, and interferon-gamma: receptors, functions, and roles in diseases

J Allergy Clin Immunol

Antigen-specific tolerance in immunotherapy of Th2-associated allergic diseases

Crit Rev Immunol

Tryptase and histamine release due to a sting challenge in bee venom allergic patients treated successfully or unsuccessfully with hyposensitization

Clin Exp Allergy

Basophil interleukin 4 and interleukin 13 production is suppressed during the early phase of rush immunotherapy

Int Arch Allergy Immunol

Early suppression of basophil activation during allergen-specific immunotherapy by histamine receptor 2

J Allergy Clin Immunol

Long-term tolerance after allergen immunotherapy is accompanied by selective persistence of blocking antibodies

J Allergy Clin Immunol

Role of interleukin 10 in specific immunotherapy

J Clin Invest

Immunotherapy for allergic rhinitis

Clin Exp Allergy

Distinct regulation of IgE, IgG4 and IgA by T regulatory cells and toll-like receptors

Allergy

Regulation of T cells and cytokines by the interleukin-10 (IL-10)-family cytokines IL-19, IL-20, IL-22, IL-24 and IL-26

Eur J Immunol

Bee venom immunotherapy results in decrease of IL-4 and IL-5 and increase of IFN-g secretion in specific allergen stimulated T cell cultures

J Immunol

IL-10 and TGF-b cooperate in regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy

Eur J Immunol

Reviews and feature article
Mechanisms of allergen-specific immunotherapy: Multiple suppressor factors at work in immune tolerance to allergens