Bronchial carcinoma
Bronchial carcinoma is one of the most common malignant tumors in humans. Despite improved therapy options, many patients still die from this disease. Therefore, our research group has set itself the goal of analyzing the immunopathogenesis of bronchial carcinoma.
Lung cancer is one of the most common cancers worldwide. Factors contributing to its development include smoking and specific genetic characteristics. Treatment options include surgical removal of the tumor, 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 involved in the analysis of T cells present in the tumor microenvironment that 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 accumulation of immunosuppressive cells or 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 of immunotherapy, our group is investigating the influence of different genes and signaling pathways on tumorigenesis and development.
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 surrounding the tumor at a distance of 2 cm, and a control area 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 performed on peripheral blood mononuclear cells (PBMC). These procedures are necessary to understand specific tumor characteristics and to develop new therapeutic strategies.
Furthermore, using murine models of lung cancer by deleting different genes in specific cell types, we want to investigate what role these might play in the regulation of the immune response to lung cancer.
Current projects include the following:
- Role of STAT5 in NSCLC
- Role of PU.1 in NSCLC
- Role of glucose in the initiation and development of NSCLC
- Role of Blimp-1 in NSCLC
Asthma bronchiale
Asthma bronchiale is a worldwide spread disease of the airways, which causes chronic inflammation in the lung. Besides genetic and environmental factors a local activation of the mucosal immune system plays a central role in the origin and perpetuation of the disease. Studies in the past have shown that here especially antigen presenting cells like dendritic cells and T-lymphocytes are involved in the pathogenesis of allergic asthma.
Our group previously showed that proinflammatory cytokines and certain transcription factors in leukocytes are involved in the immuno pathogenesis of asthma bronchiale. Here we investigated in two experimental model systems for asthma: The OVA-model and the HDM-model.
Moreover,we developed a model for tolerogenic asthma. Experiments in the OVA-model showed a central role of the transcription factors GATA-3 and T-bet in allergic asthma. The functional importance of T-bet was highlighted by the findings, that T-bet deficient mice develop a spontaneous Asthma-like phenotype. This phenotype is mediated via IL-13 and can be transfered by T-cells.
Further, we recently discovered a therapeutic effect of intranasal application of the antiviral cytokines IL-28A, IL-28B and IL-29 that are known as IFN lambda. The positive effect of recombinant IL-28A was associated with a reduction of Th2- and Th17-cells in the lung. In addition, IL-28-Receptor deficient mice in our OVA-model of asthma show more severe asthma symptoms than wild type mice. IL-28 receptor deficiency lead to a higher pro-inflammatory cytokine production like IL-6 and less anti-inflammatory cytokines like IFNγ, IL-12 and IL-10 by lung dendritic cells. These dendritic cells regulate the Th2- and Th17 immune response.
In further studies a role of IL-2 and the transcription factor NFATc2 in asthma was analyzed. Specifically we showed that NFATc2 deficiency leads to an enhanced number of CD4+CD25+Foxp3+ regulatory T-cells, which induces immunosuppression in asthma.
Long-term we anticipate, that new therapy strategies can be developed based on these new findings. Particular expectations lie on the modulation of the pro-inflammatory Th2 and Th9 axis and their regulation after activation of protective immune responses.
The role of the transcription factor NFATc in allergic asthma
The family of nuclear factor of activated T cells (NFAT) transcription factors is essentially needed for the regulation of the early transcription of TCR mediated Signals in lymphocytes. The calcium regulating members of the NFAT family (NFATc1, NFATc2 and NFATc3) are found on different Th-cell subtypes like Th2- or Th17-cells. NFATs cooperate with other factors and play a central role in the induction of different genes, which are involved in the immune response to antigens. We want to investigate the function of NFATc1 in T-cells in allergic asthma closer, because Th2 immune responses, which are characterized by IL-4, IL-5 and IL-13 production, are associated with inflammatory diseases like asthma and allergies.
Responsible: Zuqin Yang
The role of Rantes and its receptors in asthma bronchiale
In this project (IZKF Project A82: Understanding the role of Regulated on Activation, Normal T cell Expressed and Secreted (RANTES) in the resolution of allergic asthma) the role of Rantes in allergic asthma is investigated in murine models and human asthma cohorts. Rantes is a chemokine which is ligand of different receptors like CCR5 and CCR3. It is produced by activated T-cells and can attract different inflammatory cells by binding to its receptors. We found a lack of inflammatory eosinophils during asthma in CCR3 deficient mice, which also secrete less IL-5 and IgE in the lung and in serum, respectively. The role of these receptors and their ligands in asthma remains unclear and thus is under further investigations in this project.
Responsible: Susanne Krammer
Further Projects:
- The role of interferons in rhinovirus infections and asthma bronchiale (Hannah Mitländer)
- The role of vitamin D for the immune system in asthma bronchiale (Janina Grund)
Cooperations
Asthma, rhinovirus and bacteria induced asthma
Allergic asthma is a chronic inflammatory disease of the airways with high prevalence in children that affects about 10% of the population in the US and Europe.
