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PURPOSE Universal cancer peptide–based vaccine (UCPVax) is a therapeutic vaccine composed of two highly selected helper peptides to induce CD4+ T helper-1 response directed against telomerase. This phase Ib/IIa trial was designed to test the safety, immunogenicity, and efficacy of a three-dose schedule in patients with metastatic non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with refractory NSCLC were assigned to receive three vaccination doses of UCPVax (0.25 mg, 0.5 mg, and 1 mg) using a Bayesian-based phase Ib followed by phase IIa de-escalating design. The primary end points were dose-limiting toxicity and immune response after three first doses of vaccine. Secondary end points were overall survival (OS) and progression-free survival at 1 year. RESULTS A total of 59 patients received UCPVax; 95% had three prior lines of systemic therapy. No dose-limiting toxicity was observed in 15 patients treated in phase Ib. The maximum tolerated dose was 1 mg. Fifty-one patients were eligible for phase IIa. The third and sixth dose of UCPVax induced specific CD4+ T helper 1 response in 56% and 87.2% of patients, respectively, with no difference between three dose levels. Twenty-one (39%) patients achieved disease control (stable disease, n = 20; complete response, n = 1). The 1-year OS was 34.1% (95% CI, 23.1 to 50.4), and the median OS was 9.7 months, with no significant difference between dose levels. The 1-year progression-free survival and the median OS were 17.2% (95% CI, 7.8 to 38.3) and 11.6 months (95% CI, 9.7 to 16.7) in immune responders ( P = .015) and 4.5% (95% CI, 0.7 to 30.8) and 5.6 months (95% CI, 2.5 to 10) in nonresponders ( P = .005), respectively. CONCLUSION UCPVax was highly immunogenic and safe and provide interesting 1-year OS rate in heavily pretreated advanced NSCLC.

Background There is a paucity of data regarding the prognostic influence of peripheral blood CD4+ T lymphopenia in non-small cell lung cancer (NSCLC). Therefore, we investigated the prognostic value of T lymphopenia in NSCLC. Materials Treatment-naive patients with a pathological diagnosis of NSCLC, at clinical stage I to IV were included in the prospective TELOCAP1 study. Lymphocytes count was evaluated in peripheral blood by flow cytometry. CD4+ and CD8+ T lymphopenia were defined as an absolute count of Results Between July 2010 and January 2014, 169 evaluable patients with clinical stage I to IV NSCLC were prospectively enrolled. The prevalence of CD4+ and CD8+ T lymphopenia was similar in the study population (around 29%). Patients with CD4+ T lymphopenia showed lower overall survival than those with CD4+ T lymphocytes count > 500/μL (median overall survival (OS) 16.1 versus 21.7 months, hazard ratio (HR): 1.616 [95% CI: 1.1–2.36], p = 0.012). This association with OS was especially marked in local/loco-regional NSCLC stages (median OS, 21.8 versus 72 months, respectively, HR: 1.88 [95% CI: 0.9–3.8], p = 0.035). Multivariate analysis confirmed the worse prognosis associated with CD4+ T lymphopenia in local/loco-regional NSCLC, but not in metastatic patients (HR 2.028 [95% CI = 1.065–3.817] p = 0.02). Restricted cubic spline analysis showed that patients with CD4+ T lymphocytes count ≤500/μL displayed a high risk of death regardless of NSCLC clinical stage. There was no obvious relationship between CD8+ T lymphopenia and clinical outcome. Conclusion We identified CD4+ T lymphopenia as an independent prognostic factor in local/loco-regional stages of NSCLC and CD4+ T lymphopenia is also associated with a high risk of death, regardless of NSCLC clinical stage. Trial registration EUDRACT: 2009-A00642–55.

