Our immune system protects us from infections and cancer by distinguishing between ‘self’ and ‘non-self’. However, if misdirected, the activation of immune cells can result in damage to organs, and can lead to autoimmune diseases, allergies, and chronic inflammation. Despite our comprehensive knowledge of how our immune system works, many questions remain unanswered. The work of the Research Center for Infection, Inflammation, and Immunity (RCi3) is helping to improve our understanding of the immune system and to develop new treatment options.
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These questions concern us:
• How does the immune system recognize pathogens and cancer cells, and how does it fight them?
• What is the role of our microbiome – the naturally-occurring microorganisms which live in and on our body surfaces – and how does it affect our health?
• Where do new viruses and bacteria come from?
• When the body turns ‘foreign’: how does autoimmunity and inflammation work?
• ‘What comes up must come down’: What regulates immune response and inflammation, and how?
• How do we develop immunological memory?
• In what way does the immune system contribute to normal organ function and tissue repair?
Title image: © Prof. Dr. Andreas C. Hocke.
Who we are: Research Center for Infection, Inflammation, and Immunity – RCi3
The departments and institutes which specialize in the areas of infection, inflammation and immunity have joined forces under the auspices of the RCi3 Research Center, thus combining the strength and expertise of immunology-focused researchers from across Charité - Universitätsmedizin Berlin. The RCi3 represents a network of researchers and clinicians involved in interdisciplinary, basic and applied immunology research. Berlin’s wider immunology research community is known for its close collaborative links and its synergistic and cross-institutional focus. Its members include researchers from Charité, Freie Universität and Humboldt Universität, as well as non-University research organizations, such as the German Rheumatism Research Center (DRFZ) of the Leibniz Association, the Max-Delbrück Center for Molecular Medicine, the Max Planck Institute for Infection Biology, and the Robert Koch Institute. Endeavors in the area of inflammation research have led to the establishment of the Leibniz ScienceCampus Berlin C3ID (Comprehensive Center for Chronic Inflammatory Diseases), which includes research groups from Charité, the DRFZ, and the Max Planck Institute for Infection Biology.
We have set ourselves the following targets:
• To create the necessary conditions and infrastructure to produce excellent immunology research
• To promote early-career researchers
• To bring about the integration of basic and translational research in both preclinical and clinical settings
The RCi3 comprises a range of Charité-based institutes and clinical facilities:
• Department of Dermatology, Venereology and Allergology
• Institute of Immunology
• Medical Department, Division of Gastroenterology, Infectiology and Rheumatology
• Institute of Medical Immunology
• Institute of Microbiology and Hygiene
• Medical Department, Division of Hematology, Oncology and Tumor Immunology
• Medical Department, Division of Infectiology and Pneumonology
• Department of Pediatrics, Division of Pneumonology and Immunology
• Medical Department, Division of Rheumatology and Clinical Immunology
• Institute for Tropical Medicine and International Health
• Institute of Virology
• SFB-TR36: Principles and Applications of Adoptive T Cell Therapy
• SFB-TR84: Innate Immunity of the Lung
• TRR130: B cells: Immunity and Autoimmunity
• DFG Priority Programme 1596: Ecology and Species Barriers in Emerging Viral Diseases
• DFG Priority Programme 1937: Innate Lymphoid Cells
• CAPNetz/PROGRESS - CAPSys
• Leibniz ScienceCampus - Chronic Inflammatory Diseases
• Competence Network ‘Chronic Inflammatory Bowel Disease’
• German Cancer Consortium (DKTK)
• National Zoonoses Research Network
• Other collaborations
Where we come from: Infectious diseases and immunology at Charité – a historical perspective
The foundations for immunology and infectious disease research of our days were laid during the late 19th century. Alongside Paris, the workplace of the famous French microbiologist, Louis Pasteur, Berlin (and its largest hospital, Charité) was known as a major research center. It was here that Robert Koch discovered the bacterium causing tuberculosis, where he gave his famous presentation on the ‘Etiology of Tuberculosis’, and where his work on pathogens led to the foundation of modern bacteriology. Through targeted measures, he successfully controlled both typhoid and cholera epidemics.
