Inhibition of Fc epsilon RI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes.

Atopic allergy is characterized by an increase in IgE antibodies that signal through the high-affinity Fcepsilon receptor (FcepsilonRI) to induce the release of inflammatory mediators from mast cells. For unknown reasons, the prevalence of allergic diseases has recently increased steeply in the developed world. However, this increase has not been mirrored in developing countries, even though IgE concentrations are often greatly elevated in individuals from these countries, owing to nonspecific IgE induction by universally present parasitic worms. Here we offer one explanation for this paradox based on the properties of ES-62, a molecule secreted by filarial nematodes. We found that highly purified, endotoxin-free ES-62 directly inhibits the FcepsilonRI-induced release of allergy mediators from human mast cells by selectively blocking key signal transduction events, including phospholipase D-coupled, sphingosine kinase-mediated calcium mobilization and nuclear factor-kappaB activation. ES-62 mediates these effects by forming a complex with Toll-like receptor 4, which results in the sequestration of protein kinase C-alpha (PKC-alpha). This causes caveolae/lipid raft-mediated, proteasome-independent degradation of PKC-alpha, a molecule important for the coupling of FcepsilonRI to phospholipase D and mast cell activation. We also show that ES-62 is able to protect mice from mast cell-dependent hypersensitivity in the skin and lungs, indicating that it has potential as a novel therapeutic for allergy.

Nerve growth factor in serum and lymphocyte culture in pigeon fanciers' acute hypersensitivity pneumonitis.

BACKGROUND: Nerve growth factor (NGF) is a neurotrophic cytokine with immunomodulatory activity. NGF contributes to neurogenic inflammation and has been described in asthma and idiopathic pulmonary fibrosis. OBJECTIVES: To identify and quantify NGF in serum and peripheral blood lymphocyte cultures from pigeon fanciers, and to investigate an association with the immune response to inhaled avian antigens, and with symptoms of acute hypersensitivity pneumonitis (HP). METHODS: NGF was quantified and compared with serum IgG antibody against inhaled avian antigens, with serum C-reactive protein (CRP), and with KL-6, a marker of lung interstitial inflammation. These were measured using enzyme-linked immunoassay. Levels were compared with symptom history in 55 pigeon fanciers (26 subjects with acute HP but symptom-free at the time of testing) and 15 subjects with no avian exposure. RESULTS: Pigeon fanciers had higher-than-normal serum IgG antibody, CRP, and KL-6 levels (p < 0.01 each). These measures were unrelated to HP symptom category; instead, in all pigeon fanciers, the concentrations of CRP and KL-6 correlated with each other and with the antibody titers (p < 0.01 each). Serum NGF levels were normal; however, NGF production by mitogen-activated lymphocytes was higher than normal, and correlated with IgG antibody titer (p < 0.05) and with serum CRP (p < 0.05). CONCLUSIONS: Serum NGF was normal in pigeon fanciers; however, their blood lymphocytes ex vivo synthesized increased NGF in concentrations that correlated with the titer of serum IgG antibody to inhaled avian antigens. These also correlated with CRP and KL-6 levels, suggesting that antigen exposure in seropositive subjects is associated with subclinical inflammation involving coordinated synthesis of neurotrophin and immune mediators.

Induction of protective and mucosal immunity against diphtheria by a immune stimulating complex (ISCOMS) based vaccine.

There is increasing concern over the efficacy of existing vaccines for diphtheria and there is interest in the development of a mucosally active formulation which might improve local protection. Lipophilic immune stimulating complexes (ISCOMS) containing Quil A are active by both parenteral and mucosal routes and here we have established methods for incorporating palmitified diphtheria toxoid (DT) into ISCOMS. The resulting formulation was immunogenic by the subcutaneous, oral and intranasal routes, with very low doses of DT inducing systemic humoral immune responses, as well as cell mediated immunity including both gammaIFN and IL5 production. Intranasal immunisation with DT in ISCOMS also stimulated significant local antibody production in tracheal washes, as well as cellular immunity in draining lymphoid tissues and serum neutralising antibodies. Finally, subcutaneous immunisation of guinea pigs with DT in ISCOMS primed protective immunity against challenge with diphtheria holotoxin more efficiently than the equivalent doses of DT in the conventional alum vaccine. ISCOMS based vaccines may provide a novel strategy for mucosal and systemic immunisation against diphtheria.

Effects of smoking cessation on lung function and airway inflammation in smokers with asthma.