International audience; Background The effect of exposure to micro-organisms on allergic diseases has been well studied. The protective effect of early food diversity against allergic diseases was previously shown in the PASTURE cohort study. The consumption of cheese, a food potentially rich in microbial diversity, deserves further examination. We aimed to evaluate whether cheese consumption is associated with allergic diseases. Methods In the PASTURE study (birth cohort in 5 European countries), data on feeding practices, environmental factors and allergic diseases were collected by questionnaires from birth to 6 years (N=931). Cheese consumption at 18 months of age was quantified in terms of frequency and diversity (i.e., number of consumed types among 6 types: hard pressed, semi-pressed, soft, blue, fresh cheese, from the farm). Multiple logistic regressions were performed to evaluate the effect of cheese consumption on atopic dermatitis (AD), food allergy (FA), allergic rhinitis, asthma and atopic sensitization at 6 years after adjustment for confounders of atopy. Results Cheese consumption (vs. non-consumption) had a significant protective effect on AD (OR=0.51 [0.29-0.90], p=0.02) and FA (OR=0.32, [0.15-0.71], p=0.004), but no effect on atopic sensitization, allergic rhinitis and asthma at 6 years. This effect on AD and FA may be related to the diversity of consumed cheeses (OR=0.64 [0.48-0.85] per cheese type, p=0.002; OR=0.55 [0.33-0.92], p=0.02, respectively). Conclusions Although reverse causality cannot totally be ruled out, cheese diversity at 18 months had a protective effect against AD and FA at 6 years in addition to the protective effect of diversity of other foods.

Background Despite the critical roles of Th1-polarised CD4+ T cells in cancer immunosurveillance, the translation of their potential to clinical use remains challenging. Here, we investigate the clinical relevance of circulating antitumor Th1 immunity in non-small cell lung cancer (NSCLC). Methods The circulating antitumor Th1 response was assessed by the ELISpot assay in 170 NSCLC patients using a mixture of HLA class II-restricted peptides from telomerase (TERT). Phenotyping of blood immune cells was performed by flow cytometry. Results TERT-reactive CD4 T-cell response was detected in 35% of NSCLC patients before any treatment. Functional analysis showed that these cells were effector memory and Th1 polarised capable to produce effector cytokines, such as IFN-γ, TNF-α and IL-2. The presence of anti-TERT Th1 response was inversely correlated with the level of exhausted PD-1+/TIM-3+CD4 T cells. The level of these two immune parameters differentially affected the survival, so that increased level of anti-TERT Th1 response and low rate of exhausted PD-1+TIM-3+CD4+ T cells were associated with a better prognosis. Conclusions Systemic anti-TERT Th1 response plays a strong antitumor protective role in NSCLC. This study underlines the potential interest of monitoring circulating antitumor Th1 response for patients’ stratification and therapy decision.

Introduction La cohorte TELOCAP a permis d’evaluer l’influence de divers parametres immunologiques dans le cancer bronchique non a petites cellules (CBNPC). Nous presentons ici l’influence de la lymphopenie T CD4 + sanguine dans cette cohorte. Methodes Ont ete inclus les patients diagnostiques d’un CBNPC, de stade clinique I a IV, traites au CHU de Besancon et a l’hopital europeen Georges-Pompidou [1] . La lymphopenie T CD4 + la lymphopenie T CD8 + dans le sang circulant, etaient respectivement definies comme un nombre absolu de lymphocytes (ALC) [2] . Le critere principal de jugement etait la survie globale. Resultats Au total, 186 patients ont ete inclus de 2010 a 2014. Les analyses univariees ont montre que la lymphopenie T CD4 + etait correlee a une plus faible survie globale (HR 1,616 [IC95 % = 1,107 ; 2,358] p = 0,0127). En revanche, aucune association n’a ete trouvee avec la lymphopenie T CD8+. En analyse multivariee, le statut de performance ≥ 2 (HR : 2,191 [IC95 % = 1,413 ; 3,396] p = 0,0005), le stade metastatique (HR : 2,558 [IC95 % = 1,722 ; 3,802] p . Conclusion Dans la presente etude, nous avons identifie la lymphopenie T CD4 + comme un facteur pronostique independant, pejoratif, pour la survie globale dans le CPNPC chez les patients atteints de CBNPC localise.