Charité was also home to two other pioneers of modern immunology, Paul Ehrlich and Emil von Behring. Paul Ehrlich developed various techniques for staining cells, which subsequently allowed him to classify leukocytes into different types. He successfully produced an anti-diphtheria serum, which led him to develop the standardization method for therapeutic antisera. He is also considered the founding father of cancer immunology. Emil von Behring, a student of Robert Koch, developed serum therapy. Working with Paul Ehrlich, he developed effective therapeutic sera against diphtheria and tetanus. All three of these exceptional researchers were awarded Nobel Prizes in Medicine in recognition of their achievements. At the beginning of the 20th century, researchers discovered that the body’s immune system consists of both humoral and cellular components. Support for cutting-edge immunology research declined drastically as a result of the First World War. When the Nazi’s racial and political policies resulted in many of the country’s best researchers being forced to emigrate, Germany effectively ceased to make meaningful contributions to infectious disease and immunology research. Government-funded programs, such as those administered by the Federal Ministry of Education and Research, the German Research Foundation, and the European Research Council, were introduced during the late 20th century. It was only after this development that researchers were able to leave their positions at internationally-renowned institutes to return to Germany, and that funding became available to support talented early-career researchers. Today, Charité is ranked as one of the best research universities within the field of immunology research, its publications in high-quality journals placing it among the top 40 universities worldwide (US News & World Report 2016). Medical progress continues to give rise to new areas of research within the field of immunology, such as transplant immunology and immunotherapy. Because of these developments, many patients now have access to treatment options, that would not have been possible without this long tradition of immunology research.
Education and training
One of the RCi3’s most important tasks is to prepare the next generation of physician-scientists and life science researchers to work in immunology and infection biology. The ZIBI Graduate School, part of the Center for Infection Biology and Immunity (ZIBI), represents an umbrella structure for doctoral training programs, which are aimed at students from the life sciences and from medicine. The aim of ZIBI is to bridge the traditional divide between individual disciplines, and to offer students wishing to complete doctorates in immunology and infection biology a truly interdisciplinary program of study. ZIBI uses innovative concepts, techniques and topics to prepare doctoral students for their professional careers. The overarching goal of ZIBI is to train young researchers for careers in the fields of infection biology and immunology. The ZIBI Graduate School sees itself as an integrated platform, which combines and delivers all of the graduate programs available. These are:
• GRK 2046: ‘Parasite Infections: From Experimental Models to Natural Systems’
• iGRK 2290: ‘Crossing Boundaries: Molecular Interactions in Malaria’
• GRK 2318: ‘Tight junctions and their proteins: molecular features and actions in health and disease’
• International Max-Planck Research School for Infectious Diseases and Immunology” (IMPRS-IDI)
Training tracks for clinician-scientists are offered via the BIH Charité Clinician Scientist Program . Trainees follow a structured residency program, with time set aside for clinical or basic research. Intended to produce a new generation of researchers with translational research skills, this program promotes the rapid transfer of research findings into clinical practice.
Research into inflammatory skin diseases
The Department of Dermatology, Venereology and Allergology, which specializes in chronic inflammation, allergology, dermato-oncology, and pediatric dermatology, is one of the leading facilities of its kind worldwide. In addition to being committed to outstanding patient care, the department is also home to more than 100 researchers. Engaged in immunology-based research, these researchers aim to continually advance our knowledge of both the pathogenic and protective mechanisms underlying chronic inflammatory skin diseases, autoimmune diseases and allergic reactions. By promoting close links between outstanding basic research and different external academic and non-academic partner institutions (e.g. The DRFZ Leibniz ScienceCampus for Chronic Inflammatory Diseases), as well as in vivo research, clinical research, and patient care, our center facilitates a high level of synergy and encourages comprehensive translational research. Our center forms part of international networks, such as the International Psoriasis Council and the European Hidradenitis Suppurative Foundation, and is involved in collaborative projects funded by the Federal Ministry of Education and Research (eKid). It is also involved in the planning and development of Collaborative Research Centers (ImmuneAging, Renoprotection). As part of the TRR130 project, we are studying the effects of vitamins A and D on B-cell differentiation. In the field of skin allergies, we are also actively involved in the work of the Autoinflammation Network e.V., the Urticaria Network e.V., and the European Mast Cell and Basophil Research Network (EMBRN).
Cancer immunotherapy – from basic science to clinical application
Charité’s Institute of Immunology, which is situated at the Charité Campus Berlin Buch, specializes in basic and translational research in the fields of immunology and cancer immunology. According to the WHO World Cancer Report, there will be sharp increase in the incidence of cancers over the next few years. In many cases, conventional treatment options such as surgical excision, chemotherapy and radiotherapy, fail to restore health. However, we are beginning to see successes being made with new immunotherapies, such as those developed for acute lymphoblastic leukemia or malignant melanoma. This is why we work in close collaboration with working groups from the MDC and Charité’s Hematology and (Pediatric) Oncology departments to study how cancers and the immune system interact. As part of the SFB-TR36 Transregional Collaborative Research Center and other funding programs (Einstein Visiting Fellowship, BIH, the DKTK, and German Cancer Aid), we have been addressing the fundamental principles and clinical applications of T cell therapy. We are now at the stage of embarking on our first clinical trial into the use of T cell receptor gene therapy in German cancer patients. Our long-term aim is to establish an off-the-shelf ‘library’ of T cell receptors for use against various neoantigens as part of a personalized approach to cancer therapy.
