Reviews and Feature Articles: Molecular Mechanisms In Allergy And Clinical ImmunologyThe role of T lymphocytes in the pathogenesis of asthma☆
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T cells and TH2 cytokines in asthma
It is well known that allergen-specific IgE synthesis is T cell dependent through cognate activation of B lymphocytes and T cell–derived cytokines, such as IL-4 and IL-13.7 Thus in atopic asthma and allergic rhinitis allergen processing and presentation to allergen-specific T cells through antigen-presenting cells is a key initiation step. Growing interest in the role of the T cell in asthma arose from the concept that, in addition to participating in IgE synthesis, T-cell products might also
The asthma phenotypes
The contribution of allergy across the spectrum of asthma has always been vigorously debated. One study showed that only about half of asthma is atopic,18 and therefore the following is an important question: What is the role of T cells and, more particularly, TH2 cells in the nonatopic (intrinsic) form of the disease, as well as in occupational asthma and acute exacerbations, in which viruses often appear to be the triggering factor. Bronchial biopsy specimens from nonatopic patients and
Effector mechanisms: How do T cells cause asthma?
Over the past few years, a working hypothesis has been that TH2 cytokines contribute to asthma pathology through IgE synthesis, maturation and activation of mast cells and basophils (and thus acute asthma), and IL-5–mediated eosinophil infiltration, leading to epithelial damage and AHR.5 Some studies also showed TH1 cytokines in serum and BAL fluid from asthmatic patients,28 particularly during exacerbations, although most studies confirm TH2 predominance in stable disease. It also soon became
Are T cells required to perpetuate asthma?
Much attention has been focused on airway remodeling in asthma.34 This encompasses changes in the epithelium, subepithelial basement membrane deposition of collagen and other extracellular matrix proteins, increased vascularity, and smooth muscle hypertrophy and hyperplasia. It has been suggested that the smooth muscle changes alone are sufficient to sustain AHR.35 Bronchial mucosa biopsy specimens of asthmatic patients compared with those from patients with eosinophilic bronchitis (which is
New cytokines, intracellular controllers of T-cell function and animal models: What do they tell us about asthma?
In the 10 years since the description of TH2 cytokines in asthma, an array of novel cytokines has been described, and our understanding of the molecular control of T-cell activation and differentiation has improved. Studies from animal models and some human data support the relevance of some of these factors in human asthma.
Provoked asthma under controlled clinical conditions
Inhaled allergen challenge of sensitized atopic asthmatic patients has been used for many years as a model of asthma to study both the early and late reaction.75 Although the early reaction is thought be IgE and mast cell dependent, the cause and significance of the LAR and associated increased AHR is less certain. Although cutaneous late responses could be induced by passive transfer of IgE and rechallenge,76 the skin and lung response are associated with eosinophil and T-cell infiltration,
Activation of T cells in asthma: Antigen-presenting cells
In addition to presentation of antigen peptide in the context of MHC, T-cell activation requires costimulation and additional signals.88 A number of factors might influence antigen-presenting cells, and dendritic cells (DCs) are plastic in their ability to drive T-cell responses to TH1- or TH2-type responses.89 DC function is partially controlled by signals from the innate immune system, in part through toll-like receptors, through control of IL-12 and IL-10 production. Different costimulation
CD8 T cells and γδ cells
There are several reports that suggest that CD8+ cells might participate in the asthma process. An early study involving BAL after allergen inhalational challenge suggested that CD8+ cells might be involved in the regulation of the expression of the LAR because there were relative increases in OKT8+ lavage cells in early-phase compared with late-phase responders.2 On the other hand, several studies have indicated that CD8+ cells might be proinflammatory in the airways. In both atopic and
Homing of T cells to the airway in asthma
It has been established for some time that T cells use adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), during trafficking to the airway, but there is increasing interest in the role of specific chemokines in either tissue-directed T-cell homing or in recruitment of different T-cell subtypes. Most of the current data come from mouse models or human allergen challenge studies. In vitro mouse and human TH2 cells are polarized
Corticosteroids
Inhaled corticosteroids are the mainstay of asthma management, and these agents are extremely effective in vitro as inhibitors of T-cell activation and cytokine production.111 There are many studies showing a reduction in T-cell activation and cytokine expression in the airways of asthmatic patients after steroid treatment.112, 113 It is of interest that patients with corticosteroid-resistant asthma did not have reduced IL-5 levels in airway biopsy specimens after treatment with oral
Antigen-directed targeting of T cells and regulatory T cells: The future for asthma therapy?
Allergen injection immunotherapy has long been used for the treatment of allergic asthma in many countries (although not in the United Kingdom). Current evidence suggests that immunotherapy modulates the T-cell response to allergen, either through immune deviation to a TH1 response or through induction of a modified TH2 or regulatory T-cell response with high IL-10 secretion.126 IL-10 inhibits T-cell activation and cytokine secretion and switches B cells from IgE to IgG4 production.127
Conclusions
There is now considerable evidence for the role of T cells in asthma. The hypothesis has generated a number of potential avenues for future therapy. Important remaining questions include the following:
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Will direct targeting of T cells, such as through peptide therapy, be effective for chronic asthma, or does airway remodeling preclude major responses to T cell–directed treatment?
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What drives the T-cell response in nonallergic intrinsic asthma?
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Are non-TH2 products important in T cell–dependent
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Reprint requests: A. Barry Kay, MD, PhD, Department of Allergy and Clinical Immunology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Dovehouse St, London, SW3 6LY, United Kingdom.