Nasal eosinophilia and IL-5 mRNA expression in seasonal allergic rhinitis induced by natural allergen exposure: Effect of topical corticosteroids

doi:10.1016/S0091-6749(98)70277-5

Journal of Allergy and Clinical Immunology

Volume 102, Issue 4, October 1998, Pages 610-617

https://doi.org/10.1016/S0091-6749(98)70277-5 Get rights and content

Abstract

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 μg 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^–10 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.)

Section snippets

Subject populations

Forty-six nonsmoking Timothy grass pollen–sensitive patients were recruited from the outpatient clinic of the Asthma and Allergy Center, Department of Medicine, Sahlgrenska Hospital, Götheburg, Sweden. Patients were selected on the basis of (1) a history of moderate-to-severe seasonal allergic rhinitis for at least 2 years and (2) a positive skin prick test response (>5-mm wheal diameter on skin testing in the presence of positive histamine and negative diluent controls) to Timothy grass pollen

RESULTS

Randomization resulted in 23 patients receiving fluticasone treatment and 23 receiving a placebo nasal spray. The groups were well matched for age, gender, disease severity, and pollen sensitivity as assessed by responses to skin testing and serum concentrations of Timothy grass pollen–specific IgE antibodies (Table I).

. Clinical details of study patients

Empty Cell	Placebo	Fluticasone
Empty Cell	Treatment
No of patients	23	23
Sex (M:F) ratio	16:7	14:9
Age (y; mean ± SD)	33.1 ± 10.7	32 ± 8.9
RAST (Timothy grass; score 0-5; mean ±

DISCUSSION

In this study we have shown that allergic rhinitis associated with natural exposure to grass pollen is associated with both nasal mucosal eosinophilia and increases in the numbers of cells expressing mRNA encoding the proeosinophilic cytokines IL-5 and GM-CSF. In contrast, comparison of nasal biopsy specimens collected before and during the pollen season suggested that natural allergen exposure was not associated with an influx of CD3+ T cells into either the nasal epithelium or submucosa. In a

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One consistent finding was that CD11c+ DCs formed intense clusters with CD3+ T cells in inflamed tissues, suggesting a functional interaction between DCs and T cells necessary for generating effector function in these T cells. It is known that CD4+ T cells produce TH2 cytokines locally in the noses of patients with AR.3-7 Supporting the idea of local interactions between DCs and effector T cells was the observation that CD11c+ DCs expressed higher levels of the critical T cell–costimulatory molecule CD86 in patients with AR.
In allergic rhinitis (AR) CD4⁺ T_H2 lymphocytes control inflammation by secreting T_H2 cytokines, but little is known about how these cells are activated to cause disease.
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Nasal mucosal biopsy specimens were taken from patients with house dust mite allergy and perennial AR and healthy control subjects. DC numbers were evaluated by using immunohistochemistry. The functional role of DCs was studied in a novel mouse model for AR using BALB/c mice and CD11c–diphtheria toxin (DT) receptor transgenic mice.
In symptomatic patients with perennial AR, the number of CD1a⁺ and CD11c⁺ MHCII⁺ DCs was higher in the epithelium and lamina propria of the nasal mucosa compared with that seen in healthy control subjects. In patients with AR, DCs had a more mature (CD86⁺) phenotype and were found in close approximation with T lymphocytes. Similarly, in a mouse model of ovalbumin (OVA)-induced AR, CD11c⁺ DCs accumulated in areas of nasal eosinophilic inflammation and clustered with CD4⁺ T lymphocytes. CD11c⁺ DCs were conditionally depleted during allergen challenge by means of systemic administration of DT to CD11c-diphtheria toxin receptor transgenic mice to address the functional role of DCs in maintaining inflammation. In the absence of CD11c⁺ DCs, nasal OVA challenge in OVA-sensitized mice did not induce nasal eosinophilia and did not boost OVA-specific IgE levels or T_H2 cytokine production in the cervical lymph nodes. Conversely, when OVA-pulsed DCs were administered intranasally to sensitized mice, they strongly enhanced OVA-induced nasal eosinophilia and T_H2 cytokine production.
These data in human subjects and mice suggest an essential role for nasal DCs in activation of effector T_H2 function leading to AR.
Nasal DCs play an essential role in AR and therefore constitute a novel target for therapeutic intervention.
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Limited data suggest that there is increased eosinophilic inflammation in the airways of patients with seasonal allergic rhinitis (SAR) during pollen season even if they do not have asthma.
To investigate the effect of natural pollen exposure on inflammatory cells and apoptosis of eosinophils and its association with bronchial hyperresponsiveness (BHR) during and out of pollen season in SAR patients sensitized to only grass pollens.
Forty SAR patients and 10 patients with nonallergic rhinitis (NAR) from Ankara, Turkey, were recruited to participate in the study. Two induced sputum samples were taken from SAR patients during pollen season (May-June) and out of pollen season (November-January), but only 1 induced sputum sample was taken from NAR patients. Slides of induced sputum were evaluated by 2 cytologists with the use of light microscopy after cytocentrifuged and dyed with May-Grünwald-Giemsa stain. Induced sputum samples were sufficient for differential cell counts in 14 SAR and 7 NAR patients.
Eosinophil counts in SAR patients were statistically higher in pollen season (19.4% ± 16.2%) compared with out of season (4.6% ± 6.9%, P = .003) and with NAR patients (4.7% ± 9.5%, P = .01). The apoptotic eosinophil counts in SAR patients were statistically higher out of pollen season (3.0% ± 4.5%) than in pollen season (0.38% ± 0.80%, P = .02) and higher than those of NAR patients (0.14% ± 0.26%, P = .005). The apoptotic ratio was statistically higher after pollen season compared with pollen season (0.720% ± 0.394% vs 0.044% ± 0.116%, P = .002). Blood eosinophil counts of SAR patients were increased during the pollen season (364 ± 187/mm³) compared with out of season (278 ± 219/mm³, P = .04) and with NAR patients (85 ± 54/mm³, P = .001). The number of SAR patients who had BHR during the pollen season (7/14) was higher than the number who had BHR out of season (2/14, x²=4.2, P = .04).
Our data indicate that changes in eosinophil counts and eosinophil apoptosis may be related to the changes of natural pollen exposure and seasonal changes of BHR in SAR patients.
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Citation Excerpt :
In addition, they have been used to look at the effect of disease states such as perennial and seasonal rhinitis on the normal architecture.123-128 Nasal biopsies have also provided useful data on the effect of treatment on the nasal mucosa.129-132 Schneider first described the histology of the nasal mucosa in 1660.133
Allergic rhinitis is an inflammatory nasal disorder in which a range of different cells participates. A variety of approaches has been used to monitor nasal inflammation objectively to investigate disease processes and to evaluate the effect of therapeutic intervention. These approaches include nasal lavage, nasal cytology, and nasal biopsy, together with the more recently established measurement of nasal nitric oxide (NO) concentration. Although all provide information about nasal mucosal inflammation, the extent of information that can be obtained by each approach, the ease of sampling, and the complexity of sample handling differ. Such considerations influence the choice of approach when measurement of nasal inflammation is to be an objective outcome parameter in a clinical trial. In addition, the choice of approach is also determined by the questions or hypotheses that are to be addressed.
Nasal lavage is simple and rapid to perform, is well tolerated, and provides a sample that can provide information about luminal cell recruitment, cell activation, and plasma protein extravasation. Nasal cytology involves sampling and recovering mucosal surface cells. It is also easy to perform and is well tolerated in general, although some find that the procedure causes a transient unpleasant sensation. A differential cell count from the sample provides information about relative cell populations. Both nasal lavage and nasal cytology are readily applicable to clinical trials. Nasal cytology sample handling is easier, but nasal lavage offers the advantage of providing considerably greater information from the sample.
Nasal biopsy is a considerably more invasive procedure and requires expertise not only in tissue sampling but also in biopsy processing. Therefore, it is applicable only in specialist centers. However, nasal biopsy is the only sampling technique that directly informs about tissue cellular events, although these may be implied, in part from the other sampling approaches. Tissue specimens can be used to evaluate both protein and gene expression.
Measurement of nasal NO involves expensive equipment but provides an instantaneous result, unlike the other approaches, all of which require sample processing and analysis. Recommendations for standardization of measurement have been made, and measures are considered in part to reflect allergic inflammation within the nasal mucosa. The limitations of nasal NO are that it reflects only a certain aspect of allergic mucosal inflammation, and that because a proportion of nasally measured NO is derived from the sinuses under normal circumstances, nasal NO is not specific for nasal disease. The high contribution from the sinus mucosa limits the discriminatory ability of nasal NO to reflect nasal tissue–specific alterations.
The incorporation of measures of nasal inflammation in clinical trials has distinguished anti-inflammatory therapy from symptomatic therapy and has the potential to provide information about the efficacy of novel therapies for allergic rhinitis.