Streszczenie • Odwrotna zaleznośc pomiedzy spozyciem nieprzetworzonego mleka krowiego a zakazeniami ukladu oddechowego u niemowląt wskazuje na obecnośc przeciwzakaźnych i immunomodulujących cząsteczek związanych z tego typu zakazeniami u ludzi. • Zapobieganie zakazeniom ukladu oddechowego we wczesnym okresie zycia moze nie tylko ogolnie poprawiac stan tego ukladu, ale moze takze korzystnie wplywac na poźniejszy rozwoj ciezkich chorob ukladu oddechowego, jak np. astmy. Bezpieczne mikrobiologicznie, choc minimalnie przetworzone mleko moze miec istotny wplyw na zdrowie spoleczne w odniesieniu do czestych zakazen ukladu oddechowego. Wprowadzenie Karmienie piersią zapobiega zakazeniom ukladu oddechowego w pierwszych miesiącach zycia. Biorąc pod uwage wspolne ewolucyjne procesy adaptacyjne ludzi i bydla, mozliwe, ze mleko krowie wywiera podobny efekt ochronny u niemowląt u ludzi. Cel pracy Analiza wplywu spozywania surowego i przetworzonego mleka krowiego na najczestsze zakazenia ukladu oddechowego u niemowląt. Metody W ramach kohorty urodzeniowej w badaniu PASTURE obserwowano 983 niemowleta z terenow wiejskich z Austrii, Finlandii, Francji, Niemiec i Szwajcarii przez pierwszy rok zycia, obejmując lącznie 37 306 osobo-tygodni. Na podstawie cotygodniowych wpisow w dzienniczku stanu zdrowia analizowano spozycie roznych rodzajow mleka krowiego oraz wystepowanie niezytu blony śluzowej nosa, zakazenia ukladu oddechowego, zapalenia ucha i gorączki. Po 12 miesiącach pobierano probki krwi i oznaczano stezenie bialka C-reaktywnego. Wyniki W porownaniu z mlekiem UHT ( ultra-heat treatment ) spozywanie surowego mleka wykazywalo odwrotną zaleznośc z wystepowaniem niezytu blony śluzowej nosa (skorygowany iloraz szans z modeli longitudinalnych [95% CI]: 0,71 [0,54–0,94]), zakazen ukladu oddechowego (0,77 [0,59–0,99]), zapalenia ucha (0,14 [0,05–0,42]) i gorączki (0,69 [0,47–1,01]). Gotowane mleko wiejskie wykazalo podobną, choc nieco slabszą zaleznośc. Fabrycznie przetworzone mleko pasteryzowane wykazalo odwrotną zaleznośc z wystepowaniem gorączki. Spozywanie surowego mleka wiejskiego wiązalo sie odwrotnie zaleznie ze stezeniami bialka C-reaktywnego po 12 miesiącach (stosunek średnich geometrycznych [95% CI]: 0,66 [0,45–0,98]). Wnioski Spozywanie surowego mleka krowiego we wczesnym okresie zycia zmniejsza ryzyko wystepowania zakazen ukladu oddechowego i gorączki o okolo 30%. Biorąc pod uwage bardzo czeste wystepowanie zakazen ukladu oddechowego w pierwszym roku zycia oraz związane z tym koszty pośrednie i bezpośrednie wydaje sie, ze eliminacja zagrozen zdrowotnych związanych ze spozywaniem surowego mleka moglaby umozliwic ogromny wplyw minimalnie przetworzonego, ale pozbawionego patogenow mleka na zdrowie publiczne.

Background: Childhood asthma prevalence is significantly greater in urban areas compared with rural/farm environments. Murine studies have shown that TNF-alpha-induced protein 3 (TNFAIP3; A20), an anti-inflammatory regulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) signaling, mediates environmentally induced asthma protection. Objective: We aimed to determine the role of TNFAIP3 for asthma development in childhood and the immunomodulatory effects of environmental factors. Methods: In a representative selection of 250 of 2168 children from 2 prospective birth cohorts and 2 cross-sectional studies, we analyzed blood cells of healthy and asthmatic children from urban and rural/farm environments from Europe and China. PBMCs were stimulated ex vivo with dust from "asthma-protective'' farms or LPS. NF-kappa B signaling-related gene and protein expression was assessed in PBMCs and multiplex gene expression assays (NanoString Technologies) in isolated dendritic cells of schoolchildren and in cord blood mononuclear cells from newborns. Results: Anti-inflammatory TNFAIP3 gene and protein expression was consistently decreased, whereas proinflammatory Toll-like receptor 4 expression was increased in urban asthmatic patients (P

