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House dust mite sublingual immunotherapy: Results of a US trial

Background: Few trials of sublingual immunotherapy (SLIT) in the United States have been reported.Objective: This randomized, placebo-controlled feasibility SLIT study compared the safety and physiologic effects of high- versus low-dose Dermatophagoides farinae vaccine.Methods: Thirty-one D farinae–sensitive adults with allergic rhinitis with or without mild intermittent asthma were eligible for randomization to high-dose maintenance vaccine (n = 10, 4200 allergen units [approximately 70 μg of Der f 1/d]), low-dose maintenance vaccine (n = 10; 60 allergen units [approximately 1 μg of Der f 1/d]), or placebo (n = 11) over 12 to 18 months. Medication-symptom scores and adverse events were monitored, serum D farinae–specific IgE and IgG4 levels were measured, and bronchial reactivity to D farinae was determined at baseline and 6-month intervals.Results: Of the 31 randomized subjects, 6 withdrew because of non–treatment-ascribed events. Four withdrew because of treatment-ascribed effects: high-dose group, 1 of 10 (gastrointestinal symptoms); low-dose group, 1 of 10 (gastrointestinal symptoms); and placebo group, 2 of 11 (headache and increased nasal symptoms). Thus 21 subjects completed the study: high-dose group, 9; low-dose group, 7; and placebo group, 5. Eleven of the 21 subjects experienced mild-to-moderate gastrointestinal symptoms, throat irritation, or both (high-dose group, 5/9; low-dose group, 4/7; and placebo group, 2/5). No severe systemic reactions were noted. No differences in symptom-medication scores were found. High-dose SLIT increased the bronchial threshold to allergen challenge and increased serum D farinae–specific IgG4 levels, whereas low-dose SLIT and placebo had no significant effect.Conclusions: High-dose D farinae SLIT was generally tolerable, increased serum D farinae–specific IgG4 levels, and improved the bronchial threshold to allergen challenge. Larger US trials are warranted.

Ingested allergens must be absorbed systemically to induce systemic anaphylaxis

Background: IgE-mediated food allergy is a common cause of enteric disease and is responsible for approximately 100 systemic anaphylaxis deaths in the United States each year. IgG antibodies can protect against IgE-mediated systemic anaphylaxis induced by injected antigens by neutralizing antigens before they can bind to mast cell–associated IgE.Objective: We have investigated whether IgA and IgG antibodies can similarly protect against systemic, IgE-mediated anaphylaxis induced by ingested antigens and, if so, whether IgA and IgG antibodies protect by neutralizing antigens before or after their systemic absorption.Methods: Murine passive and active anaphylaxis models were used to study the abilities of serum versus gut lumenal IgA antibodies and serum IgG antibodies to inhibit systemic anaphylaxis induced by ingested allergens in normal mice, mice deficient in the ability to secrete IgA into the intestines, and mice in which intestinal IL-9 overexpression has induced intestinal mastocytosis and increased intestinal permeability.Results: IgE-mediated systemic anaphylaxis and mast cell degranulation induced by antigen ingestion are suppressed by both serum antigen-specific IgA and IgG, but not by IgA within the gut lumen.Conclusion: Systemic rather than enteric antibodies protect against systemic anaphylaxis induced by ingested antigen. This implies that ingested antigens must be absorbed systemically to induce anaphylaxis and suggests that immunization protocols that increase serum levels of antigen-specific, non-IgE antibodies should protect against severe food allergy.

Recombinant allergens for specific immunotherapy

Recombinant DNA technology provides the means for producing allergens that are equivalent to their natural counterparts and also genetically engineered variants with reduced IgE-binding activity. The proteins are produced as chemically defined molecules with consistent structural and immunologic properties.

Several hundred allergens have been cloned and expressed as recombinant proteins, and these provide the means for making a very detailed diagnosis of a patient’s sensitization profile. Clinical development programs are now in progress to assess the suitability of recombinant allergens for both subcutaneous and sublingual immunotherapy. Recombinant hypoallergenic variants, which are developed with the aim of increasing the doses that can be administered while at the same time reducing the risks for therapy-associated side effects, are also in clinical trials for subcutaneous immunotherapy. Grass and birch pollen preparations have been shown to be clinically effective, and studies with various other allergens are in progress.

Personalized or patient-tailored immunotherapy is still a very distant prospect, but the first recombinant products based on single allergens or defined mixtures could reach the market within the next 5 years.

Mast cell–associated alveolar inflammation in patients with atopic uncontrolled asthma

Background: A significant proportion of patients with asthma have persistent symptoms despite treatment with inhaled glucocorticosteroids.Objective: We hypothesized that in these patients, the alveolar parenchyma is subjected to mast cell–associated alterations.

Methods: Bronchial and transbronchial biopsies from healthy controls (n = 8), patients with allergic rhinitis (n = 8), and patients with atopic uncontrolled asthma (symptoms despite treatment with inhaled glucocorticosteroids; mean dose, 743 μg/d; n = 14) were processed for immunohistochemical identification of mast cell subtypes and mast cell expression of FcεRI and surface-bound IgE.

Results: Whereas no difference in density of total bronchial mast cells was observed between patients with asthma and healthy controls, the total alveolar mast cell density was increased in the patients with asthma (P < .01). Division into mast cell subtypes revealed that in bronchi of patients with asthma, tryptase positive mast cells (MCT) numbers decreased compared with controls (P ≤ .05), whereas tryptase and chymase positive mast cells (MCTC) increased (P ≤ .05). In the alveolar parenchyma from patients with asthma, an increased density was found for both MCT (P ≤ .05) and MCTC (P ≤ .05). The increased alveolar mast cell densities were paralleled by an increased mast cell expression of FcεRI (P < .001) compared with the controls. The patients with asthma also had increased numbers (P < .001) and proportions (P < .001) of alveolar mast cells with surface-bound IgE. Similar increases in densities, FcεRI expression, and surface-bound IgE were not seen in separate explorations of alveolar mast cells in patients with allergic rhinitis.

Conclusion: Our data suggest that patients with atopic uncontrolled asthma have an increased parenchymal infiltration of MCT and MCTC populations with increased expression of FcεRI and surface-bound IgE compared with atopic and nonatopic controls.

Mechanical induction of cough in Idiopathic Pulmonary Fibrosis

Background: Patients with idiopathic pulmonary fibrosis (IPF) frequently develop a dry, irritating cough which often proves refractory to anti-tussive therapies. The precise pathogenetic mechanisms responsible for this cough are unknown. We hypothesised that changes in nerves modulating mechanical sensitivity in areas of interstitial fibrosis might lead to enhanced cough response to mechanical stimulation of the chest in IPF.

Methods: We studied 27 non-smoking subjects with IPF (63% male), mean (SD) age 71.7 (7) years and 30 healthy non-smokers. Quality of life (Leicester Cough Questionnaire), cough symptom scores and cough severity scores (visual analog scales) were recorded. Percussion stimulation was applied over the posterior lung base, upper anterior chest and manubrium sternum at seq...

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