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Background: Although previous studies have established the presence of an eosinophil-rich cellular infiltrate in the small airways of asthmatic lungs, the expression of cytokines within the peripheral airways has been largely unexplored. The purpose of our study was to test the hypothesis that T"H"2-type cytokines are increased in the peripheral airways and parenchyma of asthmatic lungs. Methods: The presence of messenger ribonucleic acid (mRNA) encoding both T-helper (T"H"1)-type (IL-2, interferon-@c) and T"H"2-type (IL-4, IL-5) cytokines in surgically resected lungs from six asthmatic and 10 nonasthmatic subjects was determined by in situ hybridization. Colocalization of IL-5 mRNA within the large and small airways was performed by simultaneous in situ hybridization and immunocytochemistry. Results: Expression of IL-5 mRNA-positive cells was significantly increased in the large and small airways and in the lung parenchyma of asthmatic subjects compared with nonasthmatic subjects. In the asthmatic individuals, the expression of IL-5 mRNA was increased in the small airways compared with the large airways. There was also an increase in the number of cells expressing IL-4 mRNA in the large and small asthmatic airways compared with the nonasthmatic airways. In contrast, the numbers of IL-2 and interferon-@c mRNA-positive cells did not differ between asthmatic and nonasthmatic individuals. Conclusions: We conclude that there is an increased expression of T"H"2-type cytokines within the peripheral airways of asthmatic lungs and suggest that the small airways contribute to the pathophysiology of asthma. (J Allergy Clin Immunol 1998;101:386-90.)

Background: Nasal allergen provocation has demonstrated that allergen-induced rhinitis is associated with an increase in local IL-4 mRNA and IgE heavy chain (C@e) and IgE heavy chain promoter (I@e) RNA and that pretreatment with topical glucocorticosteroids inhibits the increase in these transcripts. Objective: This study was undertaken to determine whether observations made after acute allergen provocation can be extended to the case of chronic exposure experienced during the pollen season. Methods: Biopsy specimens were obtained from the inferior turbinate of 33 pollen-sensitive subjects with allergic rhinitis before and during pollen season. Patients were randomized in a double-blind fashion and treated with either topical steroids (200 @mg fluticasone propionate twice daily; n = 16) or matched placebo nasal spray ( n = 17) before the pollen season. Alkaline phosphatase anti-alkaline phosphatase immunocytochemistry was used to identify B cells (CD20+), and in situ hybridization was used to detect IL-4, C@e, and I@e RNA+ cells. Results: Baseline examination revealed IL-4 and C@e RNA but virtually no I@e RNA+ cells in the nasal mucosa. Analysis revealed a significant difference in the expression of C@e and I@e RNA+ cells ( p < 0.001). Biopsy specimens taken after antigen exposure exhibited highly significant increases in placebo-treated ( p < 0.001) but not steroid-treated patients. In both groups, the number of CD20+ cells was unchanged when preexposure and postexposure biopsy specimens were compared. Conclusions: These results show strong support for the hypothesis that IgE class switching occurs locally within the nasal mucosa of subjects with seasonal allergic rhinitis and that this response can be inhibited through strategies directed against local IgE production. (J Allergy Clin Immunol 1998;101:330-6.)

Background: Nasal allergen provocation in patients with allergic rhinitis leads to expression of the proeosinophilic cytokines IL-5 and GM-CSF and tissue eosinophilia. Objective: We sought to examine the effect of natural seasonal allergen exposure on IL-5 and GM-CSF mRNA expression and nasal eosinophilia and to evaluate the effects of topical corticosteroid therapy on these responses. Methods: Nasal biopsy specimens were collected from 46 grass pollen-sensitive patients with seasonal rhinitis before the grass pollen season. A second biopsy specimen was collected during the pollen season, by which time patients had received 6 weeks treatment with either fluticasone propionate (200 @mg twice daily) or placebo nasal spray. Results: Fluticasone treatment was clinically effective (P < .005). Patients receiving placebo, but not fluticasone, showed increased numbers of epithelial and submucosal EG2+ eosinophils (P < .005) and IL-5 and GM-CSF mRNA-expressing cells (P < .0001) during the pollen season. Colocalization experiments showed that greater than 80% of IL-5 mRNA-expressing cells were submucosal CD3+ T cells in both groups. The numbers of submucosal CD3+ T cells did not increase during the pollen season or decrease with fluticasone treatment. Fluticasone also inhibited IL-5 secretion by grass pollen-stimulated peripheral blood T cells from patients with seasonal rhinitis (n = 5, inhibitory concentration of 50% = 10^-^9 to 10^-^1^0 mol/L). Conclusions: These results suggest that topical corticosteroids may reduce eosinophilia in seasonal rhinitis by inhibiting T cell IL-5 production. (J Allergy Clin Immunol 1998;102:610-7.)

Background: Recent studies have provided evidence for increased IL-4 expression in the airways of atopic and nonatopic asthmatic subjects. IL-4 is believed to perform important regulatory roles in asthma; however, the expression of the IL-4 receptor has not been investigated. In this study we examined the mRNA and protein expression of the specific @a-subunit of the IL-4 receptor (@aIL-4R) in bronchial biopsy specimens obtained from atopic and nonatopic asthmatic subjects. Methods: Asthmatic subjects and nonasthmatic control subjects were recruited, and lung function measurements were performed before bronchoscopy. Endobronchial biopsy specimens were examined for the presence of @aIL-4R mRNA and immunoreactivity by using in situ hybridization and immunocytochemistry, respectively. Results: @aIL-4R mRNA-positive and immunoreactive cells were detected in the epithelium and subepithelium in biopsy specimens from all subjects. Expression of @aIL-4R mRNA and protein was significantly increased in the epithelium and subepithelium of biopsy specimens from atopic asthmatic subjects compared with atopic control subjects (P < .05 and P < .001, respectively). Epithelial @aIL-4R mRNA expression and immunoreactivity did not differ significantly between nonatopic asthmatic subjects and nonatopic control subjects. Although the numbers of @aIL-4R mRNA-positive cells were augmented in the submucosa of intrinsic asthmatic subjects compared with nonatopic control subjects (P < .05), @aIL-4R immunoreactivity did not differ significantly between these groups. Increased @aIL-4R immunoreactive signals were also detected in the endothelial cell layer in both atopic and intrinsic asthmatic subjects compared with atopic and nonatopic control subjects, respectively (P < .05). Combined in situ hybridization immunocytochemistry performed on biopsy sections from asthmatic and control subjects demonstrated @aIL-4R mRNA expression in CD3-positive T cells and tryptasepositive mast cells, with T cells comprising the larger proportion of @aIL-4R mRNA-positive cells. Numbers of @aIL-4R mRNA-positive or immunoreactive cells did not correlate with CD3-positive cell numbers, numbers of IL-4 mRNA-positive cells, or indices of pulmonary function. Conclusion: These results demonstrate constitutive @aIL-4R expression in normal airways and enhanced expression in airway tissue from asthmatic individuals. (J Allergy Clin Immunol 1998;102:859-66.)