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

Effect of intrapleural streptokinase administration on antistreptokinase antibody level in patients with loculated pleural effusions

BACKGROUND: Streptokinase is widely used IV for the treatment of myocardial infarction and intrapleurally for the treatment of loculated pleural effusions. IV administration of streptokinase is known to cause the production of antistreptokinase antibodies. OBJECTIVE: The aim of this study was to evaluate whether the intrapleural administration of streptokinase results in a similar elevation of the serum antistreptokinase antibody level. METHODS: During 1 year, venous blood samples were taken from 16 consecutive patients (10 men and 6 women; age range, 22 to 60 years) requiring intrapleural streptokinase administration (250,000 IU once a day, for 2 to 6 days). Blood samples were taken before treatment, on day 5, and day 14. Antistreptokinase antibodies were measured using enzyme-linked immunosorbent assay (ELISA) and were expressed in arbitrary ELISA units. Four patients with myocardial infarction treated with IV streptokinase (1,500,000 IU) were included as control subjects for the method. RESULTS: Before treatment, the median antistreptokinase antibody level in patients with loculated pleural effusions was 729 ELISA units (range, 196 to 13,529 ELISA units) and increased to 9,240 ELISA units (range, 1,456 to 77,389 ELISA units) by day 14 (p < 0.0001). In the control group, the median pretreatment level was 119 ELISA units, and by day 14 it had increased to 20,495 ELISA units. Four patients who developed an elevated body temperature after intrapleural administration of streptokinase had a significantly higher pretreatment antistreptokinase antibody level compared to other patients. CONCLUSIONS: The intrapleural administration of streptokinase results in the elevation of the serum antistreptokinase antibody level, which is similar to the case with IV administration. An increased pretreatment antistreptokinase antibody level does not influence the result of intrapleural fibrinolysis but can cause an elevation of body temperature after the administration of streptokinase

Treating Asthma with Anti-IgE or Anti-IL5

In the last decades, several key mechanisms driving asthma pathophysiooogy have been discovered. These include the role of IgE in allergic disease, and the role of IL-5 in eosinophilic inflammation. In the last few years, tools to block each of these have been developed. At this time, early clinical studies with neutralizing antibodies against both IgE and IL-5 have been performed in asthma patients, with promising results, and larger studies are underway. The mechanisms of, and possible role of, both anti-IgE and anti-IL-5 treatment in asthma are discussed in this review article. </jats:sec

Comparison of a nasal glucocorticoid, antileukotriene, and a combination of antileukotriene and antihistamine in the treatment of seasonal allergic rhinitis

BACKGROUND: Allergic rhinitis requires active intervention for symptom relief. A combination of antileukotriene and antihistamine drugs has been suggested to provide additive treatment benefits for patients with allergic rhinitis. OBJECTIVE: We evaluated how such a combination treatment would affect symptoms and local mucosal eosinophilia in comparison with a nasal glucocorticoid. METHODS: In a double-blind, randomized study 62 patients with grass pollen-induced allergic rhinitis received a nasal glucocorticoid (fluticasone propionate aqueous nasal spray [FPANS], 200 microg/d), an antileukotriene (montelukast, 10 mg/d), a combination of montelukast with an antihistamine (loratadine, 10 mg/d), or placebo throughout the season. Cromoglycate eyedrops and a limited amount of loratadine were allowed as rescue medication for severe symptoms. Patients recorded their symptoms for nasal blockage, itching, rhinorrhea, and sneezing. Before and during the season, nasal biopsy specimens were obtained from patients for evaluation of local eosinophilic inflammation. RESULTS: During the peak season, both FPANS and combined montelukast-loratadine were significantly more effective than placebo and montelukast alone for daytime symptom prevention. For nighttime symptoms, FPANS was significantly more effective compared with all other treatments, whereas combined montelukast-loratadine and montelukast alone did not provide significant symptom prevention compared with placebo. The pollen-induced increase in the numbers of epithelial eosinophils was significantly lower for FPANS-treated patients compared with that seen in all other treatment groups. CONCLUSION: In patients with seasonal allergic rhinitis, intranasal glucocorticoids are more effective than an antileukotriene drug or combined antileukotriene-antihistamine for the reduction of pollen-induced nasal eosinophilic inflammation and for control of nasal symptoms