Background Early life farm exposures have been shown to decrease the risk of allergic diseases. Dendritic cells (DCs) may mediate asthma-protective effect of farm exposures as they play an important role in the development of immunity and tolerance. Our aim was to investigate whether the numbers and phenotypes of circulating DCs at age 6 are associated with farming, asthma, and atopy in a selected sample of French and Finnish children from the PASTURE study. Methods We studied 82 farm and 86 nonfarm children with and without asthma. Using flow cytometry, BDCA1+ CD11c+ myeloid DC1s (mDC1), BDCA3+high mDC2s and BDCA2+ plasmacytoid DCs (pDCs) were identified and expressions of CD86, immunoglobulin-like transcript 3 (ILT3) and ILT4 were analyzed. Questionnaires were used to assess prenatal and lifetime patterns of farm exposures and to define asthma. Atopic sensitization was defined by specific IgE measurements. Results The percentage of mDC2 cells was lower in farm children (0.033 ± 0.001) than in nonfarm children (0.042 ± 0.001; P = 0.008). Similar associations were found between mDC2 percentage and prenatal (P = 0.02) and lifetime exposure to farm milk (P = 0.03) and stables (P = 0.003), but these associations were not independent from farming. Asthma was positively associated with ILT4 + mDCs (P = 0.04) and negatively with CD86 + pDCs (P = 0.048) but only in nonfarm children. Conclusions Inverse association between farm exposure and mDC2 percentage suggest that this DC subset may play a role in farm-related immunoregulation.

Background: Phenotypes of childhood-onset asthma are characterized by distinct trajectories and functional features. For atopy, definition of phenotypes during childhood is less clear. Objective: We sought to define phenotypes of atopic sensitization over the first 6 years of life using a latent class analysis (LCA) integrating 3 dimensions of atopy: allergen specificity, time course, and levels of specific IgE (sIgE). Methods: Phenotypes were defined by means of LCA in 680 children of the Multizentrische Allergiestudie (MAS) and 766 children of the Protection against allergy: Study in Rural Environments (PASTURE) birth cohorts and compared with classical nondisjunctive definitions of seasonal, perennial, and food sensitization with respect to atopic diseases and lung function. Cytokine levels were measured in the PASTURE cohort. Results: The LCA classified predominantly by type and multiplicity of sensitization (food vs inhalant), allergen combinations, and sIgE levels. Latent classes were related to atopic disease manifestations with higher sensitivity and specificity than the classical definitions. LCA detected consistently in both cohorts a distinct group of children with severe atopy characterized by high seasonal sIgE levels and a strong propensity for asthma; hay fever; eczema; and impaired lung function, also in children without an established asthma diagnosis. Severe atopy was associated with an increased IL-5/IFN-gamma ratio. A path analysis among sensitized children revealed that among all features of severe atopy, only excessive sIgE production early in life affected asthma risk. Conclusions: LCA revealed a set of benign, symptomatic, and severe atopy phenotypes. The severe phenotype emerged as a latent condition with signs of a dysbalanced immune response. It determined high asthma risk through excessive sIgE production and directly affected impaired lung function.

Background Childhood exposure to a farm environment has been shown to protect against the development of inflammatory diseases, such as allergy, asthma, and inflammatory bowel disease. Objective We sought to investigate whether both exposure to microbes and exposure to structures of nonmicrobial origin, such as the sialic acid N-glycolylneuraminic acid (Neu5Gc), might play a significant role. Methods Exposure to Neu5Gc was evaluated by quantifying anti-Neu5Gc antibody levels in sera of children enrolled in 2 farm studies: the Prevention of Allergy Risk factors for Sensitization in Children Related to Farming and Anthroposophic Lifestyle (PARSIFAL) study (n = 299) and the Protection Against Allergy Study in Rural Environments (PASTURE) birth cohort (cord blood [n = 836], 1 year [n = 734], 4.5 years [n = 700], and 6 years [n = 728]), and we associated them with asthma and wheeze. The effect of Neu5Gc was examined in murine airway inflammation and colitis models, and the role of Neu5Gc in regulating immune activation was assessed based on helper T-cell and regulatory T-cell activation in mice. Results In children anti-Neu5Gc IgG levels correlated positively with living on a farm and increased peripheral blood forkhead box protein 3 expression and correlated inversely with wheezing and asthma in nonatopic subjects. Exposure to Neu5Gc in mice resulted in reduced airway hyperresponsiveness and inflammatory cell recruitment to the lung. Furthermore, Neu5Gc administration to mice reduced the severity of a colitis model. Mechanistically, we found that Neu5Gc exposure reduced IL-17+ T-cell numbers and supported differentiation of regulatory T cells. Conclusions In addition to microbial exposure, increased exposure to non–microbial-derived Neu5Gc might contribute to the protective effects associated with the farm environment., published version, peerReviewed