Immunity and chronic inflammation
The Institute of Medical Immunology is one of a small number of ‘medical’ institutes in Germany which pursue a strongly translational approach to immunology. The institute is also home to the coordinating office of the FOCIS-Center of Excellence, a network for Berlin’s clinical immunology community. The institute’s main areas of research focus are immunodeficiency diseases in adults, transient immunodeficiency in intensive care patients, chronic inflammatory diseases, transplant immunology, the development of cell therapies, and (in the form of technological platforms) molecular libraries and immune monitoring. Both in terms of its research interests and technologies, the institute’s work is also closely aligned with the field of regenerative therapies (one of Charité’s main research foci), as represented by the Berlin-Brandenburg Center for Regenerative Therapies (BCRT) and the newly-founded Berlin Center for Advanced Therapies (BEACAT). Cross-disciplinary research collaborations are also being pursued by a working group involved in research into the mechanisms behind chronic inflammation of the central nervous system. Close links have been developed with the field of neurosciences (another one of Charité’s main research foci), as represented by the ECRC and the NeuroCure Cluster of Excellence. One of the areas of research focus pursued within the field of infectiology is the search for new antimicrobial substances which are based on natural antimicrobial peptides. Use of a systems medicine-based approach and the development of personalized treatment strategies play a crucial role in most of our projects. Jointly run by the Institute of Medical Immunology and the BCRT, the Core Unit ‘Immunocheck’ addresses these issues via its biomarker development units and its fully-accredited Immunology Study Lab, which is compatible with FDA/EMA standards. The Core Unit has proven expertise in the development, validation, and conduct of university-sponsored multicenter studies as well as industry-sponsored Phase I to III trials.
Good guys – bad guys: pathogens, immunology of infections, and microbiota
Researchers from the Institute of Microbiology, working both at the Campus Benjamin Franklin and at the German Rheumatism Research Center are pursuing the rather fundamental question of how multicellular organisms protect themselves against infections. Their main areas of interest are the development of our innate (and, in evolutionary terms, ancient), immune system, and the role of microbiota for immune system fitness. Over the past few years, the institute’s research has led to new paradigms for a significant role of the immune system for epithelial regeneration and organ homeostasis. Insights such as these have identified new pathways that can be harnessed to prevent and treat infections and inflammatory diseases. The institute’s research endeavors receive financial support from the German Research Foundation (through project-based funding for the projects SPP 1656 ‘Intestinal Microbiota’ and TR-SFB 156 ‘Die Haut als immunologisches Organ [the skin as an immune organ]’), and the Federal Ministry of Education and Research (in the form of the National Zoonoses Research Network). The institute also holds an ERC Starting Grant (‘NutrImmune’) and acts as the coordinator of the DFG Priority Program 1937 ‘Innate Lymphoid Cells’.
Clinical and experimental hematology and oncology
The Medical Department, Division of Hematology, Oncology and Tumor Immunology provides medical care to hematology and oncology patients. It combines this task with appropriate clinical study-related activities and work to support the department’s core competency in experimental cancer research and tumor immunology. Patients with malignant disorders of the immune system (e.g. lymphoma, leukemia, multiple myeloma) are monitored using diagnostic testing, both before and during their treatment. Longitudinal monitoring enables physicians to detect therapy-induced changes affecting the patient’s immune system or his/her cancer. It also enables physicians to detect instances of interactions between the two, and to study mechanisms involved in secondary immunodeficiency. It is therefore our aim to identify new markers and prognostic parameters, as well as new target structures to identify promising combination therapies. Our work conducted as part of the SFB-TR36 Transregional Collaborative Research Center involves the optimization and translation of adoptive T cell therapy using tumor-specific T cells. Our first clinical trial into the use of MAGE-A1-specific T cells in patients with multiple myeloma is currently at the final stage of the approval process. We are also actively involved in clinical trials into the use of virus-specific T cells following hematopoietic stem cell transplantation, as well as studies into the use of peptide-loaded dendritic cells in patients with chronic myeloid leukemia (CML) with molecular residual disease.
