Projects funded by the European Union
Within the framework of European research funding, various grants are available for researchers at German universities and research institutions.
The EU’s Horizon 2020 funding program focuses on scientific excellence, industry leadership and societal challenges and supports basic research to near-market innovations. An important pillar is the Innovative Medicines Initiative (IMI), which is a partnership between the European Union and the pharmaceutical industry. The DRFZ is involved in two IMI networks.
The European Research Council (ERC) supports promising young scientists at the beginning of an independent career through ERC Starting Grants.
The European Regional Development Fund (EFRE) supports, among other things, research and innovation projects to strengthen economic and social cohesion by eliminating inequalities between different regions. The ProFit project funding (programme for the promotion of research, innovations and technologies) is also supported by EFRE.
Innovative Medicines Initiative (IMI)
The DRFZ is partner of the largest-ever Innovative Medicine Initiative 2 (IMI2) immunology project to improve disease management of non-responders to therapy across seven immune-mediated diseases called Taxonomy, Treatment, Targets and Remission (3TR): Identification of the Molecular Mechanisms of non-response to Treatments, Relapses and Remission in Autoimmune, Inflammatory, and Allergic Conditions.
3TR brings together 69 partner organizations from 15 European member states including academic and research institutions, small and medium-sized enterprises (SME) and pharmaceutical companies. For a full partner list, please visit: www.3tr-imi.eu/partners
The project is supported with a funding of over € 80 million from the Innovative Medicines Initiative 2 (IMI2), a joint undertaking of the European Commission and the European Federation of Pharmaceutical Industries and Associations (EFPIA).
Visit the 3TR website: www.3tr-imi.eu
Follow 3TR on Twitter: @3TR_IMI
Role of DRFZ within 3TR
Within WP1 and WP4 of the 3TR project the DRFZ provides its expertise on high-throughput microbiota analysis by high-resolution microbiota cytometry, high-dimensional single cell analysis and immune monitoring as well as the knowledge of the etiopathology of chronic inflammation.
The European consortium RTCure – Rheuma Tolerance for Cure aims to develop therapies for patients in the earliest stages of rheumatoid arthritis (RA) and for people with a high risk of developing this disease.
The network is to develop new methods for biomonitoring the course of the disease and the treatment response. In addition, therapeutic approaches to restore immune tolerance are to be established that prevent or stop attacks by the immune system on the joints and at the same time ensure that the immune system remains capable of fending off infections. The long-term goal is to prevent or reverse the onset of RA and to cure patients in early stages of the disease.
The DRFZ leads work package 3 “Mechanisms of Immune Tolerance“ and contributes to different additional work-packages.
Other projects funded by the EU
The aim of the project is to establish an application laboratory for the identification of gene switches that control chronic inflammations and those that can regenerate destroyed tissue. Such gene switches, in particular regulatory ribonucleic acids and transcription factors, will be manipulated by therapeutic oligonucleotides. In cooperation with Berlin Cures GmbH, this project aims at the development of novel remission-inducing therapies using gene switches for therapies for patients with chronic inflammatory or degenerative diseases.
PI at the DRFZ
Nearly 2 million people in Germany suffer from inflammatory rheumatic diseases, including 20,000 children. In order to understand the causes of these diseases, measurement methods are necessary that robustly detect and identify pathological changes in cells. Until now, such analyses are mostly carried out with flow cytometric methods, which, however, require a complex sample preparation and the staining of the cells with cell-specific molecules. The procedures and reagents required for this can have undesirable effects on the cells, such as activation, influencing immunophenotypic characteristics, cell permeabilisation, cell loss or apoptosis. Furthermore, currently available flow cytometers have limitations with regard to the number of measurable parameters, measurement accuracy, sensitivity, comparability and reproducibility as well as stability of the measurement
In the research project “Pulse shape-based flow cytometry and cell sorting”, both points are to be addressed by a novel analysis method of pulse shape-based flow cytometry. The aim of this project is to investigate whether cells can be identified using pulse shape analysis of scattered light signals, whether an improvement in the quality of the data can be achieved in combination with conventional flow cytometry and under what conditions marker-free cell analysis and cell sorting can be carried out. Within this project the DRFZ collaborates with the company APE – Angewandte Physik und Elektronik GmbH –
People involved in the project:
Claudia Giesecke-Thiel (MPI molgen)
Conrad von Volkmann (APE)
Granulomas are a typical histological finding of several chronic inflammatory diseases. They develop as a reaction to a persistent inflammatory stimulus and consist of macrophages that differentiate into multinucleated giant cells and epithelial cells. These structures of organised inflammation replace healthy tissue causing organ dysfunction.
We revealed that macrophage precursors in granulomas experience a replication block and trigger the DNA Damage Response (DDR), a fundamental cellular process activated in response to genotoxic stress. This leads to the formation of multinucleated macrophages with tissue- remodelling signatures. We hypothesize that the DDR promotes macrophage reprogramming to inflammation-maintaining modules. Our goal is to unravel the macrophage-specific response to genotoxic stress as an essential regulator of chronic inflammation-induced pathologies such as sarcoidosis, inflammatory bowel diseases and rheumatoid arthritis. We postulate that the interruption of signalling cascades leading to granuloma formation may be a new therapeutic strategy for chronic inflammatory diseases.
