As an important prerequisite for new development approaches in translational allergy prevention and individualized asthma therapy, we focus our research on elucidating the underlying immunological mechanisms of atopic diseases such as atopic dermatitis, hay fever and allergic asthma. We pay particular attention to the early development and persistence of allergy and tolerance.

Almost one in four children between the ages of 0 and 17 in Germany is diagnosed with a medically confirmed atopic disease such as atopic dermatitis, hay fever or allergic asthma. Atopic diseases usually develop in early childhood. The maturation of the child's immune system in the first years of life is a critical phase for the development of an effective, specific immune defense and the simultaneous development of tolerance to harmless components of the environment, such as allergens. Underdevelopment can lead to sensitization and the development of allergies and asthma.

 

Clinical research:

Our research group is part of a research cooperation within the German Center for Lung Research (DZL), which aims to investigate different asthma endotypes and their pathobiological basis, as well as to find predictive biomarkers for the course of the disease. As part of the ALL AGE ASTHMA COHORT (ALLIANCE), children and adults from the age of 6 months with asthma and obstructive bronchitis (children < 6 years) are recruited and followed up in the long term. During regular visits to the study center, extensive examinations of lung function and airway inflammation are carried out and the extent to which they are sensitized to certain allergens is tested. In addition to biomaterials (e.g. blood, microbial samples, respiratory secretions), data on symptoms, disease progression, living conditions and environmental factors are collected.

Various molecular biological analysis methods ("deep phenotyping") will be used to elucidate the mechanisms of the various disease progressions.

In addition, biomarkers are to be identified that will help to recognize the respective subtype of the disease as early as possible in the future and to better tailor treatment to the individual patient.

In addition to asthma, the working group is also working on understanding the pathogenesis of allergies and tolerance to both in order to find new therapeutic approaches for prevention and treatment. As a participant in the scientific program TITUS "The First Thousand Days of Life" of the Else Kröner-Fresenius Research College, young physicians in our working group focus on the perinatal imprint of asthma and allergies in order to find preventive approaches for today's children and thus for tomorrow's society.

 

Basic research

Allergic diseases such as bronchial asthma, food allergy and atopic dermatitis and the exact underlying molecular/immunological mechanisms in the early development of allergy and tolerance are still poorly understood, but represent an important prerequisite for new development approaches in translational allergy prevention.

Under the hypothesis that the development of tolerance between different atopic diseases is controlled by common mechanisms, the identification of which may lead to new preventive strategies, early immunological mechanisms and key factors will be identified and functionally analyzed using an experimental tolerance model. As a member of CHAMP (CHildhood Allergyand tolerance: bioMarkersand Predictors) consortium, the working group, together with cooperation partners, is making a significant contribution to identifying and characterizing these immunological mechanisms and factors that underlie these allergic diseases. As part of these studies, the influence of microbial components on transmaternal allergy prevention is also analyzed.

Special attention will be paid to the functional role of the inflammasome NLRP3 in perinatal tolerance development. This multiprotein complex of the innate immune system, which controls the activation of inflammatory reactions, was found to be differentially regulated in umbilical cord blood in initial studies by a CHAMP cooperation partner (AG Schaub, Munich) in newborns with an increased risk of allergy. Furthermore, the project will be used as a platform to analyze new targets of tolerance development, which were identified in the clinical studies of the consortium for children, in the experimental allergy model and to understand the mechanisms at the cellular level. Conversely, identified tolerance signatures will be tested in human biomaterials of the CHAMP cohorts.

Another important focus of the working group is on factors that have a regulatory effect on the development and persistence of the T2 inflammation typical of allergic asthma. Research projects here are concerned with the role of regulatory B cells, the immunomodulatory properties of TLR agonists (such as resiquimod), and the importance of IL-17 for the activation and migration of myeloid antigen-presenting cells in the early phase of asthma development and its persistence.

The immunophenotyping of cells and tissues is a particular area of expertise in the working group. The data generated by various methods (cell and tissue chip cytometry) are used to develop bioinformatic multidimensional analysis methods in collaboration with the bioinformatics working group within the DZL and the MHH and to characterize cells and tissues in depth.

Respiratory syncytial virus infections in early childhood

Respiratory syncytial virus (RSV) infection is the most common cause of lower respiratory tract infections in young children and is responsible for significant morbidity and mortality in this age group. The course of primary RSV infection is highly variable. Vaccines and antiviral drugs are not available. Globally, the most severe cases of RSV in young children cause more than three million hospitalizations and 59,600 deaths annually. The factors that cause severe primary infections in young children are poorly defined.

