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Background Chronic immune diseases, such as asthma, are highly prevalent. Currently available pharmaceuticals improve symptoms but cannot cure the disease. This prompted demands for alternatives to pharmaceuticals, such as probiotics, for the prevention of allergic disease. However, clinical trials have produced inconsistent results. This is at least partly explained by the highly complex crosstalk among probiotic bacteria, the host's microbiota, and immune cells. The identification of a bioactive substance from probiotic bacteria could circumvent this difficulty. Objective We sought to identify and characterize a bioactive probiotic metabolite for potential prevention of allergic airway disease. Methods Probiotic supernatants were screened for their ability to concordantly decrease the constitutive CCL17 secretion of a human Hodgkin lymphoma cell line and prevent upregulation of costimulatory molecules of LPS-stimulated human dendritic cells. Results Supernatants from 13 of 37 tested probiotic strains showed immunoactivity. Bioassay-guided chromatographic fractionation of 2 supernatants according to polarity, followed by total ion chromatography and mass spectrometry, yielded C 11 H 12 N 2 O 2 as the molecular formula of a bioactive substance. Proton nuclear magnetic resonance and enantiomeric separation identified D-tryptophan. In contrast, L-tryptophan and 11 other D-amino acids were inactive. Feeding D-tryptophan to mice before experimental asthma induction increased numbers of lung and gut regulatory T cells, decreased lung T H 2 responses, and ameliorated allergic airway inflammation and hyperresponsiveness. Allergic airway inflammation reduced gut microbial diversity, which was increased by D-tryptophan. Conclusions D-tryptophan is a newly identified product from probiotic bacteria. Our findings support the concept that defined bacterial products can be exploited in novel preventative strategies for chronic immune diseases. [ABSTRACT FROM AUTHOR]

Background: It is currently discussed whether allergic sensitization may start in utero under the influence of the maternal immune system and environmental determinants. Objective: To investigate the relationship between allergen-specific cord blood (CB) IgE levels, parental sensitization, CB cytokine production, and environmental influences. Methods: As part of an ongoing multicenter birth cohort study, allergen-specific IgE antibodies against 20 common seasonal, perennial, and food allergens were measured in blood samples from 922 neonates, 922 mothers, and 835 fathers. Supernatants from stimulated CB cells were assessed for the production of IL-5, IFN-γ, IL-10, and TNF-α. Results: Allergen-specific IgE antibodies were detectable in 23.9% of newborns. Contamination with maternal serum was excluded by several means of analyses, including the absence of IgA antibodies. Clear correlation between maternal and fetal IgE was found only for hen''s egg, cow''s milk, and soybean allergen. Fetal IgE correlated negatively with the level of IFN-γ production, but not with IL-5 and IL-10. Conclusion: Allergen-specific IgE antibodies most probably of fetal origin are detectable in CB and correlate with a lowered CB IFN-γ production. [Copyright &y& Elsevier]

Background: Previous cross-sectional surveys have suggested that maternal exposure to animal sheds during pregnancy exerted a protective effect on atopic sensitization in children lasting until school age. Objective: We sought to evaluate the effects of maternal exposure to animal sheds and other farm-related exposures during pregnancy on cord blood IgE levels in a prospective birth cohort. Methods: Pregnant women living in rural areas in Austria, Finland, France, Germany, and Switzerland were recruited in the third trimester of pregnancy. Information on maternal farm-related exposures, nutrition, and health during pregnancy was obtained by means of interviews. Specific IgE levels for food and common inhalant allergens were assessed in cord blood of 922 children and peripheral blood samples of their mothers. Results: Different sensitization patterns in cord blood of farm and nonfarm children were observed. In multivariable analysis consumption of boiled, but not unboiled, farm milk during pregnancy was positively associated with specific IgE to cow''s milk independently from maternal IgE. In contrast, there was an inverse relationship between maternal exposure to animal sheds and cord blood IgE levels against seasonal allergens (adjusted odds ratio, 0.38; 95% CI, 0.21-0.70). This association was not confounded by maternal IgE levels. Maternal contact with hay enhanced the protective effect of exposure to animal sheds on IgE levels to grass pollen in cord blood. Conclusions: Maternal exposure during pregnancy influences atopic sensitization patterns in cord blood. The (microbial) context of allergen contact possibly modifies the risk of atopic sensitization. [Copyright &y& Elsevier]