PI at the DRFZ:
Adoptive T cell therapy is a promising approach in various clinical settings, from target-specific immune reconstitution fighting cancer and chronic infections to combating undesired immune reactivity during auto-immunity and after organ transplantation. However, its clinical application is currently hampered by a limited survival and fitness of the T cells after transfer to the patient and the functional plasticity of T cells resulting in possible functional switches (e.g. from immunosuppressive to pro-inflammatory). We showed earlier that epigenetic players such as DNA methylation essentially contribute to T cell differentiation and harbour the unique prospect to imprint a stable developmental and functional state in the genomic structure of a cell. This project aims to utilise the profound impact of epigenetic mechanisms on the senescence process as well as on the functional imprinting of T cells. Using epigenetic manipulations (e.g. CRISPR/ Cas9) during in vitro expansion, we aim to equip the cells with the required properties for their successful and safe therapeutic application.
PI at the DRFZ:
Projects recently completed
The German Epigenome Programme DEEP (2012 – 2017) has focused on the analysis of cells that play a decisive role in complex diseases with high socio-economic effects such as metabolic diseases or inflammatory diseases of the joints and intestines. Comprehensive epigenetic data from healthy and diseased cells were collected as a basis for improving clinical diagnosis, therapy and the prevention of health risks. All generated data was made publicly accessible and integrated into a sustainable worldwide data structure of the IHEC initiative (International Human Epigenome Consortium).
PI at the DRFZ:
ERC Advanced Grant Protective and pathogenic immunological memory and its organization by stroma cells (IMMEMO)
The ERC-IMMEMO project (2011 – 2016) aimed to investigate the organization and role of immunological memory, both in protective immunity and in immune-mediated diseases on the molecular and cellular level.
Immunological memory protects us against recurrent infections, but it can also cause damaging immune responses. In chronic immune-mediated diseases, pathogenic immunological memory is likely to be a key driver of inflammation. Some of this inflammation does not respond to either the body’s own regulation, or to standard immunosuppression therapy. Chronic inflammation is therefore a particular challenge for the development of new curative therapeutic strategies.
In IMMEMO, we have developed important new concepts for the organization of immunological memory by stromal cells, as well as for the definition of resting versus active pathogenic memory.
The most relevant results are:
• The long-lasting T-cell memory against systemic pathogens is maintained by memory cells, which are resting in terms of division, cell migration and protein production.
• Long-lived CD8+ memory T cells remain as resting cells in the bone marrow. IL-7 produced by mesenchymal stromal cells is essential for this.
• A protocol for unbiased transcriptome analysis of ex vivo isolated cells was developed.
• The transcription factor Twist1 promotes the survival of pro-inflammatory T-helper cells of type 1 (Th1 cells) in chronically inflamed tissue. Twist1 regulates the microRNA miR-148a, which switches off the pro-apoptotic factor Bim.
• The survival niche of memory plasma cells in the bone marrow consists of stromal cells that create a stable niche by secretion of CXCL-12. APRIL-producing eosinophils, which are subject to a constant renewal process, also contribute to the organisation of this stable niche.
• A method for the targeted depletion of plasma cells according to the specificity of the (auto) antibodies they secrete was developed.
• Protocols for ex vivo analysis of the cytokine production of T-cells were optimized.
We are convinced that our findings can make a decisive contribution to the development of new therapeutic strategies for immune-mediated diseases such as rheumatic and gastrointestinal inflammation, multiple sclerosis, transplant rejection or allergies.
The output of IMMEMO is a total of 30 publications and one patent. 5 PhD theses were completed.
PI at DRFZ:
BTCure – Be The Cure for Rheumatoid Arthritis (2012 – 2017) was the largest European research network for the development of new therapies for rheumatoid arthritis (RA).
The aim of the network was to elucidate the molecular pathomechanisms involved in the development of RA. New targets for therapies and biomarkers for improved diagnosis were identified.
Major achievements of the DRFZ within BTCure are:
• Identification of an inhibitory micro RNA (miR-148a) that is involved in the longevity of pathological T helper lymphocytes
• Development of a strategy to deplete autoantibody-secreting plasma cells
• Development of a standardized procedure for a genome-wide characterization of effector T cell subsets
• Identification of protective and pathogenic type I interferon signatures in viral infection and autoimmunity
• Characterization of a new biomarker (SIGLEC-1) for monitoring disease activity in SLE
• Identification of disease-associated gene signatures in monocytes of RA and SLE patients that are potential biomarkers
• Establishment of mass cytometry (CyTOF) to identify cellular biosensors for therapy monitoring and diagnostics in blood, synovial fluid and urine samples
BTCure was funded by the Innovative Medicines Initiative (IMI), a public-private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA).