Molecular Pneumology

Our department focuses on the immunopathogenesis of allergic bronchial asthma and immunological processes of bronchial carcinomas. A key objective here is to gain a better understanding of immunological processes in the lungs in order to develop new therapeutic approaches for these diseases.

Bronchial carcinoma

Bronchial carcinoma is one of the most common malignant tumors in humans. Despite improved treatment options, many patients still die from this disease. Our research group has therefore set itself the goal of analyzing the immunopathogenesis of bronchial carcinoma.

Lung cancer is one of the cancers with the highest mortality rate worldwide. In addition to smoking, specific genetic characteristics are also considered to be factors in its development. Treatment options include surgical removal of the tumor as well as chemotherapy and radiotherapy, which have a low treatment success rate and result in a 5-year survival rate of only 15%. Current studies are focusing on immunotherapies as a new breakthrough treatment option in oncology. Effector and cytotoxic T cells play an indispensable role in ensuring a successful anti-tumor immune response.

In recent years, our group has been working on the analysis of T cells that are present in the tumor microenvironment and influence the development and progression of lung carcinomas.

In most tumors, effector functions of tumor-infiltrating lymphocytes (TIL) are inhibited by various factors, such as the accumulation of immunosuppressive cells or the increased expression of inhibitory receptors, such as programmed cell death protein 1 (PD-1). PD-1 contributes to the functional impairment of T cell activation. Furthermore, inhibitory receptors are used by tumor cells to evade an immune response. For this reason, immunotherapies have been developed to reactivate effector immune cells by blocking so-called checkpoint receptors on immunoregulatory cells. In order to identify possible targets for immunotherapy, our group is investigating the influence of various genes and signaling pathways on tumor development and progression.

To this end, we are currently analyzing samples from more than 150 patients with non-small cell lung cancer (NSCLC) in collaboration with the Department of Thoracic Surgery. Tissue samples were taken from three different areas of the lung: the tumor region, the peri-tumoral region, which surrounds the tumor at a distance of 2 cm, and from a control area that is free of tumor cells. Histological sections are generated from these tissue samples, RNA and proteins are extracted and various cell types are isolated. Further investigations are carried out on peripheral blood mononuclear cells (PBMC). These processes are necessary to understand specific tumor characteristics and to develop new therapeutic strategies.

Furthermore, by using murine models for lung cancer, we want to investigate the role that deletion of various genes in certain cell types could play in the regulation of the immune response to lung cancer.

Bronchial asthma

Bronchial asthma is a widespread disease of the airways that can lead to chronic inflammatory reactions in the lungs. In addition to genetic and environmental factors, local activation of the mucosal immune system plays a central role in the development and perpetuation of the disease. Studies in recent years have shown that antigen-presenting cells, such as dendritic cells and T lymphocytes, are particularly important in the pathogenesis of asthma.

Our research group was recently able to show that pro-inflammatory cytokines and certain transcription factors in leukocytes play a decisive role in the immunopathogenesis of bronchial asthma. Studies were carried out on two experimental model systems of bronchial asthma: the OVA model and the HDM model. In the OVA model, variants for tolerogenic asthma were also developed. Studies in the OVA model showed a central role of the transcription factors GATA-3 and T-bet in allergic bronchial asthma. The functional importance of T-bet was further emphasized by the finding that T-bet-deficient mice spontaneously develop an asthma-like phenotype. This phenotype is mediated by the cytokine IL-13 and can be transmitted by adoptive transfer of T lymphocytes.

Recently, we have also discovered a therapeutic effect of the antiviral cytokines IL-28A, IL-28B and IL-29, known as interferon-λ, when applied intranasally in the experimental asthma model. The positive effects of recombinant IL-28A were associated with a reduction of Th2 and Th17 cells. We therefore analyzed IL-28 receptor-deficient mice in OVA models of allergic asthma. We found that IL-28 receptor-deficient mice showed increased asthma symptoms compared to wild-type mice. This included an increase in airway resistance, increased secretion of IgE and increased airway inflammation. We also discovered an increased proliferation of Th2 and Th1 cells in the lungs of IL-28 receptor-deficient mice in the asthma model. In IL-28 receptor deficiency, lung dendritic cells produced more pro-inflammatory cytokines such as IL-6 and less anti-inflammatory cytokines such as IFNγ, IL-12 and IL-10. These dendritic cells regulate the Th2 and Th17 immune response.

Further studies have also documented a role of IL-2 and the transcription factor NFATc2 in asthma. In particular, we showed that NFATc2 deficiency leads to an increased number of CD4+CD25+FoxP3+ regulatory T cells in the lung, resulting in induced immunosuppression in experimental asthma.

In the long term, it is hoped that innovative therapeutic strategies can be developed based on these new findings. Particular expectations are placed on the modulation of the pro-inflammatory Th2 and Th9 axis and the activation of protective immune responses.

Ongoing studies:

SynAir-G

The EU-funded SynAir-G stands for "Disrupting Noxious Synergies of Indoor Air Pollutants and their Impact in Childhood Health and Wellbeing, using Advanced Intelligent Multisensing and Green Interventions". Molecular Pneumology is part of an interdisciplinary team that includes researchers from France, Finland, the UK and Greece, among others.

AZCRA

The AZCRA study is investigating the role of cytokines, chemokines and their receptors in asthma patients and healthy volunteers.

AGENDAS

Investigation of genetic, age, gender and environmental factors that modify the immune response and influence the development of allergic asthma during the school years.

PreDicta

The PreDicta study is a collaboration between various European clinics and research laboratories, which is funded by the EU. In addition to our department, the Pediatric Clinic (Prof. Zimmermann) and the Institute of Microbiology (Prof. Bogdan) in Erlangen are also involved. The central hypothesis of the study is that repeated acute infections change the immune response in such a way that chronic inflammation is facilitated. The link between these infections and asthma is being investigated using the latest molecular biological, virological and cell biological methods. The focus is on investigating the interaction of infections with viruses that trigger colds and the disease bronchial asthma.