Projects funded by the European Union

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.

About 3TR

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.

PIs at DRFZ
Hyun-Dong Chang
Falk Hiepe
Tobias Alexander
Henrik Mei
Andreas Grützkau
Andreas Radbruch

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.

PIs at DRFZ:
Andreas Radbruch
Hyun-Dong Chang (coordinators WP3)
Andreas Grützkau

www.imi.europa.eu/projects-results/project-factsheets/rtcure

The aim of the project “Analysis of bacterial communities by microbiota cytometry” is to establish an application laboratory for the analysis of microbial communities by microbiota flow cytometry.

Microbial communities colonize all habitats on earth and play a crucial role in many geochemical, biological and industrial processes. Changes can have consequences for health, the environment and ecosystems. Classical analysis of the microbiota is currently relatively time-consuming and expensive, and therefore it has not yet found widespread application in clinical diagnostics or monitoring of microbiota in the environment. Microbiota flow cytometry enables rapid, inexpensive and yet detailed analysis of bacterial mixtures. Thus, the application laboratory finds utilization in all areas where bacteria are relevant, especially in the field of research of chronic inflammatory diseases for diagnosis and therapy decision. The technology will also be used for the analysis of water, wastewater, soil, as well as pure and mixed cultures in industry, food production and hygiene monitoring.

PI at DRFZ

Hyon-Dong Chang

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:
Toralf Kaiser
Claudia Giesecke-Thiel (MPI molgen)
Conrad von Volkmann (APE)
Kerstin Heinrich
Daniel Kage
Jenny Kirsch

The DRFZ is partner of the European network SIGNATURE (Single cell in inflammatory autoimmune diseases) for the training of pre-doctoral researchers:

SIGNATURE is led by the Fundación Pública Andaluza Progreso y Salud in Spain, and more specifically by the researchers Marta Alarcón-Riquelme and Concepción Marañón Lizana.

Twelve other partners are part of the network, including the academic partners such as University of Western Brittany in France, the Flemish Institute of Biotechnology in Belgium, the German Rheumatism Research Centre Berlin, a Leibniz-Institute, in Germany and the University of Catania in Italy, among others. Biotechnological companies such as Atrys Health and Altrabio are also actively participating in the network.

Specifically, and within the framework of this network, a ten pre-doctoral researchers will be recruited to follow a training programme in the consortium’s partner organisations. In this way, the doctoral students will be in contact with the academic and non-academic research sectors; receiving training related to research, innovation and long-term employability in the field of biomedical sciences. The participating researchers will have an international professional development plan supervised by the relevant scientists in each of the organisations participating in the network.

The project at DRFZ is to study imprints of mucosal immune reactions on blood leukocytes in different groups of autoimmune patients, with the aim to explore the utility of mucosal immune signatures for precision medicine, and to understand microbiota-immune system interactions implicated in chronic inflammation vs tolerance. The project includes: mass cytometry, precision medicine, single-cell bioinformatics, immune profiling, mucosal immunity and microbiota cytometry.

PIs at DRFZ:
Henrik Mei and Hyun-Dong Chang

Immunologist Chiara Romagnani is working on Natural Killer (NK) cells of the innate immune system. She has shown these cells to have similar properties to the classic adaptive memory B and T lymphocytes, as once activated, they also clonally expand and survive for many years therafter. In the project “MEM-CLONK – Imprinting and clonality of human NK cell memory”, she will study the molecular mechanisms driving epigenetic remodeling, clonal selection and maintenance of memory natural killer memory cells. In this way, these cells could be used to specifically target tumor cells.

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PI at DRFZ
Chiara Romagnani

In the project “ILCADAPT: How cells of the innate immune system respond to tissue metabolic changes“, it is investigated how innate immune cells change during pregnancy and thereafter. Andreas Diefenbach’s research group was able to show that these lymphocytes control the uptake of nutrients, such as lipids and carbohydrates, by epithelial cells of the intestine, and thus adapt the organism to the increased nutritional requirements during pregnancy. How this interaction between lymphocytes and intestinal epithelial cells exactly works will now be studied with the support of this ERC grant. This could lead to new approaches for the treatment of metabolic diseases.

News

PI at DRFZ
Andreas Diefenbach

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:
Antigoni Triantafyllopoulou

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:
Julia Polansky-Biskup

Intestinal fibrosis is a common and serious complication of inflammatory bowel disease (IBD). To date, no specific medicine can yet prevent or reverse intestinal fibrosis. The aim of the project “Interaction between the immune system and stroma in inflammation and fibrosis: using the spatio-temporal dynamics of the OSM-OSMR axis in inflammatory bowel disease to develop new antifibrotic therapies”  (iMOTIONS)  is to gain a molecular understanding of the disturbed cell communication in the intestine, define novel biomarkers to identify patients at risk of developing intestinal fibrosis and provide the means to prevent and treat fibrotic disease.

PI at DRFZ:
Ahmed Hegazy

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:
Julia Polansky-Biskup

http://www.deutsches-epigenom-programm.de/

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:
Andreas Radbruch
https://erc.europa.eu/

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).

PIs at DRFZ:
Andreas Radbruch
Hyun-Dong Chang
Andreas Grützkau

BteCure

Ziel des Projektes ist es, ein Applikationslabor zur Identifizierung von Genschaltern zu etablieren, die chronische Entzündungen kontrollieren und solche, die zerstörtes Gewebe regenerieren können. Solche Genschalter, insbesondere regulatorische Ribonukleinsäuren und Transkriptionsfaktoren, sollen durch therapeutische Oligonukleotide manipuliert werden. In Kooperation mit der Berlin Cures GmbH zielt dieses Projekt auf die Entwicklung neuartiger Remissions-induzierender Therapien mit Hilfe von Genschaltern für die Behandlung von Patienten mit chronisch-entzündlichen oder degenerativen Erkrankungen.

PI am DRFZ
Mir-Farzin Mashreghi