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Notes: Seven asthmatic and five normal subjects inhaled increasing amounts of nebulized water (“fog”). Neutrophil chemotactic activity (NCA), histamine and FEV1 measurements were undertaken before and at time intervals after challenge. In asthmatics, the mean maximal reduction in FEV1 (± 1 SD) was 46.6%± 11.5; whereas, in normal subjects, the reductions were less than 20% of pre-challenge values after the inhalation of 33 ml of water. There were no significant differences in the pre-challenge values for NCA between the asthmatics and the normal controls. When the highest values for NCA during the 30 min after challenge in the asthmatics were compared with controls there was a significant increase (P 〈 0.02). The percentage change in NCA was also significantly greater in the asthmatics compared with the controls at 10 min after challenge (P 〈 0.05). Fog-induced NCA was shown to be associated with proteins with approximate molecular weight of 600,000 daltons (as assessed by gel filtration chromatography on Sephacryl-S400). There was an increase in plasma histamine in the asthmatics after challenge but this was not significantly greater than the controls. These findings support the view that mediators might be involved in fog-induced asthma, possibly as a result of mast cell degranulation by “osmotic shock”.

Notes: Background:  Nasal lavage is a noninvasive method of obtaining inflammatory exudates following nasal allergen challenge (NAC), and permits cells and released mediators to be evaluated.Objective:  To determine the effects of a single dose of topical steroid on eosinophils and levels of chemokines and cytokines in nasal lavage fluid following NAC in patients with allergic rhinitis.Methods:  Patients with grass pollen seasonal allergic rhinitis (n = 32) out of the allergy season received either nasal budesonide (100 μg per nostril) or matched placebo before allergen challenge in a double blind two-way crossover design. A semi-automated mixed bead array system was employed to measure multiple chemokines and cytokines in small volumes (50 μl) of nasal lavage supernatants.Results:  Following NAC there was a rapid onset of nasal symptoms together with nasal eosinophilia, and the appearance of IL-5 and IL-13 in lavages between 4 and 8 h. Elevated levels of eotaxin, RANTES, IL-8 and MCP-1 were also detected following allergen challenge. A single dose of nasal budesonide caused a decrease in symptoms (P 〈 0.05) and nasal eosinophils (P 〈 0.05) with selective abrogation of IL-5 and IL-13 responses (P 〈 0.05), but a lack of effect on levels of eotaxin, RANTES, IL-8 and MCP-1.Conclusion:  This study suggests that a single dose of nasal steroid has the capacity to selectively abolish IL-5 and IL-13 responses following NAC. This model should be convenient for testing novel anti-inflammatory and immunoregulatory agents intended for the treatment of allergic rhinitis.

Notes: Allergic rhinitis is a common condition which, at its most severe, can significantly impair quality of life despite optimal treatment with antihistamines and topical nasal corticosteroids. Allergen injection immunotherapy significantly reduces symptoms and medication requirements in allergic rhinitis but its use is limited by the possibility of severe systemic reactions. There has therefore been considerable interest in alternative routes for delivery of allergen immunotherapy, particularly the sublingual route. The objective was to evaluate the efficacy of sublingual immunotherapy (SLIT), compared with placebo, for reductions in symptoms and medication requirements. The Cochrane Controlled Clinical Trials Register, MEDLINE (1966–2002), EMBASE (1974–2002) and Scisearch were searched, up to September 2002, using the terms (Rhin* OR hay fever) AND (immunotherap* OR desensiti*ation) AND (sublingual). All studies identified by the searches were assessed by the reviewers to identify Randomized Controlled Trials involving participants with symptoms of allergic rhinitis and proven allergen sensitivity, treated with SLIT or corresponding placebo. Data from identified studies was abstracted onto a standard extraction sheet and subsequently entered into RevMan 4.1. Analysis was performed by the method of standardized mean differences (SMD) using a random effects model. P-values 〈 0.05 were considered statistically significant. Subgroup analyses were performed according to the type of allergen administered, the age of participants and the duration of treatment. Twenty-two trials involving 979 patients, were included. There were six trials of SLIT for house dust mite allergy, five for grass pollen, five for parietaria, two for olive and one each for, ragweed, cat, tree and cupressus. Five studies enrolled exclusively children. Seventeen studies administered the allergen by sublingual drops subsequently swallowed, three by drops subsequently spat out and two by sublingual tablets. Eight studies involved treatment for less than 6 months, 10 studies for 6–12 months and four studies for greater than 12 months. All included studies were double-blind placebo-controlled trials of parallell group design. Concealment of treatment allocation was considered adequate in all studies and the use of identical placebo preparations was almost universal. There was significant heterogeneity, most likely due to widely differing scoring systems between studies, for most comparisons. Overall there was a significant reduction in both symptoms (SMD −0.42, 95% confidence interval −0.69 to −0.15; P = 0.002) and medication requirements [SMD −0.43 (−0.63, −0.23); P = 0.00003] following immunotherapy. Subgroup analyses failed to identify a disproportionate benefit of treatment according to the allergen administered. There was no significant reduction in symptoms and medication scores in those studies involving only children but total numbers of participants was too small to make this a reliable conclusion. Increasing duration of treatment does not clearly increase efficacy. The total dose of allergen administered may be important but insufficient data was available to analyse this factor.