Infectious disease and pneumonia research
The Medical Department, Division of Infectiology and Pneumology boasts the only Chair in Infectiology in the whole of Germany. The department’s interest in pneumonia research means that physicians involved in clinical care work alongside researchers from various academic and non-academic institutions. Pneumonia is one of the most common diseases worldwide, with a mortality rate which, for decades, has remained unchanged at over 10%. One fundamental finding, the fact that our pulmonary innate immunity appears to play a key role in the survival of patients with pneumonia, is the reason why our basic science research groups are committed to conducting systematic research into this serious disease. Their research is supported by networks and consortia sponsored by the German Research Foundation (DFG) and the Federal Ministry of Education and Research (CAPNetz, PROGRESS, CAPSys, SFB-TR84). From the molecular mechanisms involved in host-pathogen interactions (between the pneumonia-causing bacteria and the lungs) to innovative treatment concepts, our research addresses the translational principles of the disease, and applies them consistently. Thus, and for the first time, we have been able to approach the disease from a systems medicine-based point of view, and have already made significant contributions to the development of the national, evidence-based (S3) guidelines for the treatment of community-acquired pneumonia. We are also currently focused on continuing the development of proprietary treatment strategies for respiratory failure (e.g. EMEA/OD/139/09).
Rheumatology and inflammation research
As an approved ‘EULAR Center of Excellence’, Charité’s Medical Department, Division of Rheumatology and Clinical Immunology specializes in research into chronic inflammatory rheumatic diseases. Globally, it is one of the leading clinical research centers for rheumatoid arthritis, systemic connective tissue disorders (such as lupus erythematosus, Sjögren's syndrome, and scleroderma), as well as inflammatory musculoskeletal and vascular disorders. By working in close cooperation with the German Rheumatism Research Center Berlin (DRFZ) and other academic and non-academic partners, the department lays the foundations for a rapid translation of research findings into clinical application, where they can be used in the diagnosis and treatment of these challenging autoimmune diseases. Both basic and clinical research endeavors focus on autoreactive cell-mediated immunological memory (which is important in driving the processes which maintain chronic inflammation and autoimmunity), and the control mechanisms regulating the body’s immune response (for instance, to stop the processes underlying chronic inflammation by re-establishing and strengthening the body’s physiological immune response). The department’s researchers are also interested in issues pertaining to the fields of tissue regeneration and epidemiology, and the identification of biomarkers, which constitute a valuable tool for prognosis and treatment-based decision-making, and for assessing treatment response in rheumatic autoimmune diseases.
Research in Tropical Medicine
The Institute for Tropical Medicine and International Health is involved in collaborative research projects with partners primarily based in Africa and Asia (current partnerships exist with Rwanda, Uganda, Ethiopia, Sierra Leone, Ghana, South Africa, India and Sri Lanka). Main areas of research focus are the (molecular) epidemiology and the therapeutic and preventive aspects of common tropical infectious diseases, in particular malaria, intestinal helminths and protozoa, HIV/AIDS, and Dengue. Other activities touch on the areas of Public Health, and involve post-Ebola obstetrics care and reproductive health, healthcare-associated infections and antimicrobial resistance, as well as community medicine (in relation to TB and HIV). The Institute is partnered with hospitals in Rwanda, Uganda and Sierra Leone. We are also involved in international surveillance networks for infectious diseases imported by returning travelers and migrants (GeoSentinel), imported Staphylococcus aureus (StaphTrav), imported leishmaniaisis (LeishMan), as well studies into the health status of migrants (which include non-communicable diseases such as diabetes).
Where do new viruses come from?
The Institute of Virology, which is situated on Campus Mitte, is dedicated to the study of viral diversity and evolution. Viruses have particularly effective means of transmission and, as such, are capable of starting global epidemics (pandemics). This was demonstrated during recent outbreaks, from SARS and MERS to avian influenza, swine flu, Ebola, and Zika. Most viral epidemics start as zoonoses, and therefore need to be detected and tackled at this stage. In accordance with the principles of the ‘One Health’ approach, our basic research supports international health care organizations, such as the WHO, in controlling viral outbreaks. By improving the options available to modern medicine, it also helps to increase our chances of detecting even the rarest of pathogens. As a partner institution of the German Center for Infection Research (DZIF) and as partners in other collaborative projects (SPP1596, COMPARE, PREPARE, RAPID), we are committed to studying both ecological and molecular barriers to interspecies transmission during the emergence of new viral diseases. We also coordinate programs on virus identification, viral hazard assessment, and on improving epidemic preparedness. As part of the EU project ZIKAlliance, we are investigating the Zika epidemic and the impact it has had in South and Central America. Several of the institute’s projects form part of the DFG’s (German Research Foundation’s) Africa Initiative (Ghana, Ivory Coast and Kenya). The institute also hosts a BMBF (Federal Ministry of Education and Research) Junior Research Group working on the evolution and ecology of insect-borne viruses (Uganda).