Background: Altered intakes of n-3 and n-6 polyunsaturated fatty acids were suggested to modulate allergic disease, but intervention trials yielded inconclusive results. Because allergies are primed in early infancy and in utero, the fetus might be more accessible to nutritional intervention strategies. Objective: We sought to investigate how supplementation of pregnant women with a fish oil (FO) preparation modulates allergy-related immune parameters in mothers and offspring. Methods: We performed a multicenter, randomized, double-blind, placebo-controlled trial. Three hundred eleven pregnant women received daily either FO with 0.5 g of docosahexaenoic acid and 0.15 g of eicosapentaenoic acid, 400 μg of methyl-tetra-hydrofolic acid, both, or placebo from the 22nd gestational week. TH1/TH2-related molecules were quantified in 197 maternal and 195 cord blood samples by using real-time RT-PCR. Data are given as geometric means [95% CIs]. Results: FO supplementation was associated with increased TGF-β mRNA in maternal (0.85 [0.8-0.89]; placebo: 0.68 [0.64-0.72]) and cord blood (0.85 [0.81-0.9]; placebo: 0.75 [0.71-0.79]). IL-1 (0.69 [0.66-0.73]; placebo: 0.83 [0.79-0.88]) and IFN-γ (0.54 [0.51-0.57]; placebo: 0.65 [0.61-0.69]) were decreased in mothers only (P < .001). Cord blood mRNA levels of IL-4 (0.54 [0.52-0.57]; placebo: 0.64 [0.61-0.68]), IL-13 (0.61 [0.58-0.65]; placebo: 0.85 [0.80-0.89]), CCR4 (0.70 [0.67-0.73]; placebo: 0.88 [0.84-0.92]; all P < .001), and natural killer (P < .001) and CCR3+CD8+ T cells (P < .04) were decreased in the FO group. Conclusion: Supplementation with FO during pregnancy is associated with decreased mRNA levels of TH2-related molecules in the fetus and decreased maternal inflammatory cytokines. We speculate that both effects are mediated by TGF-β. [Copyright &y& Elsevier]

Background: Asthma is characterized by a TH2 immune response. CD4+CD25hi regulatory T cells (Tregs) have been proposed to prevent allergic diseases through suppression of TH2 responses. Objective: We sought to investigate the role of CD4+CD25hi T cells in children with asthma. Methods: CD4+CD25hi Tregs and forkhead/winged-helix transcription factor FOXP3 mRNA levels were quantified in peripheral blood and bronchoalveolar lavage fluid (BALF) of 18 children with asthma, 10 children with chronic cough, and 13 control subjects without lung diseases. CD4+CD25hi T cells were isolated from peripheral blood and BALF of asthmatic patients and control subjects, and their capacity to suppress proliferation and cytokine/chemokine production of autologous responder T cells was analyzed. Results: CD4+CD25hi T cells were decreased in BALF of asthmatic children compared with values in children with cough or control subjects. In children with asthma, inhaled corticosteroid treatment was associated with increased percentages of CD4+CD25hi T cells in peripheral blood and BALF. Isolated BALF and peripheral blood CD4+CD25hi T cells from nonasthmatic subjects suppressed proliferation and cytokine/chemokine production by CD4+CD25− responder T cells. BALF CD4+CD25hi T cells from asthmatic subjects failed to suppress proliferation and production of TH2-associated cytokines and chemokines by CD4+CD25− responder T cells, which was restored after use of inhaled corticosteroids. Conclusion: These findings provide the first evidence that pulmonary CD4+CD25hi Tregs are impaired in pediatric asthma. Clinical implications: Pulmonary Tregs might represent a therapeutic target in pediatric asthma. [Copyright &y& Elsevier]

