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  • Review Article
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Immunological mechanisms of allergen-specific immunotherapy

Nature Reviews Immunology volume 6, pages 761–771 (2006)Cite this article

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.

Abstract

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.

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Figure 1: Mechanisms of allergic reactions.
Figure 2: Effects of allergen-specific immunotherapy on clinical and experimental immune parameters.
Figure 3: Proposed role of regulatory T cells and cytokines in allergen-specific immunotherapy.

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Acknowledgements

The laboratory of M.L. is supported by Asthma UK, the Medical Research Council (UK), the Canada Research Chairs Program and the Canada Foundation for Innovation. The laboratory of C.A.A. is supported by the Swiss National Science Foundation and the Global Allergy and Asthma European Network (GA2LEN). The laboratory of R.V. is partly supported by the Austrian Science Fund (FWF), the Christian Doppler Research Association and the Austrian Research Promotion Agency (FFG).

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Authors and Affiliations

  1. Division of Clinical Immunology & Allergy, Department of Medicine, McMaster University, 1200 Main Street West, Hamilton, L8N 3Z5, Ontario, Canada

    Mark Larché

  2. Department of Allergy & Clinical Immunology, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, National Heart and Lung Institute, Faculty of Medicine, Imperial College, London, SW7 2AZ, UK

    Mark Larché

  3. Swiss Institute of Allergy and Asthma Research (SIAF), Obere Strasse 22, Davos Platz, CH-7270, Switzerland

    Cezmi A. Akdis

  4. Division of Immunopathology, Department of Pathophysiology, Center for Physiology and Pathophysiology, Medical University of Vienna, Währinger Gürtel 18–20, Vienna, A-1090, Austria

    Rudolf Valenta

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Correspondence to Mark Larché.

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Competing interests

Mark Larché is a consultant for Circassia Ltd (UK) and holds equity in Circassia Holdings Ltd. Cezmi A. Akdis has no competing financial interests. Rudolf Valenta is a consultant for Phadia AB (Sweden), in the field of allergy diagnostics, and for Biomay (Austria), in the fields of therapy and prevention of allergy. He also holds grants from both companies.

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Glossary

Hypersensitivity

An exaggerated and inappropriate immune response to an antigen or allergen. In the context of allergic diseases, this includes production of allergen-specific IgE to environmental or self antigens.

Class switching

The somatic-recombination process by which the class of immunoglobulin is switched from IgM to IgG, IgA or IgE.

Immediate phase of the allergic reaction

(Also known as the early phase). The biological and clinical consequences that occur within the first hour of crosslinking of IgE–FceRI (high-affinity receptor for IgE) complexes at the surface of mast cells and/or basophils by allergens. The clinical manifestations are characterized by tissue-specific effects: for example, constriction of the large airways in asthma, and wheal-and-flare reactions in the skin. Generalized symptoms in multiple target organs can include oedema and pruritus (itching). Systemic manifestations can include angio-oedema, urticaria and, in severe cases, vascular collapse (anaphylaxis).

Late phase of the allergic reaction

Clinical manifestations can be measurable (visible) two or more hours after allergen exposure but might appear much later. These manifestations peak at 6–9 hours after allergen exposure and have resolved by 24–48 hours. Reactions are characterized by oedema and the infiltration of T helper 2 cells and eosinophils. Tissue reactions are characterized by oedema, pain, warmth and erythema (redness). Reactions in the lungs are characterized by airway narrowing and mucus hypersecretion.

CpG motif

A deoxycytosine–deoxyguanosine sequence. Such sequences are prevalent in bacterial DNA but are rare in mammalian DNA. Unmethylated CpG is endocytosed by cells of the innate immune system and interacts with Toll-like receptor 9, activating a signalling cascade that results in the production of pro-inflammatory cytokines.

Plasmacytoid DC

An immature dendritic cell (DC) with a morphology that resembles that of a plasma cell. Plasmacytoid DCs produce type I interferons (that is, interferon-α and interferon-β) in response to viral infection.

TH0 cells

Precursors of T helper 1 (TH1) cells and TH2 cells. TH0 cells produce both interferon-γ and interleukin-4. They have the capacity to become TH1 cells and/or TH2 cells.

Skin-prick test

If allergen-specific IgE is present in an individual, then the introduction of tiny amounts of allergen into the epidermis by a prick or scratch induces the degranulation of mast cells. This results in a wheal-and-flare reaction, the size of which is used as a measure of the sensitivity to allergen of an individual.

Hinge region

The sequence of amino acids, which is often rich in cysteine and proline residues, that is present in the constant region of immunoglobulin heavy chains. It provides increased molecular flexibility. This region might be involved in the disulphide bonds that link adjacent immunoglobulin heavy chains.

Allergen microarray

Similar to a DNA microarray. High-density arrays of individual allergen proteins or extracts spotted onto a solid phase (usually glass). The arrays can be incubated with small volumes of serum from patients, and the binding of IgE to the arrayed allergens can be determined and this information used for diagnostic purposes.

Phage-display technology

A technology for displaying a protein on the surface of a bacteriophage that contains the gene(s) encoding the displayed protein(s), thereby physically linking the genotype and phenotype.

Microfold cells

(M cells). Specialized epithelial cells that deliver antigens from the gut lumen directly to intraepithelial lymphocytes and to subepithelial lymphoid tissues, using transepithelial vesicular transport.

Chitosan–DNA nanoparticle

A small (150–300 nm) particle that is formed by mixing plasmid DNA (in this case, encoding allergen) with the high-molecular-weight molecule chitosan, a biodegradable polysaccharide derived from crustaceans. Chitosan has been used extensively for drug delivery and increases molecular transport across the mucosal epithelial-cell barrier.

Replicon-based DNA vaccine

A vaccine that is based on DNA molecules that can replicate autonomously (for example, plasmids and phage).

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Larché, M., Akdis, C. & Valenta, R. Immunological mechanisms of allergen-specific immunotherapy. Nat Rev Immunol 6, 761–771 (2006). https://doi.org/10.1038/nri1934

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