Limited beta2-adrenoceptor haplotypes display different agonist mediated airway responses in asthmatics.

BACKGROUND: In vitro and some in vivo studies suggested that genetic haplotypes may have an impact on beta2-agonist mediated airway responses in asthmatics. Due to strong linkage disequilibrium the single nucleotide polymorphisms (SNPs) in the beta2-adrenoceptor gene result in only a limited number of haplotypes. We intended to evaluate the impact of beta2-adrenoceptor haplotypes on beta2-agonist mediated airway responses and the development of tolerance in mild to moderate asthmatics. METHODS: Patients were genotyped for the part of the beta2-adrenoceptor gene with a known bearing on receptor function and regulation. Cumulative dose response curves of fenoterol versus PD20 methacholine and FEV1 were constructed after 2 week treatment periods with either terbutaline or placebo in a double blind, randomised and cross-over design. Analysis of the dose response curves was based on a repeated measurement analysis of covariance. RESULTS: In our study population comprising 45 asthmatic patients, we found three limited allelic haplotypes, resulting in six different genotypes. Our data support the existence of differences between these six genotypes both in the shape of the dose response relationship of the beta2-adrenoceptor agonist fenoterol as well as in the propensity to develop tolerance for these effects by pre-treatment with terbutaline. However, this could only be substantiated for the endpoint PD20 methacholine. CONCLUSION: Between beta2-adrenoceptor genotypes differences exist both in baseline beta2-agonist induced airway responses as well as in the propensity to develop tolerance during maintenance beta2-agonist therapy. The net differences after two weeks of therapy are, however, of magnitudes that are unlikely to be of clinical significance.

Semiquantitative 67Ga scintigraphy as an indicator of response to and prognosis after corticosteroid treatment in idiopathic interstitial pneumonia.

UNLABELLED: The prognosis in some forms of idiopathic interstitial pneumonia (IIP), especially idiopathic pulmonary fibrosis (IPF) and fibrotic nonspecific interstitial pneumonia (NSIP), is still poor. A minority of patients will respond to immunosuppressive treatment. In patients with IPF or fibrotic NSIP, pulmonary (67)Ga scintigraphy may be useful for predicting response to therapy and prognosis. The objective of the present study was to evaluate whether semiquantitative (67)Ga scintigraphy can be used to predict responsiveness to therapy with high-dose corticosteroids in a well-defined population of patients with IIP (IPF and fibrotic NSIP). METHODS: This study was performed in a tertiary referral center. We prospectively performed (67)Ga scintigraphy in 23 consecutive patients previously diagnosed with IIP (IPF and fibrotic NSIP) before and after treatment with 3 monthly courses of high-dose methylprednisolone. Lung function tests and bronchoalveolar lavage (BAL) were performed before and after these 3 courses, and patients were monitored for 1 y after the start of the treatment. RESULTS: During follow-up, 5 patients died, none during the first 3 mo. Although pulmonary (67)Ga uptake significantly decreased after treatment (P = 0.001), there was no correlation between either initial (67)Ga uptake or change in (67)Ga uptake on treatment and 1-y prognosis. This finding was independent of prior immunosuppressive treatment, diagnosis of IPF or NSIP, or whether initial (67)Ga uptake was elevated or not. BAL cellularity was correlated with neither pulmonary (67)Ga uptake nor response to treatment. CONCLUSION: Pulmonary (67)Ga uptake cannot be used to predict response to corticosteroid treatment or prognosis in patients with IIP. Apparently, the (inflammatory) process influenced by treatment with methylprednisolone does not determine the progression of disease. This finding supports the hypothesis that although inflammation is present in IPF and fibrotic NSIP, it is neither the hallmark of the disease nor the major factor determining prognosis.

The influence of the AA 16 beta 2-adrenoceptor polymorphism on systemic and airway responses in asthma.

BACKGROUND: The impact of the polymorphic amino acids 16 and 27 of the beta 2-adrenoceptor (beta 2-AR) on the susceptibility to bronchodilator tolerance remains unclear since clinical studies thus far have shown discordant results. Tolerance towards the effects of inhaled beta 2-AR agonists generally is more easily shown for systemic parameters than for airway effects and can be substantial. This study evaluates whether differences exist between position 16 homozygous genotyped asthmatics, in tolerance development towards airway responses and the systemic effect hypokalemia. METHODS: Twenty patients were genotyped for amino acids 16 and 27 of the beta 2-AR gene. Time-effect curves for FEV1 and serum potassium concentration were constructed after s.c. administration of terbutaline after two-week treatment periods with either terbutaline inhalation or matching placebo in a double-blind, randomised and cross-over design. Statistical analysis was done by a repeated measures multivariate analysis on area under time-effect curve (AUC). MAIN RESULTS: Pre-treatment with inhaled terbutaline did not influence the improvement in FEV1 in response to s.c. terbutaline and there were no significant differences between Arg-16 and Gly-16 individuals in this respect. Pre-treatment with inhaled terbutaline resulted in an overall increase of baseline plasma potassium before administration of s.c. terbutaline (3.78-3.95 mmol/L, p=0.034). However, this effect appeared to be solely confined to the Arg-16 homozygous individuals, leading to a statistically highly significant difference between the Arg-16 and Gly-16 subjects (p=0.005). However, there was no genotype related difference in the decrease in plasma potassium response to s.c. terbutaline relative to baseline. CONCLUSION: In patients carrying the Arg-16 genotype the development of hypokalemia by s.c. terbutaline is attenuated after pre-treatment with inhaled terbutaline, be it on the basis of higher baseline values.

Allergen immunotherapy induces a suppressive memory response mediated by IL-10 in a mouse asthma model.

BACKGROUND: Human studies have demonstrated that allergen immunotherapy induces memory suppressive responses and IL-10 production by allergen-specific T cells. Previously, we established a mouse model in which allergen immunotherapy was effective in the suppression of allergen-induced asthma manifestations. OBJECTIVE: In this study, we examined whether immunotherapy induces a long-lasting effect and investigated the role of IL-10 in successful immunotherapy. METHODS: Ovalbumin-sensitized BALB/c mice were treated with 3 injections of ovalbumin (1 mg, subcutaneous) on alternate days. After a short interval (1 week) and after a long interval (5 weeks), mice were challenged by ovalbumin inhalation, and subsequently, airway reactivity, airway eosinophilia, ovalbumin-specific IgE, and T(H)2 cytokine profile were measured. Flow cytometry and blocking of IL-10 receptors in vivo were used to gain insight in the role of IL-10 in the beneficial effects of allergen immunotherapy. RESULTS: After a long interval between ovalbumin immunotherapy and ovalbumin challenge, the development of airway eosinophilia and hyperresponsiveness to methacholine were as strongly suppressed as after a short interval. These suppressive effects coincided with significantly reduced serum ovalbumin-specific IgE levels and T(H)2 cytokine production. On immunotherapy, the IL-5:IL-10 ratio in the bronchoalveolar lavage fluid shifted toward IL-10. In ovalbumin-restimulated lung cell and thoracic lymph node cultures from these mice, IL-5 levels dramatically decreased, whereas the percentage of IL-10(+)CD4(+) T cells was not affected. Finally, in mice treated with mAb against IL-10 receptors, the beneficial effects of immunotherapy were largely abrogated. CONCLUSION: These data demonstrate that allergen immunotherapy induces a memory suppressive effect in which IL-10 is essential.