Background: Pseudomonas aeruginosa infection determines the course of cystic fibrosis (CF) lung disease. Studies in human peripheral blood indicate that P aeruginosa infection is associated with a predominant TH2 immune response, whereas TH1 responses are accompanied by a better pulmonary outcome. Objective: Analyses of peripheral blood may not correspond directly with the local pulmonary immune response. Therefore, we asked whether the TH1/TH2 response is altered in bronchoalveolar lavage fluid from P aeruginosa–infected patients with CF. Methods: Bronchoalveolar lavage fluid was obtained from 12 patients with CF chronically infected with P aeruginosa, 11 noninfected patients with CF, and 8 healthy controls. Pulmonary CXCR3+ (TH1) and CCR4+ (TH2) expressing CD4+ and CD8+ lymphocytes were quantified by flow cytometry. Levels of TH1-associated (IL-2, IFN-γ, IFN-γ inducible T cell-α chemoattractant, Monokine induced by IFN-γ, IFN-γ inducible protein of 10 kd) and TH2-associated (IL-4, IL-5, IL-10, thymus and activation-regulated chemokine [TARC], macrophage-derived chemokine) cytokines and chemokines and a panel of proinflammatory molecules were quantified at the protein level. Chemokines mRNA levels were assessed by real time RT-PCR. Results: P aeruginosa–infected patients with CF had significantly higher levels of pulmonary CCR4+CD4+ (TH2) cells, IL-4, IL-13, and TARC and lower levels of IFN-γ compared with noninfected patients with CF and healthy controls. Bronchoalveolar lavage fluid levels of IL-4, IL-13, and TARC correlated inversely with FEV1 in P aeruginosa–infected patients with CF. Conclusion: These results reveal the prevalence of a pulmonary TH2 immune response in P aeruginosa–infected patients with CF. The modulation of the pulmonary TH2 response in P aeruginosa infection may be an option for the treatment of P aeruginosa lung disease in patients with CF. [Copyright &y& Elsevier]

Background: Cough is a frequent symptom in children, but the differentiation of asthmatic cough from cough of other origins can be difficult. Chemokines recruit T lymphocytes to inflamed tissues, and the corresponding chemokine receptors are differentially expressed on TH1 and TH2 cells. Objective: We sought to determine whether levels of TH1/TH2-related chemokines and their receptors differ in bronchoalveolar lavage fluid (BALF) from 12 children with allergic asthma, 15 nonatopic children with chronic cough, and 10 children without airway disease. Methods: The TH1-related (IFN-γ–inducible protein of 10 kd [IP-10], IFN-γ–inducible T cell α chemoattractant [ITAC], monokine induced by IFN-γ [Mig], and IFN-γ) and TH2-related (thymus- and activation-regulated chemokine [TARC], macrophage-derived chemokine [MDC], IL-5, and IL-4) chemokines and cytokines were quantified in BALF by ELISA and a particle-based multiplex array. Percentages of pulmonary lymphocytes expressing CXCR3+ and CCR5+ (TH1) and CCR4+ and CCR3+ (TH2) chemokine receptors were determined in BALF by flow cytometry. Results: Pulmonary CCR4+CD4+ cells and levels of TARC and MDC were significantly increased in asthmatic children versus children with chronic cough or without airway disease. In asthmatic children CCR4+CD4+ cells correlated positively with levels of TARC, MDC, and serum IgE levels and negatively with FEV1. In contrast, CXCR3+CD8+ cells and levels of ITAC were significantly increased in children with non-atopic chronic cough compared with the other groups. In children with chronic cough, CXCR3+CD8+ cells correlated with levels of ITAC and IFN-γ. Conclusion: Pulmonary CCR4+CD4+ and CXCR3+CD8+ cells and their ligands TARC, MDC, and ITAC clearly differentiate asthmatic children from nonatopic children with chronic cough. The analysis of these markers could facilitate the diagnostic discrimination of asthma versus other reasons for chronic cough in children. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

Background: Traditional farming represents a unique model situation to investigate the relationship of early-life farm-related exposure and allergy protection. Objectives: To investigate associations between maternal farm exposures and cytokine production in cord blood (CB) mononuclear cells in a prospective multinational birth cohort of 299 farm and 326 nonfarm children and their families. Methods: Supernatants from phorbol 12-myristate 13-acetate/ionomycin–stimulated CB mononuclear cells were assessed for the production of IFN-γ, TNF-α, IL-5, IL-10, and IL-12. Results: Significantly higher levels of IFN-γ and TNF-α in farm compared with nonfarm children were found, whereas IL-5, IL-10, and IL-12 levels did not differ between study groups. Maternal contact with different farm animal species and barns and consumption of farm-produced butter during pregnancy enhanced the production of proinflammatory CB cytokines, whereas maternal consumption of farm-produced yogurt resulted in significant lower levels of IFN-γ and TNF-α in umbilical blood. Conclusion: Maternal exposure to farming activities and farm dairy products during pregnancy modulated cytokine production patterns of offspring at birth. [Copyright &y& Elsevier]