Research

The research topics of iPATH.Berlin focus on the intestinal immune system.

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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", INF project "IBDome"

The INF 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 INF project is going to develop an integrated platform that merges large scale omic-datasets from IBD patients with corresponding clinical disease status: the IBDome. The IBDome will foster 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 will be realized on a platform. The data management hereby will be done in accordance with the requirements of the EU General Data Protection Regulation and Good Scientific Practice.
The IBDome will be populated in a step-wise approach: First, already existing tissue banks in Erlangen and Berlin will be harmonized in their respective set-ups and recording of the clinical data will be standardized. Prospectively this will be expanded to the structured sampling of tissues (blood, biopsie, resectates) and fecal samples. Second, four preselected projects of the consortium will provide a first set of deep profiling data generated using cutting-edge technologies on a specified exemplary patient cohort including controls. This cohort consists of Crohn´s disease patients with active and inactive terminal ileitis and respective controls. The data will 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) will be made 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. 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.    Characterization of in-vivo distribution patterns of VSOP in the healthy intestine for correlation of the local distribution of GAG and immune cells. 
2.    Confirmation of GAG-specific binding of VSOP in intestinal tissues ex vivo.
3.    Systematic comparison of VSOP binding and GAG composition in vivo in homeostatic and inflamed tissues using mouse models of intestinal inflammation. 
4.    Correlation of intestinal GAG and immune cell distribution in situ in human IBD to clinical disease state.
5.    Analysis of inflammation-dependent composition of GAG in situ in the intestinal ECM.

Collaborations

On the level of experimental models, immunopathology also connects all medical subjects. This is reflected in numerous collaborations.

Collaboration Partners

Within Berlin

PD Dr. Anton Aebischer (Robert-Koch-Institut)

PD Dr. Tobias Alexander (Charité, Hämatologie)

Prof. Dr. Stefan Bereswill (Charité, Mikrobiologie)

Prof. Dr. Thomas Blankenstein (Max-Delbrück-Center für Molekulare Medizin; MDC)

Dr. Hyun-Dong Chang (Deutsches Rheuma-Forschungszentrum; DRFZ)

Prof. Dr. Thomas Dörner (Charité, Rheumatologie)

Prof. Dr. Alf Hamann (DRFZ)

Prof. Dr. Susanne Hartmann (Freie Universität Berlin, Veterinärmedizin)

Dr. Dr. Ahmed N. Hegazy (CharitéUniversitätsmedizin Berlin, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie)

PD Dr. Markus Heimesaat (Charité, Mikrobiologie)

PD Dr. Uta E. Höpken (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)

Prof. Dr. Sergei Nedospasow (DRFZ)

Dr. Verena Moos

Prof. Dr. Andreas Radbruch (DRFZ)

Prof. Dr. Chiara Romagnani (Charité/DRFZ)

Prof. Dr. Birgit Sawitzki (Charité, Immunologie)

Prof. Dr. Alexander Scheffold (Charité/DRFZ)

Prof. Dr. Dr. Thomas Schneider

Prof. Dr. Eckart Schott (Charité, Hepatologie)

Prof. Dr. Jörg-Dieter Schulzke (Charité, Klinische Physiologie)

Prof. Dr. Britta Siegmund (Charité, Gastroenterologie)

PD Dr. Uta Syrbe (Charité/DRFZ)

Prof. Dr. Margitta Worm (Charité, Allergologie)

Outside Berlin

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)

Dr. Jörg Stange (Cambridge, Großbritannien)

Prof. Dr. Ulrich Steinhoff (Marburg)

Publications

Since the beginning of our centralized service, over 200 manuscripts were published. We here selected 5 publications per year since 2012. You find the more than 100 publications at PubMed asking for "Kühl AA" oder. "Kühl A" oder. "Kuehl AA"und "Erben U".

2018

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.

2017

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]

2016

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]

2015

Annemann M, Wang Z, Plaza-Sirvent C, Glauben R, Schuster M, Ewald Sander F, Mamareli P, Kühl AA, Siegmund B, Lochner M, Schmitz I. IκBNS regulates murine Th17 differentiation during gut inflammation and infection. J Immunol. 2015; 194:2888-98. doi: 10.4049/jimmunol.1401964.