It has been recently established that rhinovirus and gram negative bacteria are the main cause of asthma exacerbation especially in children. Thus, beside cytokines, a better understanding of the interferon pathway is relevant for understanding the pathogenesis of asthma. Specifically, the role of the interferon type I and the newly described interferon type III (interferon lambda/IL-28) family are still poorly understood in this disease. The present project aims at the visual characterization of allergen, rhinovirus and gram negative and gram positive bacteria encounter with the host cells and the subsequent regulation of interferon type I (interferon alpha and beta) as well as interferon lambda (IL-28) pathway in human and experimental murine models of asthma.
In the last 6 years our group has set up, with the help of many highly dedicated medical and PhD students and technicians, the scientific background of collaborations in Germany and in the world that would enable us to progress into a better understanding of these pathways especially in pediatric asthma.
Specifically, for a better understanding the immunological responses to rhinovirus we would not have been able to initiate this field of investigation without the help of Prof. Nikos Papadopoulos, who provided us with the rhinovirus and the background knowledge that allowed our studies to develop. Prof. Nikos Papadopoulos joined the University of Manchester in early 2014. He is also Professor of Allergy and Pediatric Allergy at the University of Athens, and immediate Past President of the European Academy of Allergy and Clinical Immunology (EAACI, www.eaaci.org). His main research focus is the role of infections in respiratory (asthma, rhinitis), as well as food allergy, with extensive collaborations in the context of EU Projects, such as EARIP, iFAAM, FAST and PreDicta. He has published more than 200 papers (h-index: >40), has received a number of international awards and is invited to speak at international scientific meetings some 30 times a year. He has served in committees of EAACI, GA2LEN, WAO, EFA and ARIA.
Moreover, we are thankful to the continued collaboration with Prof. Tytti Vuorinen, who has and is analyzing the respiratory viruses in the airways of our cohorts of children. She is head of the Institute of Virology and Microbiology at the University of Turku. The Institute of Virology has had research focus on respiratory viral infections over 3 decades. During the last decade rhinovirus has been one of her main interests.
The understanding of gene regulation upon allergen, virus and bacteria encounter would not be possible without a personalized medicine approach in which the response of the host to infectious agents or allergens can be translated into personal host gene regulation. To this understanding has been and is a great help the gene array analysis performed at the laboratory directed by Prof. Scott T. Weiss. He is in fact the Scientific Director of Partners HealthCare Personalized Medicine where he supervises a faculty of 6 and a staff of over 100 who are dedicated to translating the results of human genome research into clinical medical practice. His laboratory has close working relationships with the Department of Environmental Health at the Harvard School of Public Health, where he is a Professor of Environmental Health (Respiratory Biology Program), the Biostatistics Department at HSPH, the Pulmonary and Critical Care Division, and the Immunology Division, Department of Medicine, in Brigham and Women’s Hospital. This background research would also receive a major development at the molecular level by the recently established collaboration with Prof. Vahid Sandoghdar, Director and Scientific Member at the Max Planck Institute for the Science of Light in Erlangen since 2012.
Funding IZKF
Project-No. A59
Applicant: Prof. Dr. Dr. Susetta Finotto
DFG
"Immunoregulatory role of lambda-interferons in allergic asthma"
2010-2013
Applicant: Prof. Dr. Dr. Susetta Finotto
Bayerisches Staatsministerium für Wissenschaft, Forschung und Kunst
Förderprogramm für neuberufene Professorinnen
2010
Applicant: Prof. Dr. Dr. Susetta Finotto
European Grant
"Post-infections immune reprogramming and its association with persistence and chronicity of respiratory allergic disease"
2010-2015
Applicant: Prof. Dr. Dr. Susetta Finotto
PhD-Student: Anna Graser
Collaborations: Kinderklinik, Pädiatrische Pneumologie and Allergologie, Universitätsklinikum Erlangen Mikrobiologisches Institut, Universitätsklinikum Erlangen
SFB643 - Teilprojekt B12
"Die immunregulatorische Rolle des Transkriptionsfaktors NFAT bei Entzündungsvorgängen in den Atemwegen sowie bei Lungenkrebs"
2013-2016
Applicant: Prof. Dr. Dr. Susetta Finotto
Graduiertenkolleg 1660 Schlüsselsignale der Adaptiven Immunantwort
"Rolle von BATF bei der Generierung von Effektor- und regulatorischer T-Zell-Antworten bei Asthma bronchiale"
2010-2015
Applicant: Prof. Dr. Dr. Susetta Finotto
PhD-Student: Nina Sopel
Courses
- "Current Principles of the infectionsimmunology and their applications in the medicine including example cases" Voluntary seminar for bachelor students of the molecular medicine in the module "Immunology" (practical course)
BSc molecular medicine module immunology - Masterstudents: module 'Microbiology, Immunology and virology': Seminar Immunology
MSc moleculare medicine - Seminars of Cellbiology, Tuesday at 10 - 11 am
- Seminars of molecular Medicine , Wednesday at 12 am - 1 pm
