Quantitative expression of osteopontin in nasal mucosa of patients with allergic rhinitis: effects of pollen exposure and nasal glucocorticoid treatment

<p>Abstract</p> <p>Background</p> <p>Osteopontin (OPN) is a multifunctional cytokine that has been primarily investigated in Th1 diseases. Recently, it has also been implicated in Th2-mediated allergic diseases, such as asthma. The expression of OPN in allergic rhinitis (AR) is currently unknown, as is the effect of intranasal glucocorticosteroids (GCs) on that expression.</p> <p>Methods</p> <p>Subjects with AR were randomised to receive treatment with fluticasone propionate (FP) (n = 12) or a placebo (n = 16) over the grass pollen season and nasal biopsies were taken prior to, and during the season. OPN expression in the nasal mucosa was examined with immunohistochemistry. Healthy non-AR controls (n = 5) were used as a comparator.</p> <p>Results</p> <p>OPN expression was detected in epithelial cells, subepithelial infiltrating/inflammatory cells and cells lining the vessels and glands of all subjects. Comparison of the pre- and peak-pollen season biopsy sections in placebo treated patients revealed no increase in OPN expression during the grass pollen season (5.7% vs 6.4%). Treatment with a local glucocorticosteroid did not alter the expression of OPN during pollen exposure (6.2% vs 6.7%).</p> <p>Conclusion</p> <p>OPN has been increasingly associated with the pathogenesis of various Th2-mediated diseases. However, our finding that the OPN expression in the nasal mucosa of AR patients is not significantly affected by allergen exposure and is comparable to that of the healthy controls, suggests that intracellular OPN is not directly involved in the pathogenesis of allergic rhinitis.</p

Intervention studies in rat allergy model and in human patients with seasonal allergic rhinitis

Allergic diseases are common disorders requiring active intervention. Several theoretically promising approaches for management of allergic diseases have recently evolved, but not all aspects of these interventions have been extensively studied. Furthermore, concerns about the use of the effective and common anti-allergic treatment with glucocorticoids have emerged, based on in vitro evidence and on some in vivo suggestions, that glucocorticoids can enhance production of immunoglobulin (Ig)E.The aims of this thesis were to determine the regulatory effects of glucocorticoids, IL-2 and IL-2 receptor (IL-2R) targeted treatment and the bystander suppression phenomenon on in vivo IgE production and the effect of a leukotriene receptor antagonist on clinical symptoms in human patients with seasonal allergic rhinitis. For that purpose, Brown-Norway rats (BNR) were sensitised with occupational allergen trimellitic anhydride (TMA), and randomised double-blind placebo-controlled clinical trials were performed with human patients with seasonal allergic rhinitis.Intradermal sensitisation with TMA in BNR resulted in production of IgE anti-TMA antibodies with the highest levels at 7 weeks after sensitisation with 3% of TMA. The production of IgE anti-TMA antibodies was attenuated by administration of a glucocorticoid betamethasone if given both during and after sensitisation and by cyclosporin A only if given during sensitisation. By contrast, an IL-2-toxin DAB389IL-2, which reduced the number of IL-2R bearing cells by 30%, enhanced IgE anti-TMA antibody production, but suppressed delayed-type hypersensitivity (DTH) reaction.A phenomenon of bystander suppression has been observed after inducing oral tolerance by feeding a soluble antigen and subsequent sensitisation with this antigen together with a bystander antigen. The possibility to induce bystander suppression against the hapten TMA in rats made tolerant to ovalbumin (OvA) was evaluated. OvA-tolerant rats showed a suppressed DTH, but unaffected IgE antibody production against TMA, implying bystander suppression at the Th1 level. Thus, it is possible to induce bystander suppression against the hapten TMA, but this suppression is more pronounced for the Th1-type of immune responses.In a placebo controlled study in human patients with seasonal allergic rhinitis, treatment with nasal beclomethasone (BDP), started from the beginning of the birch pollen season, inhibited the pollen induced increase in specific IgE levels by the end of the 5-week birch-pollen season, whereas the total IgE levels were not affected. Together with results from the study with rats, these findings demonstrate that in vivo administration of glucocorticoids does not increase, but on the contrary, decreases IgE antibody production.Leukotriene receptor antagonists have recently become available for asthma treatment and they have been suggested to be beneficial also in the treatment of allergic rhinitis. In a randomised placebo-controlled study, the effect of a leukotriene receptor antagonist, zafirlukast was compared to nasal BDP in allergic rhinitis patients over a grass-pollen season. Zafirlukast-treated patients had similar degree of nasal symptoms compared to the placebo group, whereas BDP-treated patients had significantly less symptoms compared to both placebo and zafirlukast groups. Also, only treatment with BDP protected against the seasonal increase in the number of local eosinophils. These results favour the use of nasal glucocorticoid over leukotriene receptor antagonist in the treatment of seasonal allergic rhinitis.In conclusion, this thesis demonstrates the beneficial role of glucocorticoids both during the sensitisation and effector phases of allergic diseases with attenuation of antigen-specific IgE production, arguing strongly against glucocorticoids upregulating IgE in vivo. The bimodal effect of IL-2 in the immune system may depend on the degree of changes in the number of IL-2R bearing cells. The presented results were unable to demonstrate the beneficial role of bystander suppression in downregulation of Th2 (allergic)-type of immune responses nor a leukotriene receptor antagonist, zafirlukast, in the treatment of seasonal allergic rhinitis