Background: Accurate diagnosis of allergic sensitization is essential in clinical practice and allergy research, and the choice of assessment method may have an important impact. The PASTURE study (Protection against Allergy: Study of Rural Environment) examines the influence of exposure to a dairy farm environment on the occurrence of allergy in a cohort of rural European children from birth to 10 years. The aim of our study was to analyze agreement between skin prick tests (SPTs), to aeroallergens and food allergens, and specific IgE and to evaluate the association of SPT with atopic dermatitis in the 204 French children of the PASTURE study. Methods: SPT, atopic dermatitis assessment, and specific IgE measurements were performed at 1, 4.5, and 6 years. Results: A total of 137 children attended all three visits. The agreement between SPTs and specific IgE was poor except for perennial aeroallergens at 6 years and for an IgE cutoff greater than 0.7 IU/ml (κ = 0.69, 0.5202 - 0.8621). The prevalence of positive SPTs increased with age. Positive SPTs were transient at 1 year, whereas they were persistent between 4.5 and 6 years. Positive SPTs at 1 year were predictive of the occurrence of atopic dermatitis during follow-up. Conclusion: SPTs did not have good agreement with serum-specific IgE in early childhood. Both tests (SPT and specific IgE) should be used. Skin allergenic reactivity increased with age and was transient at 1 year but associated with the occurrence of atopic dermatitis.

International audience; BACKGROUND: European cross-sectional studies have suggested that prenatal and postnatal farm exposure decreases the risk of allergic diseases in childhood. Underlying immunologic mechanisms are still not understood but might be modulated by immune-regulatory cells early in life, such as regulatory T (Treg) cells. OBJECTIVE: We sought to assess whether Treg cells from 4.5-year-old children from the Protection against Allergy: Study in Rural Environments birth cohort study are critical in the atopy and asthma-protective effect of farm exposure and which specific exposures might be relevant. METHODS: From 1133 children, 298 children were included in this study (149 farm and 149 reference children). Detailed questionnaires until 4 years of age assessed farming exposures over time. Treg cells were characterized as upper 20% CD4(+)CD25(+) forkhead box protein 3 (FOXP3)(+) (intracellular) in PBMCs before and after stimulation (with phorbol 12-myristate 13-acetate/ionomycin or LPS), and FOXP3 demethylation was assessed. Atopic sensitization was defined by specific IgE measurements; asthma was defined by a doctor's diagnosis. RESULTS: Treg cells were significantly increased in farm-exposed children after phorbol 12-myristate 13-acetate/ionomycin and LPS stimulation. Exposure to farm milk was defined as a relevant independent farm-related exposure supported by higher FOXP3 demethylation. Treg cell (upper 20% CD4(+)CD25(+), FOXP3(+) T cells) numbers were significantly negatively associated with doctor-diagnosed asthma (LPS stimulated: adjusted odds ratio, 0.26; 95% CI, 0.08-0.88) and perennial IgE (unstimulated: adjusted odds ratio, 0.21; 95% CI, 0.08-0.59). Protection against asthma by farm milk exposure was partially mediated by Treg cells. CONCLUSIONS: Farm milk exposure was associated with increased Treg cell numbers on stimulation in 4.5-year-old children and might induce a regulatory phenotype early in life, potentially contributing to a protective effect for the development of childhood allergic diseases.

