Inhaled Glucocorticoid Therapy of Childhood Asthma Is Associated With Reduced Peripheral Blood T Cell Activation and ‘Th2-Type’ Cytokine mRNA Expression

Abstract

Objective. To investigate the role of activated T cells and their cytokine products in the pathogenesis of childhood asthma. Methods. PBMC were obtained from 17 symptomatic asthmatic children (age 7 to 15 yr) and 7 nonasthmatic controls matched for age and atopic status. Asthmatics were placed in 2 groups with initial prebronchodilator FEV1 <75% (Group I, n = 9) or ≥75% (Group II, n = 8) predicted. Expression of activation markers on peripheral blood T cells (asthmatics), and expression of cytokine mRNA (asthmatics and controls) were measured using flow cytometry and in situ hybridization respectively. Measurements were repeated in the asthmatics 3 to 6 months later following initiation or escalation of inhaled GC therapy for control of symptoms. Results. The more severe (Group I) as compared with the milder (Group II) asthmatics showed evidence of increased peripheral blood T cell activation, with elevated percentages of CD4 cells expressing the activation markers CD25 and HLA-DR, and CD8 cells expressing CD25. Elevated percentages of CD4 cells also expressed CD45RO, consistent with ongoing cellular activation. The asthmatics had higher percentages of PBMC expressing mRNA encoding IL-5, IL-4, GM-CSF and IL-2, but not IFN-γ, as compared with controls. The percentages of PBMC expressing IL-5 mRNA correlated with disease severity (% predicted FEV1). During follow up, patients in both groups required increased mean daily dosages of inhaled GC. In Group I this was associated with improvements in PEFR, FEV1 and night time wheeze and reduced percentages of CD4/CD25 and CD4/HLA-DR peripheral blood T cells. Reductions in the percentages of CD4/CD25 T cells correlated with improvements in baseline FEV1. Group II patients showed improvement in FEV1 and day time cough and wheeze but no significant changes in PEFR, other symptoms or peripheral blood T cell marker expression. Increased GC therapy of both groups taken together was associated with significant reductions in the percentages of PBMC expressing mRNA encoding IL-5, IL-4 and IL-2 and an increase in those expressing IFN-γ mRNA. Conclusions. Compared with controls, children with symptomatic asthma have higher percentages of activated peripheral blood T cells synthesising cytokines believed to regulate bronchial mucosal eosinophilic inflammation. Clinical improvement with increased inhaled GC therapy is associated with reduced T cell activation and cytokine mRNA expression.