In a collaboration with Prof. Pietschmann's group (Twincore ), our group was able to detect 346 polymorphisms (SNPs) associated with severe RSV infection in a cohort of 160 children under 2 years of age using exome sequencing (patent application, Hansen, Wetzke, Pietschmann EP17195522.2). Following on from this project, the working group is working as a cooperation partner of the INDIRA joint project to identify further genetic markers and biomarkers for the prognosis of severe RSV infections and to elucidate their role in the course of infection using multi-dimensional OMICs data and machine learning methods. These newly identified biomarkers will be validated in virological, immunological and cell biological experiments. In addition, the research group is using organoid cultures grown from selected donor materials to investigate the consequences of RSV infection at the single-cell level using state-of-the-art techniques. Finally, as part of the Cluster of Excellence RESIST, a replica cohort will be established to verify the biomarkers already identified and to extend the discovery of new genetic markers to the entire human genome. In this way, the working group is working to elucidate the determinants of severe RSV infection and to use this knowledge to develop diagnostics for personalized prophylaxis of the most susceptible children.

 

 

Community-acquired pneumonia

Pediatric community-acquired pneumonia(pedCAP) is one of the leading infectious diseases in Central Europe. The estimated incidence of pneumonia requiring hospitalization in children up to five years of age is up to 90 cases/1,000 children. Despite the epidemiological relevance of the disease, there are no current data on the etiology of pedCAP in Germany.

In cooperation with the CAPNETZ FOUNDATION, whose CAPNETZ cohort is one of the largest and best characterized adult pneumonia cohorts in the world, our group is working on the joint project pedCAPNETZ. The aim of this project is to establish and scientifically evaluate a comparable national cohort for community-acquired pneumonia in children and adolescents. For this purpose, a multicenter recruitment is being carried out to obtain a comprehensive data set of clinical parameters and biomaterials. This will be comprehensively characterized clinically and molecularly. Our scientific work focuses on capturing all relevant aspects of CAP in childhood. These range from epidemiology to risk stratification (biomarkers, clinical score), pathogen distribution, pathogen resistance, therapy management and prevention through to healthcare research with the aim of improving the quality of care for children with community-acquired pneumonia.

 

Pulmonary alveolar proteinosis (PAP) is a group of heterogeneous, life-threatening diseases of the lungs in which there is a massive accumulation of surfactant, a surface-active substance, in the alveoli. The hereditary form of PAP (herPAP) is caused by a gene mutation (CSF2RA or CSF2RB) in the α or β subunit of the receptor for granulocyte-macrophage colony-stimulating factor (GM-CSF). The resulting disruption of GM-CSF-dependent maturation and function of alveolar macrophages leads to an accumulation of surfactant material in the alveoli and consecutively to a disruption of gas exchange, which often leads to life-threatening respiratory insufficiency and sometimes early death in childhood. Symptoms of herPAP often appear at preschool age, with affected children suffering from progressive dyspnea, coughing, lung infections and failure to thrive. The only effective treatment to date is repeated whole-lung lavage under general anesthesia, a symptomatic and highly invasive procedure.

In the search for new therapeutic approaches, the research group investigated the suitability of organotropic transplantation of myeloid progenitor cells. In the mouse model, intrapulmonary transplantation of macrophage precursors led to selective, long-term pulmonary growth and differentiation into functional alveolar macrophages. A single transplantation resulted in an improvement in herPAP phenotype for at least 9 months as well as significantly reduced alveolar proteinosis, normalized lung densities on chest computed tomography and improved lung function. This significant and sustained improvement in disease symptoms was also observed after intrapulmonary transplantation of human macrophage precursors in a mouse model. The therapeutic effect was mediated by long-lived, lung-resident macrophages that showed functional and phenotypic characteristics of primary human alveolar macrophages. These promising results from the animal model suggest that pulmonary transplantation of macrophage precursors could be an effective and long-lasting therapy for children and adults with herPAP and could greatly improve their quality of life and life expectancy.

Together with cooperation partners, this new therapeutic approach is to be brought into the Clinical Department. A phase I study of intrapulmonary cell therapy for herPAP is currently being prepared under the direction of Prof. Bruce Trapnell, Cincinnati, in cooperation with the applicants, in which the MHH is the only European partner and thus the future European site for the planned phase I study.