Dietrich Reinhardt

Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease

Interleukin-8 (IL-8) activates neutrophils via the chemokine receptors CXCR1 and CXCR2. However, the airways of individuals with cystic fibrosis are frequently colonized by bacterial pathogens, despite the presence of large numbers of neutrophils and IL-8. Here we show that IL-8 promotes bacterial killing by neutrophils through CXCR1 but not CXCR2. Unopposed proteolytic activity in the airways of individuals with cystic fibrosis cleaved CXCR1 on neutrophils and disabled their bacterial-killing capacity. These effects were protease concentration–dependent and also occurred to a lesser extent in individuals with chronic obstructive pulmonary disease. Receptor cleavage induced the release of glycosylated CXCR1 fragments that were capable of stimulating IL-8 production in bronchial epithelial cells via Toll-like receptor 2. In vivo inhibition of proteases by inhalation of α1-antitrypsin restored CXCR1 expression and improved bacterial killing in individuals with cystic fibrosis. The cleavage of CXCR1, the functional consequences of its cleavage, and the identification of soluble CXCR1 fragments that behave as bioactive components represent a new pathophysiologic mechanism in cystic fibrosis and other chronic lung diseases.

Traffic-related air pollution and respiratory health during the first 2 yrs of life

As part of an international collaborative study on the impact of Traffic-Related Air Pollution on Childhood Asthma (TRAPCA), the health effects associated with long-term exposure to particles with a 50% cut-off aerodynamic diameter of 2.5 µm (PM2.5), PM2.5 absorbance, and nitrogen dioxide (NO2) were analysed. The German part of the TRAPCA study used data from subpopulations of two ongoing birth cohort studies (German Infant Nutrition Intervention Programme (GINI) and Influences of Lifestyle Related Factors on the Human Immune System and Development of Allergies in Children (LISA)) based in the city of Munich. Geographic information systems (GIS)-based exposure modelling was used to estimate traffic-related air pollutants at the birth addresses of 1,756 infants. Logistic regression was used to analyse possible health effects and potential confounding factors were adjusted for. The ranges in estimated exposures to PM2.5, PM2.5 absorbance, and NO2 were 11.9–21.9 µg·m−3, 1.38–4.39×10−5 m−1, and 19.5–66.9 µg·m3, respectively. Significant associations between these pollutants and cough without infection (odds ratio (OR) (95% confidence interval (CI)): 1.34 (1.11–1.61), 1.32 (1.10–1.59), and 1.40 (1.12–1.75), respectively) and dry cough at night (OR (95% CI): 1.31 (1.07–1.60), 1.27 (1.04–1.55), and 1.36 (1.07–1.74), respectively) in the first year of life were found. In the second year of life, these effects were attenuated. There was some indication of an association between traffic-related air pollution and symptoms of cough. Due to the very young age of the infants, it was too early to draw definitive conclusions from this for the development of asthma.

Preventive effect of hydrolyzed infant formulas persists until age 6 years: Long-term results from the German Infant Nutritional Intervention Study (GINI)

BACKGROUND The long-term effect of nutritional intervention with hydrolyzed infant formulas on allergy development has not been sufficiently evaluated. OBJECTIVE We performed a follow-up of the German Infant Nutritional Intervention study until 6 years of life to investigate the long-term allergy-preventive effect of 3 hydrolyzed infant formulas compared with cows milk formula (CMF) in a randomized, double-blind trial. METHODS Between 1995 and 1998, 2252 newborns with atopic heredity were randomly assigned at birth to receive one of 4 blinded formulas: partially or extensively hydrolyzed whey formula, extensively hydrolyzed casein formula, or CMF as milk substitute for the first 4 months when breast-feeding was insufficient. The cohort was followed from birth until 6 years of age with yearly questionnaires. Outcomes were physician-diagnosed allergic diseases (atopic dermatitis, food allergy, allergic urticaria, asthma, and hay fever/allergic rhinitis). Log-binomial regression modeled with generalized estimation equations was used for the statistical analysis. RESULTS In the intent-to-treat analysis the relative risk of a physicians diagnosis of allergic manifestation (AM) compared with CMF was 0.82 (95% CI, 0.70-0.96) for partially hydrolyzed whey formula, 0.90 (95% CI, 0.78-1.04) for extensively hydrolyzed whey formula, and 0.80 (95% CI, 0.69-0.93) for extensively hydrolyzed casein formula. The corresponding figures for atopic eczema were 0.79 (95% CI, 0.64-0.97), 0.92 (95% CI, 0.76-1.11), and 0.71 (95% CI, 0.58-0.88), respectively. In the per-protocol analysis all effects were stronger and significant. No significant effect on other AMs was found. CONCLUSION The data confirm a long-term allergy-preventive effect of hydrolyzed infant formulas on AM and atopic eczema until 6 years of age.

