Grass pollen allergoids conjugated with mannan for subcutaneous and sublingual immunotherapy: a dose-finding study.

Background: Polymerized allergoids conjugated with mannan represent a novel approach of allergen immunotherapy targeting dendritic cells. In this study, we aimed to determine the optimal dose of mannan-allergoid conjugates derived from grass pollen (Phleum pratense and Dactylis glomerata) administered via either the subcutaneous or sublingual route. Methods: A randomized, double-blind, placebo-controlled trial with a double-dummy design was conducted, involving 162 participants across 12 centers in Spain. Subjects were randomly allocated to one of nine different treatment groups, each receiving either placebo or active treatment at doses of 500, 1,000, 3,000, or 5,000 mTU/mL over four months. Each participant received five subcutaneous (SC) doses of 0.5 mL each, every 30 days, and a daily sublingual (SL) dose of 0.2 mL. Participants who received active treatment through SC, received placebo through SL. Participants who received active treatment through SL, received placebo SC. One Group, as control, received bot SC and SL placebo. The primary efficacy outcome was the improvement in titrated nasal provocation tests (NPT) at the end of the study compared to baseline. Secondary outcomes included specific antibody (IgG4, IgE) and cellular (IL-10 producing and regulatory T cell) responses. All adverse events and side reactions were recorded and assessed. Results: Post-treatment, the active groups showed improvements in NPT ranging from 33% to 53%, with the highest doses showing the greatest improvements regardless of the administration route. In comparison, the placebo group showed a 12% improvement. Significant differences over placebo were observed at doses of 3,000 mTU/mL (p=0.049 for SL, p=0.015 for SC) and 5,000 mTU/mL (p=0.011 for SL, p=0.015 for SC). A dose-dependent increase in IgG4 was observed following SC administration, and an increase in IL-10 producing cells for both routes of administration. No serious systemic or local adverse reactions were recorded, and no adrenaline was required. Conclusion: Grass pollen immunotherapy with mannan-allergoid conjugates was found to be safe and efficacious in achieving the primary outcome, whether administered via the subcutaneous or sublingual routes, at doses of 3,000 and 5,000 mTU/mL. Clinical trial registration: https://www.clinicaltrialsregister.eu/ctr-search (EudraCT), identifier 2014-005471-88; https://www.clinicaltrials.gov, identifier NCT02654223.

Influence of environmental drivers on allergy to pollen grains in a case study in Spain (Madrid): meteorological factors, pollutants, and airborne concentration of aeroallergens.

The aim of this study was to compare airborne levels of Phl p 1 and Phl p 5, with Poaceae pollen concentrations inside and outside of the pollen season, and to evaluate their association with symptoms in grass allergic patients and the influence of climate and pollution. The Hirst and the Burkard Cyclone samplers were used for pollen and allergen quantification, respectively. The sampling period ran from 23 March 2009 to 27 July 2010. Twenty-three patients with seasonal allergic asthma and rhinitis used an electronic symptom card. The aerosol was extracted and quantified for Phl p 1 and Phl p 5 content. Descriptive statistics, non-parametric paired contrast of Wilcoxon, Spearman's correlations, and a categorical principal component analysis (CatPCA) were carried out. Significant variations in pollen, aeroallergen levels, pollen allergen potency, and symptoms score were observed in this study. Phl p 5 pollen allergen potency was higher at the beginning of the 2010 grass pollen season. Presence of Phl p 1 outside the pollen season with positive O3 correlation was clinically relevant. 45.5% of the variance was explained by two dimensions in the CatPCA analysis, showing the symptom relationships dissociated in two dimensions. In the first one, the more important relationship was with grass pollen grains concentration and Phl p 5 and to a lesser extent with Phl p 1 and levels of NO2 and O3, and in the second dimension, symptoms were associated with humidity and SO2. Clinically relevant out-season Phl p 1 was found with a positive O3 correlation. The effect of climate and pollution may have contributed to the higher seasonal allergic rhinitis symptom score recorded in 2009.

Novel vaccines targeting dendritic cells by coupling allergoids to nonoxidized mannan enhance allergen uptake and induce functional regulatory T cells through programmed death ligand 1.

