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  • Review Article
  • Published:

Treatment strategies for allergy and asthma

Nature Reviews Immunology volume 8, pages 218–230 (2008)Cite this article

Key Points

  • Allergic diseases, including asthma, rhinitis, conjunctivitis and food allergies, have reached epidemic proportions worldwide. Allergic inflammatory responses are mediated by expansion of the T helper 2 (TH2)-cell subset of T cells together with isotype switching of B cells to generate IgE antibodies specific for common environmental allergens.

  • A comprehension of the cellular and soluble mediator components of allergic inflammatory responses is important for understanding the mechanisms of current treatment modalities and in leading to the identification of new therapeutic targets.

  • In theory, allergen avoidance should be beneficial as a primary or secondary prophylaxis, but most studies show discrepancies. Inhaled corticosteroids, and short- and long-acting β2-adrenoceptor agonists (SABAs and LABAs) are now the mainstay of asthma treatment, having established anti-inflammatory and bronchodilator effects. Immunomodulators are an option for those patients whose symptoms are not controlled by conventional treatments, although cytokine-directed therapies offer new promise.

  • Allergen immunotherapy is known to induce immunological tolerance and has been recommended for the management of allergic diseases. Allergen extracts or recombinant allergens can be administered either by regular subcutaneous injections or sublingually, and these are the only treatments that influence the natural history of allergic disease.

  • IgE and mast cells are cogent therapeutic targets. A humanized, non-anaphylactic, IgE-specific IgG1 antibody has been developed recently and is effective for the treatment of severe allergic asthma and allergic rhinoconjunctivitis. Several therapies that inhibit FcÉ›RI-mediated activation of mast cells have been identified and are now in clinical development.

  • Allergic inflammation has been characterized as being mainly a TH2-cell-mediated disease; therefore, efforts to alter the balance between TH2 cells, TH1 cells and regulatory T (TReg) cells in asthma have been aggressively pursued, either by inhibiting TH2-cell cytokines — in particular, interleukin-4 (IL-4), IL-13 and IL-5 — or by promoting TH1-cell and TReg-cell responses. Given that tissue injury and aberrant repair are also important components of chronic allergic diseases, restoration of the barrier function by administration of growth factors is another promising therapeutic strategy.

Abstract

Allergic diseases have reached epidemic proportions worldwide. An understanding of the cellular and soluble mediators that are involved in allergic inflammatory responses not only helps in understanding the mechanisms of current treatments, but is also important for the identification of new targets that are amenable to both small-molecule and biological interventions. There is now considerable optimism with regards to tackling the allergy epidemic in light of improvements in systemic and mucosal allergen-specific immunotherapy, the identification of key cytokines and their receptors that drive T-helper-2-cell polarization, a clearer understanding of the pathways of leukocyte recruitment and the signalling pathways that are involved in cell activation and mediator secretion, and new approaches to vaccine development.

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Figure 1: Allergic mechanisms.
Figure 2: Inflammatory and remodelling responses in asthma with activation of the epithelial–mesenchymal unit.
Figure 3: Anti-inflammatory actions of corticosteroids.
Figure 4: Effects of allergen-specific immunotherapy (SIT) on immune parameters.
Figure 5: The effects of targeting IgE on allergic responses.
Figure 6: Cytokine-based therapies in asthma.

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Acknowledgements

R.P. is a Professor of Medicine and he is supported by the University of Catania, Italy. S.T.H. is a UK Medical Research Council Clinical Professor.

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  1. IIR Division, F Level, South Block, Southampton General Hospital, Southampton, SO16 6YD, UK

    Stephen T. Holgate

  2. Dipartimento di Medicina Interna e Specialistica, University of Catania, Via Passo Gravina, 187, 95, 125, Catania, Italy

    Riccardo Polosa

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Holgate, S. T. & Polosa, R. Treatment strategies for allergy and asthma. Nature Reviews Immunology 15 February 2008 (doi: 10.1038/nri2262)

Stephen Holgate is a consultant for Novartis, Cambridge Antibody Technology, Merck, Synairgen and Centocor. He occasionally participates in sponsored lectures overseas. He is also a non-executive board member of Synairgen and holds shares in the company.