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^☆: From ^a Upper Respiratory Medicine, Imperial College School of Medicine at the National Heart and Lung Institute, London; ^b Meakins-Christie Laboratories, Departments of Medicine and Pathology, McGill University, Montreal; ^c Sergrein: Hals-net-ogeymalaekninger, Reykjavik; ^d Sahlgrenska Hospital, Götheburg; and ^e Allergy and Clinical Immunology, Imperial College School of Medicine at National Heart and Lung Institute, London.

^☆☆: Supported by grants from the Medical Research Council, UK; the Medical Research Council, Canada; and financial assistance from Glaxo Wellcome, UK.

^★: Reprint requests: Stephen R. Durham, MD, Upper Respiratory Medicine, Imperial College School of Medicine at National Heart and Lung Institute, Dovehouse St, London, United Kingdom, SW3 6LY.

^★★: 0091-6749/98 $5.00 + 0 1/1/92895

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Nasal eosinophilia and IL-5 mRNA expression in seasonal allergic rhinitis induced by natural allergen exposure: Effect of topical corticosteroids☆,☆☆,★,★★

Abstract

Section snippets

Subject populations

RESULTS

DISCUSSION

Blood

Eur J Pharmacol

J Allergy Clin Immunol

J Allergy Clin Immunol

Immunohistology of the nasal mucosa following allergen-induced rhinitis. Identification of activated T lymphocytes, eosinophils, and neutrophils

Am Rev Respir Dis

Cytokine messenger RNA expression for IL-3, IL-4, IL-5, and granulocyte/macrophage-colony-stimulating factor in the nasal mucosa after local allergen provocation: relationship to tissue eosinophilia

J Immunol

IL-13 mRNA and immunoreactivity in allergen-induced rhinitis: comparison with IL-4 expression and modulation by topical glucocorticoid therapy

Am J Respir Cell Mol Biol

Expression of ϵ germ-line gene transcripts and mRNA for the ϵ heavy chain of IgE in nasal B cells and the effects of topical corticosteroid

Eur J Immunol

Associations between IL-13 and IL-4 (mRNA and protein), vascular cell adhesion molecule-1 expression, and the infiltration of eosinophils, macrophages, and T cells in allergen-induced late-phase cutaneous reactions in atopic subjects

J Immunol

Recombinant human interleukin 5 is a selective activator of human eosinophil function

J Exp Med

IL-5-dependent conversion of normodense human eosinophils to the hypodense phenotype uses 3T3 fibroblasts for enhanced viability, accelerated hypodensity, and sustained antibody-dependent cytotoxicity

J Immunol