Introduction et but de l’étudeUne diversité alimentaire importante et précoce a été montrée protectrice contre des maladies allergiques (Roduit C. et al, JACI2012 Jul;130(1): 130-6). L’effet de la diversité de consommation de fromages, riches en microorganismes, n’a pas été étudié. Or l’exposition aux microorganismes est suspectée pour son rôle protecteur contre la survenue de maladies allergiques. Le but de notre étude était d’évaluer l’effet protecteur de la diversité de consommation de fromages contre des maladies allergiques (MA) : allergie alimentaire (AA), dermatite atopique (DA), asthme (AS), rhinite allergique (RA) et bronchite (BR).Matériel et méthodesL’étude a porté sur 941 enfants de la cohorte PATURE (Protection contre l’Allergie : étude du milieu Rural et de son Environnement) qui étudie l’influence de l’exposition à l’environnement fermier sur le développement des maladies allergiques dans 5 pays européens (France, Allemagne, Autriche, Suisse et Finlande). Les données concernant les habitudes alimentaires, l’atopie parentale et les facteurs environnementaux ont été colligées par questionnaire de la naissance à 6 ans. Les MA ont été définies par un diagnostic médical rapporté par les parents. Les fromages ont été classés en 6 catégories (à pâte dure pressée, semi-pressée, molle, bleu, frais, de la ferme). La diversité de consommation de fromages à 18 mois (DC18) a été définie par le nombre de différentes catégories de fromages consommées. L’effet de la diversité de consommation de fromages contre chaque MA à l’âge de 6 ans a été analysé par régressions logistiques linéaires multiples ajustées pour la diversité alimentaire à 6 mois, le pays, l’environnement fermier et les facteurs confondants d’atopie, comme l’atopie parentale.Résultats et Analyse statistiqueDC18 n’était pas corrélée à la diversité alimentaire à 6 ou 12 mois (P < 0,001). Une diversité élevée de fromages consommés avait un effet significativement protecteur contre la DA à 6 ans (P < 0,0007 ; OR = 0,60; IC[0,44;0,81]) et les AA à 6 ans (P < 0,041 ; OR = 0,57; IC[0,33;0,98]), mais pas contre les autres MA à 6 ans (AS, RA, BR).ConclusionLa consommation d’une diversité de fromages à 18 mois semble avoir un effet protecteur contre la DA et les A A à 6 ans, indépendamment de la diversité de consommation des autres groupes d’aliments.

Introduction et but de l’etude Une diversite alimentaire importante et precoce a ete montree protectrice contre des maladies allergiques (Roduit C. et al, JACI2012 Jul;130(1): 130-6). L’effet de la diversite de consommation de fromages, riches en microorganismes, n’a pas ete etudie. Or l’exposition aux microorganismes est suspectee pour son role protecteur contre la survenue de maladies allergiques. Le but de notre etude etait d’evaluer l’effet protecteur de la diversite de consommation de fromages contre des maladies allergiques (MA) : allergie alimentaire (AA), dermatite atopique (DA), asthme (AS), rhinite allergique (RA) et bronchite (BR). Materiel et methodes L’etude a porte sur 941 enfants de la cohorte PATURE (Protection contre l’Allergie : etude du milieu Rural et de son Environnement) qui etudie l’influence de l’exposition a l’environnement fermier sur le developpement des maladies allergiques dans 5 pays europeens (France, Allemagne, Autriche, Suisse et Finlande). Les donnees concernant les habitudes alimentaires, l’atopie parentale et les facteurs environnementaux ont ete colligees par questionnaire de la naissance a 6 ans. Les MA ont ete definies par un diagnostic medical rapporte par les parents. Les fromages ont ete classes en 6 categories (a pâte dure pressee, semi-pressee, molle, bleu, frais, de la ferme). La diversite de consommation de fromages a 18 mois (DC18) a ete definie par le nombre de differentes categories de fromages consommees. L’effet de la diversite de consommation de fromages contre chaque MA a l’âge de 6 ans a ete analyse par regressions logistiques lineaires multiples ajustees pour la diversite alimentaire a 6 mois, le pays, l’environnement fermier et les facteurs confondants d’atopie, comme l’atopie parentale. Resultats et Analyse statistique DC18 n’etait pas correlee a la diversite alimentaire a 6 ou 12 mois (P Conclusion La consommation d’une diversite de fromages a 18 mois semble avoir un effet protecteur contre la DA et les A A a 6 ans, independamment de la diversite de consommation des autres groupes d’aliments.

