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Scientific work is based on basic principles
First and foremost it is honesty towards yourself and others. It is at the same time the ethical norm and the basis of scientific professionalism. Good scientific practice. Research by iPATH.Berlin follows the Principles of good science practise.
TRR241 "Immune-Epithelial Communication in Inflammatory Bowel Diseases", Z03 project "IBDome"
The Z03 project is the central part of the TRR 241, as it represents an indispensable interface between (immuno)biological and clinical information in inflammatory bowel diseases (IBD). The Z03 project developed an integrated platform that merges large scale omic-datasets from IBD patients with corresponding clinical disease status: the IBDome. The IBDome fosters translational research activities within this CRC and will allow the conceptional integration of the clinical impact on the analyzed immune-epithelial crosstalk in IBD. The database is realized on a platform. The data management hereby is done in accordance with the requirements of the EU General Data Protection Regulation and Good Scientific Practice.
The IBDome was populated in a step-wise approach: First, already existing tissue banks in Erlangen and Berlin were harmonized in their respective set-ups and recording of the clinical data was standardized. This was expanded to the structured sampling of tissues (blood, biopsie, resectates) and fecal samples. A first set of deep profiling data generated using cutting-edge technologies on a specified exemplary patient cohort including controls was analysed. This cohort consists of Crohn´s disease patients with active and inactive terminal ileitis and respective controls. The data consist of biomedical information derived from comprehensive molecular characterization of collected intestinal tissue, peripheral blood and stool using RNA sequencing, exome sequencing, 16s microbiome sequencing, mass cytometry (cytometry by time of flight; CyTOF), and histopathology. The integrated biomolecular, imaging, and clinical data (disease phenotype, disease activity, medication, complications) are available through a web-based front-end to all researchers within this CRC in order to enable further exploration of the data and generation of testable hypotheses. We envision to further develop the IBDome to a reference database for IBD during the course of the project, which will be populated with a large number of patient samples analyzed using both, deep and broad profiling. Additional cohorts are included (e.g., Crohn´s colitis, left-sided colitis, proctitis). Hence, we will provide a central resource platform not only for for the TRR 241 but also for the scientific community and thereby strengthen translational research and enable novel insights into IBD pathogenesis and ultimately the discovery of novel therapeutic strategies.
SFB1340 "Matrix-in-vision", TP B06 "Inflammatory activity and targeting of the extracellular matrix in inflammatory bowel diseases"
Ulcerative colitis (UC) and Crohn´s disease (CD) are the main forms of inflammatory bowel diseases. The optimal therapy depends on the diagnosis and on the follow-up. Especially in CD, magnetic resonance imaging (MRI) is the today’s technique of choice providing information about extraluminal complications and extraintestinal manifestations. Complications like fibrosis, scarring and stenosis are caused by massive remodeling of the extracellular matrix (ECM). The early prediction of deleterious ECM accumulation remains challenging in monitoring disease progress and in developing strategies for personalized treatment.
TP B06 is going to develop novel strategies addressing the ECM as integral part of the immediate surrounding for and modulated by immune cells in intestinal inflammation.
Addressing the effect of immune cells on ECM remodeling in CD, the TP B06 aims to elucidate in vivo accessible glucosaminoglycans (GAG) within the ECM that mark processes involved either in intestinal inflammation or in ECM remodeling. In-vivo imaging in mouse models combined with endoscopy and histology also in human CD will uncover distinct patterns of composition and distribution of GAG in intestinal inflammation and ECM accumulation. In the long run, GAG-related criteria will help to establish non-invasive procedures to early predict complications in CD and to suggest treatment options targeting harmful ECM to rationalize individual CD treatment. Using relevant mouse models of intestinal inflammation and comparison to human diseases, TP B06 will complete the following work program:
(1) Detection of intravenously applied VSOP in vivo, ex vivo and in situ in various tissues of mouse models of intestinal inflammation and fibrosis in correlation to the ECM, viscoelastic properties and immune cells including the crosstalk of immune cells and the ECM.
(2) Analysis of long-term effects of intravenously applied VSOP on the mucosal immune system of mice with intestinal inflammation/fibrosis.
(3) Elucidation of the diagnostic value and the sensitivity of viscoelastic properties of the inflamed gut in correlation to ECM changes and inflammation compared to ultrasound, MRI and histopathology in IBD patients.
(4) Analysis of VSOP-mediated effects on transcription and function of blood cells derived from IBD patients.
