| dc.description.abstract | 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. | en |
