Immunregulation & Leberentzündung

  • Entzündungsregulation in der Leber und Autoimmune Lebererkrankungen

    Leberentzündung ist eine physiologische Antwort auf Verletzungen, die zur Heilung und Regeneration des Organs nötig ist. Eine falsch regulierte Entzündungsantwort kann jedoch zu Lebererkrankungen führen. Unsere Forschungsprojekte zielen darauf, die Regulation von Entzündung in der Leber besser zu verstehen, um diese bei Krankheiten gezielt beeinflussen zu können.

    Insbesondere interessiert uns, wie Autoimmune Lebererkrankungen entstehen und wie sie behandelt werden können. Zu diesen gehören die Autoimmune Hepatitis (AIH), die Primär Biliäre Cholangitis (PBC) und die Primär Sklerosierende Cholangitis (PSC). Bei allen drei Erkrankungen stellen unterschiedliche Teile der Leber das Ziel einer Immunantwort dar, bei der das Immunsystem das eigene Gewebe angreift. Unsere Forschungsprojekte versuchen zu entschlüsseln, wie diese Erkrankungen entstehen und wie sie möglicherweise besser behandelt werden können.

    Kontakt

    Mitarbeiter

    Prof. Dr. rer. nat. Johannes Herkel (Projektleiter)

    Prof. Dr. med. Christoph Schramm (Projekteiter)

    Dr. rer. nat. Antonella Carambia (Projektleiterin)

    Dr. rer. nat. Dorothee Schwinge (Projektleiterin)

    Dr. Marcial Sebode (Projektleiter)

    Dr. rer. nat. Max Preti (Postdoc)

    Dr. rer. nat. Daria Krzikalla (Postdoc)

    Dr. rer. nat. Stephanie Stein (Postdoc)

    Dr. rer. nat. Tobias Poch (Postdoc)

    Lara Kauer (Ph.D. student)

    Fenja Schuran (Ph.D. student)

    Cornelia Gottwick (Ph.D. student)

    Victor Haas (Ph.D. student)

    Nicola Iuso (Ph.D. student)

    Laura Liebig (Ph.D. student)

    Dr.med. Silja Steinman (clinical scientist)

    Fabian Glaser (clinical scientist)

    Marko Hilken (technician)

    Sabrina Kreß (technician)

    Angelika Schmidt (technician)

    Jennifer Wigger (technician)

    Nina Verse (technician)

    Maik Karnus (MD PhD student)

    Jonas Bahn (MD PhD student)

    Jasper Meyer (MD PhD student)

    Links

    Ausgewählte Publikationen

    Poch T*, Krause J*, Casar C, Liwinski T, Glau L, Kaufmann M, Ahrenstorf AE, Hess LU, Ziegler AE, Martrus G, Lunemann S, Sebode M, Li J, Schwinge D, Krebs CF, Franke A, Friese MA, Oldhafer KJ, Fischer L, Altfeld M, Lohse AW, Huber S, Tolosa E*, Gagliani N*, Schramm C*. Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4+ T cells in primary sclerosing cholangitis. J Hepatol 2021;S0168-8278(21)00219-1. Epub ahead of print.

    Schumacher N, Yan K, Gandraß M, Müller M, Krisp C, Häsler R, Carambia A, Nofer JR, Bernardes JP, Khouja M, Thomsen I, Chalupsky K, Bolik J, Hölscher C, Wunderlich T, Herkel J, Rosenstiel P, Schramm C, Schlüter H, Renné T, Mittrücker HW, Rose-John S, Schmidt-Arras D.Cell-autonomous hepatocyte-specific GP130 signaling is sufficient to trigger a robust innate immune response in mice. J Hepatol 2021;74:407-18.

    Preti M, Schlott L, Lübbering D, Krzikalla D, Müller AL, Schuran FA, Poch T, Schakat M, Weidemann S, Lohse AW, Weiler-Normann C, Sebode M, Schwinge D, Schramm C, Carambia A, Herkel J. Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver. JCI Insight 2021;6:e141462.

    Schuran FA, Lommetz C, Steudter A, Ghallab A, Wieschendorf B, Schwinge D, Zuehlke S, Reinders J, Heeren J, Lohse AW, Schramm C, Herkel J, Carambia A. Aryl Hydrocarbon Receptor Activity in Hepatocytes Sensitizes to Hyperacute Acetaminophen-Induced Hepatotoxicity in Mice. Cell Mol Gastroenterol Hepatol 2021;11:371-88.