Respiratory health and individual estimated exposure to traffic-related air pollutants in a cohort of young children

Objectives: To estimate long-term exposure to traffic-related air pollutants on an individual basis and to assess adverse health effects using a combination of air pollution measurement data, data from geographical information systems (GIS) and questionnaire data. Methods: 40 measurement sites in the city of Munich, Germany were selected at which to collect particulate matter with a 50% cut-off aerodynamic diameter of 2.5 µm (PM2.5) and to measure PM2.5 absorbance and nitrogen dioxide (NO2). A pool of GIS variables (information about street length, household and population density and land use) was collected for the Munich metropolitan area and was used in multiple linear regression models to predict traffic-related air pollutants. These models were also applied to the birth addresses of two birth cohorts (German Infant Nutritional Intervention Study (GINI) and Influence of Life-style factors on the development of the Immune System and Allergies in East and West Germany (LISA)) in the Munich metropolitan area. Associations between air pollution concentrations at birth address and 1-year and 2-year incidences of respiratory symptoms were analysed. Results: The following means for the estimated exposures to PM2.5, PM2.5 absorbance and NO2 were obtained: 12.8 μg/m3, 1.7×10−5 m−1 and 35.3 μg/m3, respectively. Adjusted odds ratios (ORs) for wheezing, cough without infection, dry cough at night, bronchial asthma, bronchitis and respiratory infections indicated positive associations with traffic-related air pollutants. After controlling for individual confounders, significant associations were found between the pollutant PM2.5 and sneezing, runny/stuffed nose during the first year of life (OR 1.16, 95% confidence interval 1.01 to 1.34) Similar effects were observed for the second year of life. These findings are similar to those from our previous analysis that were restricted to a subcohort in Munich city. The extended study also showed significant effects for sneezing, running/stuffed nose. Additionally, significant associations were found between NO2 and dry cough at night (or bronchitis) during the first year of life. The variable “living close to major roads” (<50 m), which was not analysed for the previous inner city cohort with birth addresses in the city of Munich, turned out to increase the risk of wheezing and asthmatic/spastic/obstructive bronchitis. Conclusions: Effects on asthma and hay fever are subject to confirmation at older ages, when these outcomes can be more validly assessed.

The IL-1 Family Member 7b Translocates to the Nucleus and Down-Regulates Proinflammatory Cytokines

The IL-1 family member 7b (IL-1F7b) is a novel homolog of the IL-1 cytokine family discovered by computational cloning. We have reported that IL-1F7b shares critical amino acid residues with IL-18 and binds the IL-18-binding protein; in doing so, IL-1F7b augments the inhibition of IFN-γ by the IL-18-binding protein. IL-1F7b also binds IL-18Rα but neither induces signal nor acts as a receptor antagonist. Hence, the function of IL-1F7b remains unknown. In the present study, we analyzed the intracellular expression pattern of IL-1F7b. Using two variants of GFP fusion constructs of human IL-1F7b stably expressed in RAW macrophages, only the postcleavage mature form of the IL-1F7b precursor—but not the N-terminal propiece—specifically translocates to the nucleus following LPS stimulation. IL-1F7b, like IL-1β, IL-18, and IL-33, is processed by caspase-1 to generate the mature cytokines. Therefore, we tested whether caspase-1-mediated cleavage of the IL-1F7b precursor is required for mature IL-1F7b to translocate actively into the nucleus. Indeed, a specific caspase-1 inhibitor markedly reduced nuclear entry of IL-1F7b. In stable transfectants of human IL-1F7b in RAW macrophages stimulated with LPS, levels of TNF-α, IL-1α, IL-6, as well as the chemokine MIP-2, were substantially reduced (72–98%) compared with LPS-stimulated cells transfected with the empty plasmid. These results demonstrate that IL-1F7b translocates to the nucleus after caspase-1 processing and may act as a transcriptional modulator reducing the production of LPS-stimulated proinflammatory cytokines, consistent with IL-1F7b being an anti-inflammatory member of the IL-1 family.

