ArticlesDevelopment of allergen-specific T-cell memory in atopic and normal children
Introduction
In the past 20–30 years, there has been a progressive increase in the prevalence of allergic respiratory diseases, in particular atopic asthma,1 with an associated increase in management costs. Primary prevention aims to identify atrisk individuals at an early stage and to begin prophylactic therapy to prevent development of chronic disorders. Targets for primary prevention are the underlying immune responses that potentially trigger allergic reactions to inhaled antigens.2, 3 Although only some atopic people develop chronic asthma, the substantial overlap between current skin-test reactivity to one or more inhalant allergens and active asthma in schoolchildren and in adults4 suggests that atopy is an important risk factor for expression of asthma. Interruption of the process of primary allergic sensitisation to inhalants might delay or prevent the onset of allergic diseases such as atopic asthma.
A detailed understanding of the T-cell immunology underlying the sensitisation process is required. Atopy in adults is associated with the long-term expression of allergen-specific immunity, characterised by production of T-helper 2 (Th2) cytokines such as interleukin-4 and interleukin-5, which promote IgE production and eosinophilia.5, 6 By contrast, non-atopic people show mainly T-helper 1 (Th1) immunity characterised by production of interferon γ, which inhibits the growth of Th2 cells.
Research into the pathogenesis of atopic diseases is focused on how these patterns of allergen-specific T-cell memory develop, particularly in early childhood, when the immature immune system first comes into direct contact with inhalant allergens. Compartmentalisation of allergen-specific T-cell immunity into adult-equivalent Th1 patterns rather than Th2 patterns occurs in most children before the age of 5 years,7, which suggests that research should focus on the immediate postnatal period. In addition, the DNA genotyping of T-cell clones has proved the existence of fetally derived allergen-reactive T cells in cord blood, indicative of intrauterine T-cell priming.8 Moreover, these primed cells typically display a Th2-polarised pattern of cytokine production.8
We tested the hypothesis that individuals who develop atopic disorders in infancy and those who do not develop such disorders show opposing patterns of regulation of allergen-specific, in-utero-primed, Th2 responses. We undertook a prospective study of peripheral-blood mononuclear cells (PBMC) taken from children regularly from birth to 2 years. We analysed T-cell cytokine responses to a panel of allergens and sought clinical and laboratory markers of atopy.
Section snippets
Study groups
We compared allergen-specific T-cell responses during infancy in two groups of children—one group at high genetic risk of atopy, with a positive family history, who developed definite atopic disease during the 2-year study period; and the other at low risk, with no family history, who remained symptom-free at 2 years of age.
Participants were selected from a cohort of children followed from birth to 2 years old. All babies entered the study at birth, before cord-blood collection, and were
Results
After 2 years of prospective follow-up, there were 13 low-risk non-atopic children without symptoms and 18 atopic children with diagnosed allergic disease in the study (table). Age-related changes in allergen-specific lymphoproliferation (data not shown) confirmed contrasting patterns in response to food and aeroallergens.7, 9 Neonates with an immediate family history of atopy tended to show higher allergen-specific CBMC proliferative responses than neonates at low risk of allergy (data not
Discussion
Cross-sectional studies from our laboratory and elsewhere have given a broad outline of the events underlying primary allergic sensitisation. Initial T-cell priming commonly occurs across the placenta,10 particularly to allergens encountered by the mother in the last trimester of pregnancy.11 The cytokine phenotype of these T cells is typically Th2-polarised.8, 12
During early childhood, these T-cell responses are subject to various regulatory mechanisms that are driven by direct exposure to
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