    Carambia A, Gottwick C, Schwinge D, Stein S, Digigow R, Şeleci M, Mungalpara D, Heine M, Schuran FA, Corban C, Lohse AW, Schramm C, Heeren J, Herkel J. Nanoparticle-mediated targeting of autoantigen peptide to cross-presenting liver sinusoidal endothelial cells protects from CD8 T-cell-driven autoimmune cholangitis. Immunology 2021;162:452-63.

    Kummen M*, Thingholm LB*, Rühlemann MC, Holm K, Hansen SH, Moitinho-Silva L, Liwinski T, Zenouzi R, Storm-Larsen C, Midttun Ø, McCann A, Ueland PM, Høivik ML, Vesterhus M, Trøseid M, Laudes M, Lieb W, Karlsen TH, Bang C, Schramm C, Franke A*, Hov JR*. Altered gut microbial metabolism of essential nutrients in primary sclerosing cholangitis. Gastroenterology 2021;160:1784-1798.e0.

    Reich M, Spomer L, Klindt C, Fuchs K, Stindt J, Deutschmann K, Höhne J, Liaskou E, Hov JR, Karlsen TH, Beuers U, Verheij J, Ferreira-Gonzalez S, Hirschfield G, Forbes SJ, Schramm C, Esposito I, Nierhoff D, Fickert P, Fuchs CD, Trauner M, García-Beccaria M, Gabernet G, Nahnsen S, Mallm JP, Vogel M, Schoonjans K, Lautwein T, Köhrer K, Häussinger D, Luedde T, Heikenwalder M, Keitel V. Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis. J Hepatol 2021;S0168-8278(21)00244-0.

    Stein S, Henze L, Poch T, Carambia A, Krech T, Preti M, Schuran FA, Reich M, Keitel V, Fiorotto R, Strazzabosco M, Fischer L, Li J, Müller LM, Wagner J, Gagliani N, Herkel J, Schwinge D*, Schramm C*. IL-17A/F enable cholangiocytes to restrict T cell-driven experimental cholangitis by upregulating PD-L1 expression. J Hepatol 2021;74:919-30.

    Creutzfeldt AM, Piecha F, Schattenberg JM, Schramm C, Lohse AW. Long-term outcome in PSC patients receiving azathioprine: Does immunosuppression have a positive effect on survival? J Hepatol 2020;73:1285-87.

    Kunzmann LK*, Schoknecht T*, Poch T, Henze L, Stein S, Kriz M, Grewe I, Preti M, Hartl J, Pannicke N, Peiseler M, Sebode M, Zenouzi R, Horvatits T, Böttcher M, Petersen BS, Weiler-Normann C, Hess LU, Elise Ahrenstorf A, Lunemann S, Martrus G, Fischer L, Li J, Carambia A, Kluwe J, Huber S, Lohse AW, Franke A, Herkel J, Schramm C, Schwinge D. Monocytes as potential mediators of pathogen-induced Th17 differentiation in patients with primary sclerosing cholangitis (PSC). Hepatology 2020;72:1310-26.

    Liwinski T*, Zenouzi R*, John C, Ehlken H, Rühlemann MC, Bang C, Groth S, Lieb W, Kantowski M, Andersen N, Schachschal G, Karlsen TH, Hov JR, Rösch T, Lohse AW, Heeren J, Franke A, Schramm C. Alterations of the bile microbiome in primary sclerosing cholangitis. Gut 2020;69:665-72.

    Glaser F*, John C*, Engel B*, Höh B*, Weidemann S, Dieckhoff J, Stein S, Becker N, Casar C, Schuran FA, Wieschendorf B, Preti M, Jessen F, Franke A, Carambia A, Lohse AW, Ittrich H, Herkel J, Heeren J, Schramm C*, Schwinge D*. Liver infiltrating T cells regulate bile acid metabolism in experimental cholangitis. J Hepatol 2019;71:783-92.

    van Heesch S, Witte F*, Schneider-Lunitz V*, Schulz JF*, Adami E, Faber AB, Kirchner M, Maatz H, Blachut S, Sandmann CL, Kanda M, Worth CL, Schafer S, Calviello L, Merriott R, Patone G, Hummel O, Wyler E, Obermayer B, Mücke MB, Lindberg EL, Trnka F, Memczak S, Schilling M, Felkin LE, Barton PJR, Quaife NM, Vanezis K, Diecke S, Mukai M, Mah N, Oh SJ, Kurtz A, Schramm C, Schwinge D, Sebode M, Harakalova M, Asselbergs FW, Vink A, de Weger RA, Viswanathan S, Widjaja AA, Gärtner-Rommel A, Milting H, Dos Remedios C, Knosalla C, Mertins P, Landthaler M, Vingron M, Linke WA, Seidman JG, Seidman CE, Rajewsky N, Ohler U, Cook SA, Hubner N. The Translational Landscape of the Human Heart. Cell 2019;178:242-260.e29.