Effect of exclusive breast‐feeding and early solid food avoidance on the incidence of atopic dermatitis in high‐risk infants at 1 year of age

The aim of this study was to assess the preventive effect of exclusive breast‐feeding and early solid food avoidance on atopic dermatitis (AD) in infancy. This study is part of a dietary clinical trial in a prospective cohort of healthy term newborns at risk of atopy. It was recommended to breast‐feed for at least 4 months and to avoid solid food in the same time‐period. Eight hundred and sixty‐five infants exclusively breast‐fed, and 256 infants partially or exclusively formula‐fed, were followed‐up until the end of the first year following birth. AD and sensitization to milk and egg were considered as study end‐points. The 1‐year incidence of AD was compared between the two study groups. Adjusted odds ratios (OR) with 95% confidence intervals (CI) were calculated by multiple logistic regression. The incidence of AD was calculated in relation to age at introduction of solid food and amount of food given. In the breast‐fed group, the adjusted OR for AD was 0.47 (95% CI 0.30–0.74). The strongest risk factor was the occurrence of AD in the subjects core family. The risk of infants with AD to be sensitized to milk was four times higher, and to egg eight times higher, than in infants without AD. Age at first introduction of solid food and diversity of solid food showed no effect on AD incidence. We conclude that in infants at atopic risk, exclusive breast‐feeding for at least 4 months is effective in preventing AD in the first year of life.

Pulmonary complications after bone marrow transplantation in children: Twenty-four years of experience in a single pediatric center

In children, pulmonary sequelae contribute to early and late morbidity after bone marrow transplantation (BMT). Between 1975–1999, we performed 152 BMTs in 138 pediatric patients with malignant and nonmalignant diseases. Allogenic bone marrow was used from 99 HLA identical siblings and from 23 other related or unrelated donors. Autologous marrow was used in 30 transplantations. Median age was 8.6 years (range, 1.1–22.4) at time of BMT. The median survival was 42%, the survival time was 6.5 years (range, 0.8–23.1), and the median follow‐up time was 6.8 years (range, 0.8–23.2).

Impact of early feeding on childhood eczema: development after nutritional intervention compared with the natural course – the GINIplus study up to the age of 6 years

Background Nutritional intervention with hydrolysed infant formulas has been shown efficacious in preventing eczema in children predisposed to allergy. However, this preventive effect has never been related to the natural course of eczema in children with or without a family history of allergy. The aim of this study therefore was to compare the course of eczema in predisposed children after nutritional intervention to the natural course of eczema.

Allergies in high-risk schoolchildren after early intervention with cow's milk protein hydrolysates: 10-year results from the German Infant Nutritional Intervention (GINI) study

BACKGROUND The long-term effect of nutritional intervention with hydrolysate infant formulas on allergic manifestations in high-risk children is uncertain. OBJECTIVE We sought to investigate the effect of hydrolysate infant formulas on allergic phenotypes in children with family history of allergies at school age. METHODS We analyzed data from participants of the prospective German Infant Nutritional Intervention study after 10 years of follow-up. At birth, children were randomly assigned to receive, for the first 4 months, one of 4 blinded formulas as breast milk substitute, if necessary: partially hydrolyzed whey formula (pHF-W), extensively hydrolyzed whey formula (eHF-W), extensively hydrolyzed casein formula (eHF-C), or standard cows milk formula. Outcomes were parent-reported, physician-diagnosed allergic diseases. Log-binomial regression models were used for statistical analysis. RESULTS The relative risk for the cumulative incidence of any allergic disease in the intention-to-treat analysis (n = 2252) was 0.87 (95% CI, 0.77-0.99) for pHF-W, 0.94 (95% CI, 0.83-1.07) for eHF-W, and 0.83 (95% CI, 0.72-0.95) for eHF-C compared with standard cows milk formula. The corresponding figures for atopic eczema/dermatits (AD) were 0.82 (95% CI, 0.68-1.00), 0.91 (95% CI, 0.76-1.10), and 0.72 (95% CI, 0.58-0.88), respectively. In the per-protocol analysis (n = 988) effects were stronger. The period prevalence of AD at 7 to 10 years was significantly reduced with eHF-C in this analysis, but there was no preventive effect on asthma or allergic rhinitis. CONCLUSION The significant preventive effect on the cumulative incidence of allergic diseases, particularly AD, with pHF-W and eHF-C persisted until 10 years without rebound, whereas eHF-W showed no significant risk reduction. There is insufficient evidence of ongoing preventive activity at 7 to 10 years of age.

Gene delivery to respiratory epithelial cells by magnetofection.

For the topical application of DNA vector complexes to the airways, specific extracellular barriers play a major role. In particular, short contact time of complexes with the cell surface caused by the mucociliary clearance hinders cellular uptake of complexes. The aim of this study was to evaluate the ability of magnetofection, a technique based on the principle of magnetic drug targeting, to overcome these barriers in comparison with conventional nonviral gene transfer methods such as lipofection and polyfection.