Riccardo Polosa is a consultant for CV Therapeutics, Duska Therapeutics and NeuroSearch and has received lecture fees from Pharmaxis, Merck and Novartis.

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Glossary

T helper 2 cells

(TH2 cells). A T-helper-cell subset that has an important role in humoral immunity and in allergic responses. TH2 cells produce cytokines that regulate IgE synthesis (IL-4), eosinophil proliferation (IL-5), mast-cell proliferation (IL-9) and airway hyper-responsiveness (IL-13). A TH2-cell pattern of cytokine expression is observed in allergic inflammation and in parasitic infections, conditions that are both associated with IgE production and eosinophilia.

Atopy

This term (from the Greek ατοπια, meaning placelessness) refers to the susceptibility to develop exaggerated IgE responses to common environmental allergens, defined clinically by the presence of one or more positive skin-prick tests. Atopy represents a genetic predisposition towards allergic diseases.

Regulatory T cells

(TReg cells). These are specialized cells that act to suppress the function of other cells. In allergic inflammation, TReg cells can have an important role in limiting allergic responses by suppressing the function of TH2 cells. The molecular mechanism by which TReg cells exert their activity is either through cell-to-cell contact with the cell being suppressed or through secretion of the immunosuppressive cytokines TGFβ and IL-10.

Transactivation

A transcriptional mechanism by which gene transcription is induced resulting in the de novo synthesis of susceptible proteins.

Transrepression

A transcriptional mechanism by which gene transcription is prevented resulting in an overall repressive effect.

Xanthine

A purine base found in most body tissues and fluids as a result of purine degradation. Theophylline is a methylated xanthine with activities as both a cyclic-AMP phosphodiesterase inhibitor and adenosine-receptor antagonist, which is commonly used for its effects as a mild stimulant and as a bronchodilator.

CpG oligonucleotide motifs

DNA oligonucleotide sequences that include a cytosine–guanosine sequence and certain flanking nucleotides. They have been found to induce innate immune responses through interaction with TLR9. When coupled to allergens, CpG DNA seems to increase immunological tolerance by shifting the balance of T-cell phenotypes from TH2 to TH1 cells. CpG motifs are also known as immunostimulatory oligodeoxynucleotides (ISS ODNs).

Airway hyper-responsiveness

An abnormally increased sensitivity of the airways to otherwise innocuous stimuli, resulting in increased responses to inhaled allergen and airway smooth-muscle spasmogens (for example, methacholine or histamine). In humans, this is generally defined by PC20 (the provocation concentration of the spasmogen that causes a 20% decrease in forced expiratory volume in one second, FEV1).

Immunoreceptor tyrosine-based activation motif

(ITAM). Activating receptors often have ITAMs consisting of a consensus amino-acid sequence with paired tyrosines and leucines (YxxI/Lx(6–12) YxxI/L). These are normally located in the cytoplasmic domains of ligand-binding transmembrane receptors (such as FcεRI and TCR) and they mediate interaction between the transmembrane receptor complex and protein tyrosine kinase activity, which is required to initiate early and late signalling events.

Immunoreceptor tyrosine-based inhibitory motif

(ITIM). Inhibitory receptors often have one or more ITIMs (consensus, S/I/V/LxYxxI/V/L). Ligand engagement by inhibitory receptors (such as CTLA4 in T cells) results in ITIM phosphorylation and the recruitment of phosphotyrosine phosphatases, which leads to decreased tyrosine phosphorylation of activation-pathway effectors.

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Holgate, S., Polosa, R. Treatment strategies for allergy and asthma. Nat Rev Immunol 8, 218–230 (2008). https://doi.org/10.1038/nri2262

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