Allergic diseases are caused by aberrant T-helper-2 immune responses in susceptible individuals. Both naturally occurring CD4+CD25+ regulatory T cells and inducible populations of antigen-specific interleukin-10-secreting regulatory T cells inhibit these inappropriate immune responses in experimental models. This article discusses the evidence that regulatory T-cell function might be impaired in allergic and asthmatic disease and that certain therapeutic regimens might function, at least in part, to promote regulatory T-cell generation. Current research strategies seek to exploit these observations to improve the generation of allergen-specific regulatory T-cell populations with the potential to provide the safe and long-term alleviation of disease symptoms.
Allergic diseases — such as allergic rhinitis, asthma and atopic dermatitis — have diverse clinical features, but they have analogous immunological characteristics. Patients show upregulation of allergen-specific CD4+ T helper 2 (TH2) cells and allergen-specific IgE.
Strategies to promote long-term relief from the symptoms of allergic disease aim to inhibit allergen-specific TH2-cytokine responses.
Recently, several T-cell populations with the capacity to regulate immune responses have been described. These are known as regulatory T cells, and evidence is emerging that the function of regulatory T cells might be impaired in some allergic diseases.
Interleukin-10 (IL-10) is an anti-inflammatory cytokine, and it is produced by some populations of regulatory T cells (called IL-10-secreting regulatory T cells), as well as by antigen-presenting cells. It is an attractive candidate for the treatment of allergic asthma.
Some existing therapies for allergic diseases — both non-specific therapies, such as treatment with glucocorticoids, and specific therapies, such as allergen-desensitization immunotherapy — might function, at least in part, to promote the function of IL-10-secreting regulatory T cells.
Novel approaches that build on these observations are discussed, both experimental and those being tested in clinical trials.
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We gratefully acknowledge helpful discussions with A. Faith, at King's College London (United Kingdom), and D. Robinson, at Imperial College London. C.M.H. is supported, in part, by grants from Asthma UK and from Euro-Thymaide (European Union).
The authors declare no competing financial interests.
Having a clinically evident reaction to ubiquitous allergens, which is reflected by acquired immune responses that are marked, phenotypically, by the presence of allergen-specific IgE, together with mast-cell and eosinophil recruitment and activation. CD4+ T cells producing a T-helper-2 profile of cytokines (interleukin-4 (IL-4), IL-5, IL-9 and IL-13) are thought to be central to the development of allergic responses.
Inflammation of the mucous-membrane lining of the nose. The membrane becomes swollen, leading to partial or complete obstruction of air-flow, with excess local mucus production.
- ATOPIC DERMATITIS
A chronic skin disease in which the skin becomes extremely itchy and inflamed, causing redness, swelling, cracking, weeping, crusting and scaling. Its multifactorial pathogenesis involves genetic susceptibility, environmental triggers and immune dysregulation (typically dominated by T-helper-2 cells), with the involvement of IgE contributing to its classification as an atopic disease.
The generalized release of histamine and other inflammatory mediators following systemic induction of mast-cell degranulation by allergen. Anaphylaxis can cause bronchospasm, cardiovascular collapse and death.
The development of strong IgE responses to common environmental antigens.
Hormones produced by the adrenal gland. Synthetic derivatives are commonly used to suppress a wide range of inflammatory conditions and are used topically, intranasally or orally for the control of allergic and asthmatic reactions. Commonly used derivatives include fluticasone and prednisolone.
- ALLERGEN-DESENSITIZATION THERAPY
Allergen immunotherapy was introduced in the early 1900s. In general, it involves subcutaneous injection of increasing doses of specific allergen into the patient. This is carried out under carefully controlled clinical conditions because of the potential for life-threatening adverse reactions. On average, it results in ∼50% reduction of clinical symptoms and medication usage, and it also results in beneficial modifications of the patient's immune response to allergen. Following the initial course of injections (either conventional or rushed), patients receive maintenance injections (less frequently) of allergen for optimal clinical benefit.
- CLASS SWITCHING
The somatic-recombination process by which immunoglobulin isotypes are switched from IgM to IgG, IgA or IgE.
- β2 AGONISTS
β2-Adrenergic receptors are expressed by smooth-muscle cells, mast cells, endothelial cells, epithelial cells and a range of inflammatory cells. Short-acting agonists of these receptors (for example, albuterol) and long-acting agonists (for example, salmeterol (Serevent; GlaxoSmithKline) and formeterol) are used to induce bronchodilation in patients with asthma. Long-acting derivatives are also proposed to have anti-inflammatory properties.
- AIRWAY HYPER-RESPONSIVENESS
(AHR). 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 FEV1: that is, the forced expiratory volume in 1 second). Current hypotheses regarding the underlying process include mechanisms that lead to thickening of the airway wall, swelling of the airway-wall lining, epithelial damage that causes exposure of sensory nerve-fibre endings or changes in the contractile properties of smooth muscle.
Local application in the mouth, with or without swallowing. For allergen immunotherapy, sublingual application is less commonly used than subcutaneous injection. It is proposed to be associated with fewer systemic adverse events, but it might be less effective. The clinical efficacy is thought to range from 20% to 50% based on the reduction of symptom scores and medication usage.
- IMMUNODOMINANT EPITOPES
Epitopes present in a complex mixture of proteins (such as provided by a whole virus, tumour cell, bacterium or allergen) that induce strong T-cell responses.
- CRYPTIC EPITOPES
Antigenic peptides that are generated at sub-threshold levels or do not normally form epitopes after antigen processing. When cryptic epitopes become 'visible' to the immune system, they can elicit an immune response that induces autoimmune disease and possibly allergy.
- CpG 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 Toll-like receptor 9. Also known as immunostimulatory oligodeoxynucleotides (ISS ODNs).
- SKIN-PRICK TESTING
Clinical investigation to determine allergic sensitivity to various substances by injecting small quantities into or under the skin. A positive response is measured by the size of a red wheal and compared with reactions caused by histamine and saline as positive- and negative-control reactions.
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