Muñoz M, Eidenschenk C, Ota N, Wong K, Lohmann U, Kühl AA, Wang X, Manzanillo P, Li Y, Rutz S, Zheng Y, Diehl L, Kayagaki N, van Lookeren-Campagne M, Liesenfeld O, Heimesaat M, Ouyang W. Interleukin-22 induces interleukin-18 expression from epithelial cells during intestinal infection. Immunity. 2015; 42:321-31. doi: 10.1016/j.immuni.2015.01.011.

Erben U, Pawlowski NN, Doerfel K, Loddenkemper C, Hoffmann JC, Siegmund B, Kühl AATargeting human CD2 by the monoclonal antibody CB.219 reduces intestinal inflammation in a humanized transfer colitis model. Clin Immunol. 2015; 157:16-25. doi: 10.1016/j.clim.2015.01.004.

Ziegler T, Rausch S, Steinfelder S, Klotz C, Hepworth MR, Kühl AA, Burda PC, Lucius R, Hartmann S. A novel regulatory macrophage induced by a helminth molecule instructs IL-10 in CD4+ T cells and protects against mucosal inflammation. J Immunol. 2015; 194:1555-64. doi: 10.4049/jimmunol.1401217.

Mei HE, Wirries I, Frölich D, Brisslert M, Giesecke C, Grün JR, Alexander T, Schmidt S, Luda K, Kühl AA, Engelmann R, Dürr M, Scheel T, Bokarewa M, Perka C, Radbruch A, Dörner T. A unique population of IgG-expressing plasma cells lacking CD19 is enriched in human bone marrow. Blood. 2015; 125:1739-48. doi: 10.1182/blood-2014-02-555169.

2014

Duque-Correa MA, Kühl AA, Rodriguez PC, Zedler U, Schommer-Leitner S, Rao M, Weiner J 3rd, Hurwitz R, Qualls JE, Kosmiadi GA, Murray PJ, Kaufmann SH, Reece ST. Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas. Proc Natl Acad Sci U S A. 2014; 111:E4024-32. doi: 10.1073/pnas.1408839111.

Erben U, Loddenkemper C, Doerfel K, Spieckermann S, Haller D, Heimesaat MM, Zeitz M, Siegmund B, Kühl AA. A guide to histomorphological evaluation of intestinal inflammation in mouse models. Int J Clin Exp Pathol. 2014; 7:4557-76. eCollection 2014.

Neumann C, Heinrich F, Neumann K, Junghans V, Mashreghi MF, Ahlers J, Janke M, Rudolph C, Mockel-Tenbrinck N, Kühl AA, Heimesaat MM, Esser C, Im SH, Radbruch A, Rutz S, Scheffold A. Role of Blimp-1 in programing Th effector cells into IL-10 producers. J Exp Med. 2014; 211:1807-19. doi: 10.1084/jem.20131548.

Okhrimenko A, Grün JR, Westendorf K, Fang Z, Reinke S, von Roth P, Wassilew G, Kühl AA, Kudernatsch R, Demski S, Scheibenbogen C, Tokoyoda K, McGrath MA, Raftery MJ, Schönrich G, Serra A, Chang HD, Radbruch A, Dong J. Human memory T cells from the bone marrow are resting and maintain long-lasting systemic memory. Proc Natl Acad Sci U S A. 2014; 111:9229-34. doi: 10.1073/pnas.1318731111.

Shen P, Roch T, Lampropoulou V, O'Connor RA, Stervbo U, Hilgenberg E, Ries S, Dang VD, Jaimes Y, Daridon C, Li R, Jouneau L, Boudinot P, Wilantri S, Sakwa I, Miyazaki Y, Leech MD, McPherson RC, Wirtz S, Neurath M, Hoehlig K, Meinl E, Grützkau A, Grün JR, Horn K, Kühl AA, Dörner T, Bar-Or A, Kaufmann SH, Anderton SM, Fillatreau S. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature. 2014; 507:366-70. doi: 10.1038/nature12979.