Clinician scientist program "Immune phenotyping in fistulas"
Clinician scientist program "Immune phenotyping in fistulas"
Crohn´s disease is a recurring inflammation of the whole gastrointestinal tract affecting all layers. 23-35% of the CD patients develop fistulas. A fistula is an abnormal connection of the intestine and another (hollow) organ like the bladder or the skin. Surgery is the main treatment option. So far, little is known about the development, treatment, or inflammation of fistulas. This project elucidates the immune cells infiltrating the tissue of and around a fistula. For this, imaging mass cytometry (IMC) is used as this allows the simulatenous staining and analysis of about 40 markers on tissue sections for a more comprehensive picture of the immune cells and the microenvironment. Eventually, the mechanismus of fistula development and optimal treatment options will evolve.
PD Dr. Anton Aebischer (Robert-Koch-Institut)
Prof. Dr. Stefan Bereswill (Charité, Mikrobiologie)
Prof. Dr. Gerald Willimsky (Charité, Institut für Immunologie; CBB)
Dr. habil. Hyun-Dong Chang (Deutsches Rheuma-Forschungszentrum; DRFZ)
Prof. Dr. Susanne Hartmann (Freie Universität Berlin, Veterinärmedizin)
PD Dr. Markus Heimesaat (Charité, Mikrobiologie)
PD Dr. Uta E. Höpken (Max Delbrück Center, MDC)
Prof Dr. Stefan H. E. Kaufmann (Max-Planck-Institut für Infektionsbiologie; MPI-IP)
Dr. Andrej Kruglov (DRFZ)
Dr. Désirée Kunkel (BCRT, Core Unit Flow Cytometry & Mass Cytometry)
Prof. Dr. Achim Leutz (MDC, Zelldifferenzierung und Tumorigenese)
Prof. Dr. Christoph Loddenkemper (Pathotres)
Prof. Dr. Max Löhning (Charité/DRFZ)
Dr. Mir-Farsin Mashregi (DRFZ)
Prof. Dr. Thomas F. Meyer (MPI-IB)
Dr. Verena Moos (Charité, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie)
Prof. Dr. Andreas Radbruch (DRFZ)
Prof. Dr. Chiara Romagnani (Charité/DRFZ)
Prof. Dr. Birgit Sawitzki (Charité, Immunologie)
Prof. Dr. Jörg-Dieter Schulzke (Charité, Klinische Physiologie)
PD Dr. Uta Syrbe (Charité/DRFZ)
PD Dr. Minka Breloer (Hamburg)
Prof. Dr. Simon Fillatreau (Paris, Frankreich)
Prof. Dr. Jens Geginat (Mailand, Italien)
Dr. Marco Gerling (Stockholm, Schweden)
Prof. Dr. Zhihai Qin (Beijing, China)
Prof. Dr. Thomas Schüler (Magdeburg)
Prof. Dr. Tim Sparwasser (Hannover)
Prof. Dr. Ulrich Steinhoff (Marburg)
Stanko K, Iwert C, Appelt C, Vogt K, Schumann J, Strunk FJ, Ahrlich S, Schlickeiser S, Romagnani C, Jürchott K, Meisel C, Willimsky G, Kühl AA, Sawitzki B. CD96 expression determines the inflammatory potential of IL-9-producing Th9 cells. PNAS; 115(13):E2940-E2949, 2018.
Sbierski-Kind J, Kath J, Brachs S, Streitz M, Von Herrath MG, Kühl AA, Schmidt-Bleek K, Mai K, Spranger J, Volk H-D. Distinct housing conditions reveal a major impact of adaptive immunity on the course of obesity-induced type 2 diabetes. Frontiers in Immunology; 28;9:, 2018.
Hoser D, Schön C, Loddenkemper C, Lohneis P, Kühl AA, Sommermann T, Blankenstein T, Willimsky G. Oncogene-specific T cells fail to eradicate lymphoma-initiating B cells in mice. Blood; 132(9):924-934, 2018.
Ritschl PV, Günther J, Hofhansel L, Kühl AA, Sattler A, Ernst S, Friedersdorff F, Ebner S, Weiss S, Bösmüller C, Weissenbacher A, Oberhuber R, Cardini B, Öllinger R, Schneeberger S, Biebl M, Dennecke C, Margreiter C, Resch T, Aigner F, Maglione M, Pratschke J, Kotsch K. Graft Pre-conditioning by Peri-operative Perfusion of Kidney Allografts with Rabbit Anti-human T-lymphocyte Globulin – A Prospective, Randomized Placebo-controlled Trial. Frontiers in Immunology; 9:1911, 2018.