    Schramm C. Bile Acids, the Microbiome, Immunity, and Liver Tumors. N Engl J Med 2018;379:888-90.

    Schwinge D*, von Haxthausen F*, Quaas A, Carambia A, Otto B, Glaser F, Höh B, Thiele N, Schoknecht T, Huber S, Steffens N, Lohse AW, Herkel J, Schramm C. Dysfunction of hepatic regulatory T cells in experimental sclerosing cholangitis is related with IL-12 signaling. J Hepatol 2017;66:798-805.

    Katt J, Schwinge D, Schoknecht T, Quaas A, Sobottka I, Burandt E, Becker C, Neurath MF, Lohse AW, Herkel J, Schramm C. Increased T helper type 17 response to pathogen stimulation in patients with primary sclerosing cholangitis. Hepatology 2013;58:1084-93.

    *equally contributing authors

    Verantwortlich für den Inhalt
    Autoren: Prof. Dr. rer. nat. Johannes Herkel / Prof. Dr. med. Christoph Schramm
    Erstellung: 09.12.2016
    Letzte Änderung: 13.07.2021


Molekulare Immunologie und Gastroenterologie

  • General Information and list of ongoing projects

    The incidence and prevalence of immune mediated inflammatory diseases (IMIDs) are steadily increasing. Unfortunately, most therapies used against these diseases have as of yet palliative character and mostly do not offer a cure. Thus life-long treatment using immune-suppressive agents is required in the majority of cases. As a consequence, patients with IMID must live with side effects of these treatments, such as increased risk of opportunistic infections and relapsing flares of the disease itself. Furthermore, chronic inflammation can also promote the development of certain forms of cancer. For example, it has been observed that inflammatory bowel disease (IBD) is associated with an increased risk of developing colorectal cancer, especially in patients suffering from chronic uncontrolled intestinal inflammation. Therefore, there is major need for new therapies, which can modulate the immune response more specifically.

    Recent studies by others and by our group have shown that a specific subset of CD4 T cells, the TH17 cells, and their associated cytokines play an important but ambiguous role in these diseases. These cells are known to play a key role in chronic inflammatory diseases and carcinogenesis. But on the other hand, these same cells and their cytokine products, such as IL-22, also have beneficial properties, like promotion of wound healing and defence against pathogens. This obviously reveals that it is crucial to find out the molecular and cellular mechanisms, which physiologically control TH17 cells. The main goal is to develop therapies which would not just simply deplete them, but rather reset them to their beneficial state. We have indeed already identified several mechanisms, which explain how TH17 cells and their cytokines can be physiologically controlled. Strikingly, we have found that the intestine is an organ which plays a major role in controlling the immunological process. We refer to this concept as Intestinal Immune Regulation, where we propose that the intestine is indeed one of the controlling centers of the immune system and in turn, of the systemic homeostasis. In support of this, we found that TH17 cells can be recruited to the intestine, where they are then controlled by Foxp3+ regulatory T cells (Tregs) and T regulatory type 1 cells (Tr1) via IL-10. Furthermore, TH17 cells can also acquire regulatory properties and can convert into Tr1 cells in the intestine. Finally, IL-22, a key cytokine produced by TH17 cells, can be controlled via a soluble inhibitor, namely IL-22 binding protein (IL-22BP). As described above, however, TH17 cells are one of the causes of several immune mediated diseases in several different organs, such as kidney and central nervous system (CNS). This usually results from a failure of the physiological regulatory mechanisms which are in place, especially in the intestine. We were indeed able to show in mouse models that the Intestinal Immune Regulation can also actually be used to prevent and treat diseases in peripheral organs. Thus, we are working on the hypothesis that the Intestinal Immune Regulation can be targeted for a wide variety of inflammatory diseases.

    List of ongoing research topics

    • Regulation of TH17 cell migration from several other organs to the intestine and vice versa.

    • Tissue specific control of TH17 cells by regulatory T cells.

    • Modulation of TH17 cell phenotype, stability and plasticity.