BACKGROUND: Allergen immunotherapy (AIT) is the only curative treatment for allergy. AIT faces pitfalls related to efficacy, security, duration, and patient compliance. Novel vaccines overcoming such inconveniences are in demand. OBJECTIVES: We sought to study the immunologic mechanisms of action for novel vaccines targeting dendritic cells (DCs) generated by coupling glutaraldehyde-polymerized grass pollen allergoids to nonoxidized mannan (PM) compared with glutaraldehyde-polymerized allergoids (P) or native grass pollen extracts (N). METHODS: Skin prick tests and basophil activation tests with N, P, or PM were performed in patients with grass pollen allergy. IgE-blocking experiments, flow cytometry, confocal microscopy, cocultures, suppression assays, real-time quantitative PCR, ELISAs, and ELISpot assays were performed to assess allergen capture by human DCs and T-cell responses. BALB/c mice were immunized with PM, N, or P. Antibody levels, cytokine production by splenocytes, and splenic forkhead box P3 (FOXP3)(+) regulatory T (Treg) cells were quantified. Experiments with oxidized PM were also performed. RESULTS: PM displays in vivo hypoallergenicity, induces potent blocking antibodies, and is captured by human DCs much more efficiently than N or P by mechanisms depending on mannose receptor- and dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin-mediated internalization. PM endorses human DCs to generate functional FOXP3(+) Treg cells through programmed death ligand 1. Immunization of mice with PM induces a shift to nonallergic responses and increases the frequency of splenic FOXP3(+) Treg cells. Mild oxidation impairs these effects in human subjects and mice, demonstrating the essential role of preserving the carbohydrate structure of mannan. CONCLUSIONS: Allergoids conjugated to nonoxidized mannan represent suitable vaccines for AIT. Our findings might also be of the utmost relevance to development of therapeutic interventions in other immune tolerance-related diseases.

A topical microemulsion for the prevention of allergic rhinitis symptoms: results of a randomized, controlled, double-blind, parallel group, multicentre, multinational clinical trial (Nares study).

BACKGROUND: Since barrier protection measures to avoid contact with allergens are being increasingly developed, we assessed the clinical efficacy and tolerability of a topical nasal microemulsion made of glycerol esters in patients with allergic rhinitis. METHODS: Randomized, controlled, double-blind, parallel group, multicentre, multinational clinical trial in which adult patients with allergic rhinitis or rhinoconjunctivitis due to sensitization to birch, grass or olive tree pollens received treatment with topical microemulsion or placebo during the pollen seasons. Efficacy variables included scores in the mini-RQLQ questionnaire, number and severity of nasal, ocular and lung signs and symptoms, need for symptomatic medications and patients' satisfaction with treatment. Adverse events were also recorded. RESULTS: Demographic characteristics were homogeneous between groups and mini-RQLQ scores did not differ significantly at baseline (visit 1). From symptoms recorded in the diary cards, the ME group showed statistically significant better scores for nasal congestion (0.72 vs. 1.01; p = 0.017) and mean total nasal symptoms (0.7 vs. 0.9; p = 0.045). At visit 2 (pollen season), lower values were observed in the mini-RQLQ in the ME group, although there were no statistically significant differences between groups in both full analysis set (FAS) and patients completing treatment (PPS) populations. The results obtained in the nasal symptoms domain of the mini-RQLQ at visit 2 showed the highest difference (-0.43; 95% CI: -0.88 to 0.02) for the ME group in the FAS population. The topical microemulsion was safe and well tolerated and no major discomforts were observed. Satisfaction rating with the treatment was similar between the groups. CONCLUSIONS: The topical application of the microemulsion is a feasible and safe therapy in the prevention of allergic symptoms, particularly nasal congestion. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01478425.

Dermatitis de contacto, rinoconjuntivitis y asma bronquial

La alergia respiratoria del esma es una entidad conocida, en la que se vienen encontrando cada vez más factores desencadenantes. Se describen un paciente afectado de asma bronquial y dermatitis de contacto y tres de rinoconjuntivitis intensa tras contacto con la cebolla paiteña. En los cuatro pacientes se realizan pruebas cutáneas (prick, prick-prick y patch test), pruevas de provocación bronquial nasal y oral y pruebas in vitro para detectar IgE especifica frente a cebolla paiteña y se estudia su reactividad cruzada con otros antigenos. como control de este estudio y para evaluar la prevalencia de sensibilidad cutánea a la cebolla paiteña, se realizó el prick-prick test a 106 sujetos escogidos al azar en nuestra consulta. En los cuatro pacientes encontramos reacciones positivas en el prick y prick-prick test e IgE especifica frente a cebolla paiteña. Se obtuvieron reacciones positivas en las pruevas de provocación bronquial, oral y patch test y en la provocación nasal y oral. Encontramos además inhibición del CAP a cebolla paiteña consigo misma, polen de gramineas pero no con D. pteronnysinus. Ocho (7.5 por ciento) de los 106 individuos usados como control, tuvieron un prick-prick positivo, dos de ellos con sintomatología sospechosa de alergia. Todos ellos eran alergicos a pólems y/o ácaros. En los sujetos estudiados demostramos que la cebolla paiteña puede ser la causa de asma, rinoconjuntivitis y dermatitis de contacto. El mecanismo implicado parece ser IgE mediado en los dos primeros casos y mediado por células en el último. Se demuestra además reactividad cruzada con los pólems de gramineas.

Conjuntivitis alérgica causada por cromoglicato disódico

Se describen los estudios realizados en un paciente afectado de conjuntivitis aguda tras la administración de un colirio que contenía cromoglicato disódico. Se detectó alergia de tipo I, mediante pruebas cutáneas. Pruebas de provocación conjuntival y detección de IgE específica frente a ésta sustancia.