2013

Schuster M, Glauben R, Plaza-Sirvent C, Schreiber L, Annemann M, Floess S, Kühl AA, Clayton LK, Sparwasser T, Schulze-Osthoff K, Pfeffer K, Huehn J, Siegmund B, Schmitz I. IκB(NS) protein mediates regulatory T cell development via induction of the Foxp3 transcription factor. Immunity. 2012; 37:998-1008. doi: 10.1016/j.immuni.2012.08.023.

Kredel LI, Batra A, Stroh T, Kühl AA, Zeitz M, Erben U, Siegmund B. Adipokines from local fat cells shape the macrophage compartment of the creeping fat in Crohn's disease. Gut. 2013; 62:852-62. doi: 10.1136/gutjnl-2011-301424.

Peine M, Rausch S, Helmstetter C, Fröhlich A, Hegazy AN, Kühl AA, Grevelding CG, Höfer T, Hartmann S, Löhning M. Stable T-bet(+)GATA-3(+) Th1/Th2 Hybrid cells arise in vivo, can develop directly from naive precursors, and limit immunopathologic inflammation. PLoS Biol. 2013; 11:e1001633. doi: 10.1371/journal.pbio.1001633.

Wang C, Xiao M, Liu X, Ni C, Liu J, Erben U, Qin Z. IFN-γ-mediated downregulation of LXA4 is necessary for the maintenance of nonresolving inflammation and papilloma persistence. Cancer Res. 2013; 73:1742-51. doi: 10.1158/0008-5472.CAN-12-2801.

Listopad JJ, Kammertoens T, Anders K, Silkenstedt B, Willimsky G, Schmidt K, Kuehl AA, Loddenkemper C, Blankenstein T. Fas expression by tumor stroma is required for cancer eradication. Proc Natl Acad Sci U S A. 2013; 110:2276-81. doi: 10.1073/pnas.1218295110.

2012

Schuster M, Glauben R, Plaza-Sirvent C, Schreiber L, Annemann M, Floess S, Kühl AA, Clayton LK, Sparwasser T, Schulze-Osthoff K, Pfeffer K, Huehn J, Siegmund B, Schmitz I. IκB(NS) protein mediates regulatory T cell development via induction of the Foxp3 transcription factor. Immunity. 2012; 3:998-1008. doi: 10.1016/j.immuni.2012.08.023.

Daridon C, Loddenkemper C, Spieckermann S, Kühl AA, Salama A, Burmester GR, Lipsky PE, Dörner T. Splenic proliferative lymphoid nodules distinct from germinal centers are sites of autoantigen stimulation in immune thrombocytopenia. Blood. 2012; 120:5021-31. doi: 10.1182/blood-2012-04-424648.

Herda S, Raczkowski F, Mittrücker HW, Willimsky G, Gerlach K, Kühl AA, Breiderhoff T, Willnow TE, Dörken B, Höpken UE, Rehm A. The sorting receptor Sortilin exhibits a dual function in exocytic trafficking of interferon-γ and granzyme A in T cells. Immunity. 2012; 37:854-66. doi: 10.1016/j.immuni.2012.07.012.

Zhao X, Rong L, Zhao X, Li X, Liu X, Deng J, Wu H, Xu X, Erben U, Wu P, Syrbe U, Sieper J, Qin Z. TNF signaling drives myeloid-derived suppressor cell accumulation. J Clin Invest. 2012; 122:4094-104. doi: 10.1172/JCI64115.

Heimesaat MM, Heilmann K, Kühl AA, Erben U, Rühl M, Fischer A, Farndale RW, Bereswill S, Göbel UB, Zeitz M, Somasundaram R, Freise C. The synthetic hydroxyproline-containing collagen analogue (Gly-Pro-Hyp)10 ameliorates acute DSS colitis. Eur J Microbiol Immunol (Bp).; 2012 2:192-200. doi: 10.1556/EuJMI.2.2012.3.4. 

Research database

 For more details, please use the Research database of the Charité.