    • Identifying the network controlling the IL-22 – IL-22BP axis for targeted therapies

    • Basic and translational research aiming to validate the role of the Intestinal Immune Regulation in IBD, Hepatitis, Nephritis, Multiple Sclerosis, and intestinal carcinogenesis.

    Objectives

    Our long-term goal is to further explore and prove the hypothesis that the intestine serves as a key organ in regulating immune responses. Initially the thymus and the bone marrow were thought to be the sole control center with the ability to set or reset the immune system. In the last years however, we and others have revealed that the intestine is a key organ, which is able to finely-tune the immune system. Furthermore, this regulation also affects diseases in other peripheral organs. Thus, we hypothesize that by controlling the intestinal immune system we can prevent or cure chronic inflammatory and autoimmune diseases in seemingly unrelated organs, such as the CNS, liver and kidney. This hypothesis is based on recent findings by others and by us showing that the intestine plays a key role in modulating the balance between regulatory T cells, such as Foxp3+ Treg, Tr1 cells, and effector T cells, thereby influencing Immune-mediated inflammatory diseases in several organs. However, most T cells and cytokines have both context dependent pathogenic and protective functions. The right balance must be achieved. Thus, one key aspect of our study is to dissect complex biological systems in order to regulate rather than to block immune responses in order to facilitate the beneficial functions of these cells.

    On the basis of our previous work we are working on four connected but independent projects as shown in Figure 1.

    Methods

    General experimental approach

    The aim of our studies is to dissect complex biological systems regulating inflammation, tissue regeneration and carcinogenesis. In order to do so, we are using a step-by-step approach (Figure 2). First, we reduce a complex system to a few key factors. In particular, we break down the complexity of the system to the T cells, cytokines, microbiota, and tissues. Using a reductionist approach, we then try to understand how each factor contributes to the overall picture, depicted in Figure 2 as a house. After that, we formulate a working hypothesis which still needs to hold through in the original complex system. This will be achieved by combining the analysis of knock in and knock out mice, mouse models for human diseases and tissue samples from patients suffering from these diseases.

    Mouse Models

    We are currently maintaining a variety of well-defined transgenic mouse lines, which are important for our research projects. These include several knock in reporter mice, conditional and total knock out strains for example for IL-22, IL-22BP, and IL-22R1. Below is a list of selected mouse lines, which play key roles in the proposed projects.

    Mouse Models of intestinal inflammation, tissue damage and carcinogenesis

    We are using well-established mouse models for intestinal inflammation, tissue damage and carcinogenesis. We will monitor intestinal inflammation and tumor development by colonoscopy, weight loss and end point histology. These include the following:

    • Dextran sodium sulfate (DSS-) colitis
    • T cell transfer Colitis
    • Citrobacter Rodentium infection
    • Colitis associated colon cancer model
    • Intestinal wounding using the endoscopy and a biopsy forceps.
    • Endoscopic disease monitoring

    Mouse models for autoimmune diseases

    • EAE (Experimental autoimmune encephalomyelitis
    • NTN /Nephrotoxic Nephritis)

    16S rRNA sequence analysis:

    One key component influencing the immune system in the intestine is the microbiota. We have established a collaboration with the group from Dr. Till Strowig from the Helmholtz Zentrum für Infektionsforschung in Braunschweig, who is performing these analyses with us.

    Next Gene Seq: to deconvolute the transcriptional changes during the conversion of T helper cells toward alternative fates.

    The usage of unbiased approaches is a key step in analysing complex systems. We have accumulated a lot of experience with the SMARTer Ultra Low RNA kit from Clontech. This kit allows us to sequence the transcriptome from a small number of cells (500). Furthermore, we have established in collaboration with Prof. Gagliani the DropSeq technique, which allows us to simultaneously profile the transcriptome of huge amounts of cells with single-cell resolution. The bioinformatics analysis is performed by Dr. Babett Steglich in my lab. Principle component analysis, heat map, hierarchical cluster analysis, volcano plot and several other analyses will be performed within the scope of the experiment.

    CRISPR/Cas9: to analyse in vivo the role of the candidate genes identified by Next Gen Seq. Our aim is to test the role of candidate genes, identified by next gen sequencing analysis in vivo. With this technology, it is possible to generate multiple conditional knock out mouse lines and test the role of the candidate molecules and in turn disease susceptibility. This technique has been established in the last years in collaboration with Prof. Gagliani and Dr. Irm Hermans-Borgmeyer (transgenic mouse core facility of the UKE), who is also performing the injections into the cytoplasm of fertilized eggs.