RATIONALE: Active smoking in asthma is associated with worsening of symptoms, accelerated decline in lung function, and impaired response to corticosteroids. OBJECTIVES: To examine the short-term effects of smoking cessation on lung function, airway inflammation, and corticosteroid responsiveness in smokers with asthma. METHODS AND MEASUREMENTS: Smokers with asthma were given the option to quit or continue smoking. Both groups underwent spirometry and induced sputum at baseline and at 1, 3, and 6 wk. Cutaneous vasoconstrictor response to topical beclometasone, airway response to oral prednisolone, and sensitivity of peripheral blood lymphocytes to corticosteroids were measured before smoking cessation and at 6 wk. MAIN RESULTS: Of 32 subjects recruited, 11 opted to continue smoking (smoking control group). Of 21 subjects who opted for smoking cessation, 10 quit smoking for 6 wk (quit group). In the comparison of quitters with smokers at 6 wk, the mean (confidence interval [CI]) difference in FEV(1) was 407 ml (21, 793), p = 0.040, and the proportion of sputum neutrophils was reduced by 29 (51, 8), p = 0.039. Total cutaneous vasoconstrictor response score to topical beclometasone improved after smoking cessation with a mean (CI) difference of 3.56 (0.84, 6.28), p = 0.042, between quitters and smokers. There was no change in airway corticosteroid responses after smoking cessation. CONCLUSIONS: By 6 wk after smoking cessation, subjects who quit smoking had achieved considerable improvement in lung function and a fall in sputum neutrophil count compared with subjects who continued to smoke. These findings highlight the importance of smoking cessation in asthma.

Short and long-term effects of cigarette smoking independently influence exhaled nitric oxide concentration in asthma.

BACKGROUND: The fractional concentration of nitric oxide in exhaled breath (FeNO) is elevated in asthma. FeNO measurement has been proposed as a noninvasive index of disease activity. Cigarette smoking suppresses FeNO, which limits its use in smokers. OBJECTIVE: To identify and model short-term and long-term influences of cigarette smoking on FeNO. METHODS: The smoking history, FeNO, and fractional concentration of carbon monoxide in exhaled breath (FeCO) were measured in 53 subjects with asthma and 51 control subjects. A mathematical model of the short-term and long-term effects of cigarette smoking on FeNO was derived. RESULTS: Subjects with asthma had higher FeNO than controls ( P < .001). Smokers had increased FeCO ( P < .001). The short-term effect (hours since last cigarette) was associated with increased FeNO ( P < .01) and decreased FeCO ( P < .05). The long-term effect (years smoked) was associated with decreasing FeNO only in the subjects with asthma ( r = -0.62; P = .005). These short-term and long-term effects were independent and were combined in a model predicting FeNO, predicted log 10 FeNO = 1.23 - 0.58 e -0.34t - 0.00000103 x (lifetime cigarettes), where t = hours since the last cigarette. This gave a convincing prediction of FeNO ( r = 0.83; P < .0001). CONCLUSION: Short-term and long-term effects of smoking influenced the measurement of FeNO. We defined a model that describes these effects. The use of this formula may improve the value of FeNO measurements in smokers with asthma.

Effect of inhaled corticosteroids on symptom severity and sputum mediator levels in chronic persistent cough.

BACKGROUND: Chronic cough often lasts for more than 1 year and is associated with airway inflammation. The effect of inhaled corticosteroids on symptom severity and inflammatory mediator levels in these patients is unknown. OBJECTIVE: We sought to determine whether inhaled corticosteroids reduce cough severity and sputum mediator concentrations in patients with chronic persistent cough. METHODS: We performed a double-blind, randomized, placebo-controlled crossover study with inhaled fluticasone, 500 microg twice daily, and placebo for 14 days in 88 patients with cough for more than 1 year, with normal chest radiography and spirometry results. Outcome measures were a daily cough visual analogue scale and induced sputum concentrations of eosinophilic cationic protein (ECP), myeloperoxidase, leukotriene B(4) (LTB(4)), leukotrienes C(4)/D(4)/E(4) (cysteinyl leukotrienes [Cys-LTs]), prostaglandin E(2) (PGE(2)), IL-8, and TNF-alpha. Sputum cell counts, exhaled nitric oxide levels, and carbon monoxide levels were also measured. RESULTS: There was a significant improvement in the cough visual analogue scale after inhaled fluticasone compared with placebo (mean difference, 1.0; 95% CI, 0.4-1.5; P <.001). LTB(4), Cys-LT, and PGE(2) levels were increased in all causes of cough. Sputum ECP counts, exhaled nitric oxide levels, and carbon monoxide levels decreased significantly after inhaled fluticasone. There was no change in sputum cell counts and other mediator concentrations. CONCLUSION: Cough severity and sputum ECP levels are modestly reduced by inhaled corticosteroids in patients with chronic cough persisting for more than 1 year. LTB(4), Cys-LT, PGE(2), IL-8, myeloperoxidase, and TNF-alpha levels are unaltered by this therapy. This raises the possibility that drugs targeted to reduce the effects of these mediators might be of benefit in chronic persistent cough.