Kredel LI, Jödicke LJ, Scheffold A, Gröne J, Glauben R, Erben U, Kühl AA, Siegmund B. T-cell composition in ileal and colonic creeping fat - separating ileal from colonic Crohn´s disease. J Crohns Colitis; 13(1):79-91, 2018.
Kenngott EE, Pfeil J, Hoffmann U, Lauer U, Kühl AA, Rigby A, Pernthaner A, Hamann A. Facilitated Peptide Transport via the Mucosal Epithelium: Impact on Tolerance Induction. Frontiers in Immunology; 8, 2017. [doi: 10.3389/fimmu.2017.00216]
West NR, Hegazy AN, Owens BM, Bullers SJ, Linggi B, Buonocore S, Coccia M, Görtz D, This S, Stockenhuber K, Pott J, Friedrich M, Ryzhakov G, Baribaud F, Brodmerkel C, Cieluch C, Rahman N, Müller-Newen G, Owens RJ, Kühl AA, Maloy KJ, Plevy SE, Oxford IBD Cohort Investigators, Keshav S, Travis SPL, Powrie F. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat Med.; 23(5): 579-589, 2017. [doi: 10.1038/nm.4307]
Steinfelder S, Rausch S, Michael D, Kühl AA, Hartmann S. Intestinal helminth infection induces highly functional resident memory CD4+ T cells in mice. Eur J Immunol.;47(2):353-363, 2017. [doi: 10.1002/eji.201646575]
Zimmermann J, Durek P, Kühl AA, Schattenberg F, Maschmeyer P, Siracusa F, Lehmann K, Westendorf K, Weber M, Riedel R, Müller S, Radbruch A, Chang H-D. The intestinal microbiota determines the colitis-inducing potential of T-bet-deficient Th cells in mice. Eur J Immunol; 2017. [doi: 10.1002/eji.201747100]
Beigier-Bompadre M, Montagna GN, Kühl AA, Lozza L, Weiner J 3rd, Kupz A, Vogelzang A, Mollenkopf HJ, Löwe D, Bandermann S, Dorhoi A, Brinkmann V, Matuschewski K, Kaufmann SHE. Mycobacterium tuberculosis infection modulates adipose tissue biology. PLoS Pathog. 2017 Oct 17;13(10):e1006676. [doi: 10.1371/journal.ppat.1006676]
Reitz M, Brunn ML, Rodewald HR, Feyerabend TB, Roers A, Dudeck A, Voehringer D, Jönsson F, Kühl AA, Breloer M. Mucosal mast cells are indispensable for the timely termination of Strongyloides ratti infection. Mucosal Immunol. 2016; Jul 6. doi: 10.1038/mi.2016.56. [Epub ahead of print]
Kieback E, Hilgenberg E, Stervbo U, Lampropoulou V, Shen P, Bunse M, Jaimes Y, Boudinot P, Radbruch A, Klemm U, Kühl AA, Liblau R, Hoevelmeyer N, Anderton SM, Uckert W, Fillatreau S. Thymus-Derived Regulatory T Cells Are Positively Selected on Natural Self-Antigen through Cognate Interactions of High Functional Avidity. Immunity. 2016; 44:1114-26. doi: 10.1016/j.immuni.2016.04.018.
Kühl AA, Erben U, Cieluch C, Spieckermann S, Gröne J, Lohneis P, Pape UF, Arsenic R, Utku N. Tissue-infiltrating plasma cells are an important source of carboxylesterase 2 contributing to the therapeutic efficacy of prodrugs. Cancer Lett. 2016; 378:51-8. doi: 10.1016/j.canlet.2016.04.041.
Xu X, Meng Q, Erben U, Wang P, Glauben R, Kühl AA, Wu H, Ma CW, Hu M, Wang Y, Sun W, Jia J, Wu X, Chen W, Siegmund B, Qin Z. Myeloid-derived suppressor cells promote B-cell production of IgA in a TNFR2-dependent manner. Cell Mol Immunol. 2016; May 2. doi: 10.1038/cmi.2015.103. [Epub ahead of print]
Zimmermann J, Kühl AA, Weber M, Grün JR, Löffler J, Haftmann C, Riedel R, Maschmeyer P, Lehmann K, Westendorf K, Mashreghi MF, Löhning M, Mack M, Radbruch A, Chang HD. T-bet expression by Th cells promotes type 1 inflammation but is dispensable for colitis. Mucosal Immunol. 2016; Feb 17. doi: 10.1038/mi.2016.5. [Epub ahead of print]
For more details, please use the Research database of the Charité.