Combination of budesonide/formoterol on demand improves asthma control by reducing exercise-induced bronchoconstriction

Background In mild asthma exercise-induced bronchoconstriction (EIB) is usually treated with inhaled short-acting β2 agonists (SABAs) on demand. Objective The hypothesis was that a combination of budesonide and formoterol on demand diminishes EIB equally to regular inhalation of budesonide and is more effective than terbutaline inhaled on demand. Methods Sixty-six patients with asthma (>12 years of age) with verified EIB were randomised to terbutaline (0.5 mg) on demand, regular budesonide (400 μg) and terbutaline (0.5 mg) on demand, or a combination of budesonide (200 μg)  + formoterol (6 μg) on demand in a 6-week, double-blind, parallel-group study (ClinicalTrials.gov identifier: NCT00989833). The patients were instructed to perform three to four working sessions per week. The main outcome was EIB 24 h after the last dosing of study medication. Results After 6 weeks of treatment with regular budesonide or budesonide+formoterol on demand the maximum post-exercise forced expiratory volume in 1 s fall, 24 h after the last medication, was 6.6% (mean; 95% CI −10.3 to −3.0) and 5.4% (−8.9 to −1.8) smaller, respectively. This effect was superior to inhalation of terbutaline on demand (+1.5%; −2.1 to +5.1). The total budesonide dose was approximately 2.5 times lower in the budesonide+formoterol group than in the regular budesonide group. The need for extra medication was similar in the three groups. Conclusions The combination of budesonide and formoterol on demand improves asthma control by reducing EIB in the same order of magnitude as regular budesonide treatment despite a substantially lower total steroid dose. Both these treatments were superior to terbutaline on demand, which did not alter the bronchial response to exercise. The results question the recommendation of prescribing SABAs as the only treatment for EIB in mild asthma

The triad of current asthma, rhinitis and eczema is uncommon among adults: Prevalence, sensitization profiles, and risk factors

Background: Coexistence of asthma, rhinitis, and eczema has been studied in children, but data are lacking in adults. As new treatments emerge, epidemiological data on the coexistence are needed. Aims: To study the prevalence of concomitant asthma, rhinitis and eczema in the general adult population and among those sensitized to aeroallergens, and to study associations between background characteristics and risks of phenotypes of asthma, rhinitis, and eczema. Methods: In the West Sweden Asthma Study, phenotypes and sensitization profiles of 1103 randomly selected adults (16–75 years) were assessed. The methods included measures of serum-IgE and structured interviews on asthma, rhinitis, eczema, their associated symptoms, and relevant risk factors. Results: Among all participants and in those sensitized, 2% and 6% had concomitant asthma, rhinitis, and eczema, respectively, and the condition did not differ by age or sex. Corresponding figures for asthma and rhinitis, but not eczema, was 8% and 19%, respectively. Determinants of coexistence of the three conditions were family history of asthma/allergy, body mass index, and occupational exposure to gas, dust and fumes. Allergic sensitization in those with asthma, rhinitis and eczema was found in 78%, in those with asthma and rhinitis but not eczema in 65%, in those with asthma and eczema but not rhinitis in 40%, while only 5% were sensitized among those having asthma only. Conclusions: In the general adult population about 2% have concomitant asthma, rhinitis, and eczema. Of sensitized adults, about 6% has coexistence of the three conditions