Prospective studies investigating the role of serum vitamin E concentrations during early life in the development of childhood allergies and asthma are limited.; To study the associations between serum vitamin E concentrations at first year of life and longitudinal development of atopy, atopic dermatitis, wheeze, and asthma up to 6 years of age.; The setting was the PASTURE study, a multicenter prospective birth cohort study in five European rural settings. Children of 1133 mothers recruited during pregnancy were followed from birth with measurement of serum vitamin E levels at year 1 and repeated assessments of serum immunoglobulin E antibodies (year 1, 4.5, 6), atopic dermatitis, wheezing symptoms, and asthma (year 1, 1.5, 2, 3, 4, 5, 6).; At 6 years of age, 66% and 82% of the original 1133 subjects underwent blood test for IgE and answered the questionnaire, respectively. We did not observe any statistically significant associations between serum vitamin E concentrations at year 1 and the endpoints, but borderline inverse associations between alpha tocopherol and wheezing without cold (OR 0.45, 95% CI 0.19-1.09) and any wheezing symptom (OR 0.52, 95% CI 0.27-1.02).; Serum vitamin E concentrations at year 1 were not associated with allergies or asthma by 6 years of age. While further prospective studies with repeated assessments of vitamin E during early life may clarify its putative role in the development of the diseases, it is also possible that the antioxidant hypothesis in the development of allergies and asthma does not hold.

International audience; BACKGROUND: There is conflicting evidence on whether allergen-specific memory is primed prenatally, whether this priming affects persistent immunologic effects, and whether it is modulated by the first environmental exposures in infancy. OBJECTIVE: We sought to explore the course of atopic sensitization between birth and 12 months of age. METHODS: Specific IgE levels for 6 food and 13 common inhalant allergens were assessed in cord blood and 1-year blood samples in the Protection against Allergy-Study in Rural Environments (PASTURE) birth cohort including 793 children from rural regions of 5 European countries. Detailed information on children's health, nutrition, and farm-related exposures was gathered by using a pregnancy questionnaire, 2 questionnaires at 2 and 12 months of age, and a diary covering the time in between. RESULTS: Sensitization was more common at 12 months of age than at birth for almost all specificities. On an individual level, persistent sensitization to the same allergens was rare (1%), whereas transient (only at birth, 11%) and incident (only at 12 months, 34%) sensitization was seen in substantial proportions of children. Associations of transient sensitization with maternal sensitization differed with the allergen specificities, with the strongest associations for food allergens (odds ratio [OR], 10.6; 95% CI, 6.0-18.6) and the weakest associations for seasonal allergens (OR, 1.64; 95% CI, 0.94-2.86). Associations of maternal sensitization with incident sensitization were also seen. Incident sensitization was related to distinct prenatal and postnatal environmental exposures of mother and child, such as consumption of cereals for incident sensitization to seasonal allergens (OR, 0.66; 95% CI, 0.50-0.88). CONCLUSION: IgE sensitization patterns change between birth and 12 months and are related to maternal and environmental influences.

International audience; BACKGROUND: Early-life exposure to environmental microbial agents may be associated with development of wheezing and allergic diseases. OBJECTIVE: To assess the association of microbial exposure in rural homes with the risk of asthma, wheezing, atopic dermatitis and sensitization. METHODS: Birth cohorts of rural children (n = 1133), half from farmer families, were followed up from birth to 2 years of age by questionnaires in five European centres. Endotoxin and extracellular polysaccharides (EPS) of Penicillium and Aspergillus spp. were determined from living room floor and mother's mattress dust samples collected at 2 months of age. Specific IgE against 19 allergens was measured at 1 year of age. Discrete-time hazard models, generalized estimations equations (GEE) and logistic regression were used for statistical analyses. RESULTS: The incidence of asthma was inversely associated with the amount of dust (adjusted odds ratio (aOR) 0.73, 95% CI 0.58-0.93) and the loads (units/m(2)) of EPS (aOR 0.75, 95% CI 0.55-1.04) and endotoxin (aOR 0.79, 95% CI 0.60-1.05) in the mother's mattress. Similar associations were seen with wheezing and with living room floor dust. The microbial markers were highly correlated and their effects could not be clearly separated. The inverse associations were seen especially among non-farmers. The risk of sensitization to inhalant allergens increased with increasing endotoxin exposure from mattress dust. No associations were observed with concentrations (units/g) or with atopic dermatitis. CONCLUSION AND CLINICAL RELEVANCE: The amount and microbial content of house dust were inversely associated with asthma and wheezing, but due to high correlations between microbial agents and amount of dust, it was not possible to disentangle their individual effects. New ways to better measure and represent exposure to environmental microbes, including indexes of biodiversity, are needed especially among farmers.