Notes: Background:  Monophosphoryl lipid A (MPL®) is a nontoxic derivative of the lipopolysaccharide (LPS) of Salmonella minnesota R595. MPL has been used as an adjuvant in grass and tree pollen vaccines for the treatment of seasonal allergic rhinitis. Little is known about the influence of MPL on cellular responses to allergens in man. We therefore studied the effects of MPL in vitro on peripheral blood mononuclear cells (PBMC) obtained from patients with grass pollen hay fever.Methods:  The PBMCs from 13 subjects were cultured with grass pollen Phleum pratense extract (0, 2 and 20 μg/ml) and MPL (0 and 10 μg/ml; defined as an optimal concentration in preliminary studies) and after 6 days proliferative responses were measured by thymidine incorporation and cytokine production by enzyme-linked immunosorbent assay (ELISA).Results:  Proliferative responses were unaffected by the presence of MPL whereas MPL induced a significant increase in allergen-induced interferon (IFN)-γ production [allergen alone, 645 ± 466 pg/ml (mean ± SE) vs allergen + MPL, 3232 ± 818 pg/ml; P 〈 0.001]. In addition, there was a significant decrease in interleukin (IL)-5 production (4307 ± 1030 pg/ml vs 2997 ± 826 pg/ml; P 〈 0.01). Although MPL alone could induce modest increases in IL-10 production, MPL did not influence the production of this cytokine in allergen-stimulated cultures. Addition of neutralizing antibody against IL-12 resulted in 95% inhibition of MPL-induced IFN-γ production. Depletion of monocytes from the culture system abrogated the effects of MPL on elevated cytokine production.Conclusions:  In summary, use of MPL with grass pollen extract results in immune deviation of allergen-induced peripheral Th2-cell responses in favour of ‘protective’ Th1 responses in an IL-12 and monocyte-dependent fashion.

Notes: A greater understanding of the basic mechanisms of allergic inflammation is pertinent to the development of new treatments. Previous studies have focused on the role of mediators of hypersensitivity and effector cells, including mast cells and eosinophils. Recent evidence suggests that IgE-dependent activation and tissue eosinophilia are under the local regulation of distinct cytokines. Originally described as products from T lymphocytes, these peptide messengers are produced by alternative cells, including mast cells, eosinophils and the respiratory epithelium. In vitro studies in murine models and using cloned human T lymphocytes indicate the preferential production of “Th2-type” cytokines, including interleukin-4 (IL-4) and IL-5. This review considers the evidence from in vivo studies in humans that “Th2-type” cytokines have a primary role in orchestrating both IgE-dependent events and local tissue eosinophilia. Novel therapeutic approaches might include a broad strategy directed against T lymphocytes, including the use of immunosuppressive agents or anti CD4 antibodies or more precise targeting of IL-4 and/or IL-5.

Notes: Background Eoswinophil granule proteins may contribute to hyperresponsiveness in asthma.Objective To measure eosinophil cationic protein (ECP) and eosinophil protein X (EPX) in sereum and bronchial lavage fluid from 20 asthmatics and 16 control subjects. To asses the effect on these eosinophil proteins of corticosteroid treatment of asthma. To determine ehether serum ECP and EPX measured weekly in a longitudina study for 10 weeks reflected changes in lung function.Methods Eosinophil granule proteins were measured by radiommunoassy of bronchial wash (BW), bronchoalveolar lavage (BAL) serum.Results Eosinophils were elevated in BAL(P〈0.01), BW (P〈0.01) and blood (P〈0.01) from asthmatic compared with control subjects. Eosinophil cationic protein concentration was significantly elevated in BAL (P〈0.05) and BW from asthmatics (P〈0.01) and EPX was increased in BAL (P〈0.05)and BW (P〈0.01). These changes were also reflected in elevated serum ECP(P〈0.01) and EPX (P〈0.01)concentrations is asthmatic subjects. There was no significant difference between sujects receiving prednisolone and the placebo group, but there was a fall in ECP in BW (P〈0.05) and serum (P〈0.01) and in EPX in BW (P〈0.01) and serum (P〈0.01) within the group receiving prednisolone. In the longitudinal study there was only significant difference between ECP values associated with highest and lowest peak expiratory flow rate (PEFR) (P〈0.05).Conclusion These data confirm a role for cosinophil activation in the airway in asthma pathogenesis, and add some support to the hypothesis that corticosteroids may inhibit cosinophil activation in asthma.