    Selected Publications

    Kempski J, Giannou AD, Riecken K, Zhao L, Steglich B, Lücke J, Garcia-Perez L, Karstens KF, Wöstemeier A, Nawrocki M, Pelczar P, Witkowski M, Nilsson S, Konczalla L, Shiri AM, Kempska J, Wahib R, Brockmann L, Huber P, Gnirck AC, Turner JE, Zazara DE, Arck PC, Stein A, Simon R, Daubmann A, Meiners J, Perez D, Strowig T, Koni P, Kruglov AA, Sauter G, Izbicki JR, Guse AH, Rösch T, Lohse AW, Flavell RA, Gagliani N*, Huber S*. IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans. Gastroenterology 2020;159:1417-30.e3.

    Perez LG, Kempski J, McGee HM, Pelzcar P, Agalioti T, Giannou A, Konczalla L, Brockmann L, Wahib R, Xu H, Vesely MCA, Soukou S, Steglich B, Bedke T, Manthey C, Seiz O, Diercks BP, Gnafakis S, Guse AH, Perez D, Izbicki JR, Gagliani N, Flavell RA*, Huber S*.TGF-beta signaling in Th17 cells promotes IL-22 production and colitis-associated colon cancer. Nat Commun 2020;11:2608.

    Brockmann L, Soukou S, Steglich B, Czarnewski P, Zhao L, Wende S, Bedke T, Ergen C, Manthey C, Agalioti T, Geffken M, Seiz O, Parigi SM, Sorini C, Geginat J, Fujio K, Jacobs T, Roesch T, Izbicki JR, Lohse AW, Flavell RA, Krebs C, Gustafsson JA, Antonson P, Roncarolo MG, Villablanca EJ, Gagliani N*, Huber S*. Molecular and functional heterogeneity of IL-10-producing CD4(+) T cells. Nat Commun 2018;9:5457.

    Pelczar P, Witkowski M, Perez LG, Kempski J, Hammel AG, Brockmann L, Kleinschmidt D, Wende S, Haueis C, Bedke T, Witkowski M, Krasemann S, Steurer S, Booth CJ, Busch P, König A, Rauch U, Benten D, Izbicki JR, Rösch T, Lohse AW, Strowig T, Gagliani N, Flavell RA*, Huber S*. A pathogenic role for T cell-derived IL-22BP in inflammatory bowel disease. Science 2016;354:358-62.

    Gagliani N, Amezcua Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW, de Zoete MR, Licona-Limón P, Paiva RS, Ching T, Weaver C, Zi X, Pan X, Fan R, Garmire LX, Cotton MJ, Drier Y, Bernstein B, Geginat J, Stockinger B, Esplugues E, Huber S*, Flavell RA*. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 2015;523:221-5.

    Gagliani N*, Magnani CF*, Huber S*, Gianolini ME, Pala M, Licona-Limon P, Guo B, Herbert DR, Bulfone A, Trentini F, Di Serio C, Bacchetta R, Andreani M, Brockmann L, Gregori S, Flavell RA, Roncarolo MG. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med 2013;19:739-46.

    Huber S*, Gagliani N*, Zenewicz LA, Huber FJ, Bosurgi L, Hu B, Hedl M, Zhang W, O'Connor W Jr, Murphy AJ, Valenzuela DM, Yancopoulos GD, Booth CJ, Cho JH, Ouyang W, Abraham C, Flavell RA. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 2012;491:259-63.

    Esplugues E*, Huber S*, Gagliani N, Hauser AE, Town T, Wan YY, O'Connor W Jr, Rongvaux A, Van Rooijen N, Haberman AM, Iwakura Y, Kuchroo VK, Kolls JK, Bluestone JA, Herold KC, Flavell RA. Control of TH17 cells occurs in the small intestine. Nature 2011;475:514-8.

    Huber S*, Gagliani N*, Esplugues E*, O'Connor W Jr, Huber FJ, Chaudhry A, Kamanaka M, Kobayashi Y, Booth CJ, Rudensky AY, Roncarolo MG, Battaglia M, Flavell RA. Th17 cells express interleukin-10 receptor and are controlled by Foxp3 and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 2011;34:554-65.

    *equally contributing authors

    Kontakt

    • Telefon
      Telefon/Fax

      Office ( Jaana Hellmuth, Mo.-Mi. 9-14 Uhr)

      Phone: +49 (0) 40 7410 - 20982

      Fax: +49 (0) 40 7410 - 40313

      Lab

      Phone: +49 (0) 40 7410 - 56398

      Fax: +49 (0) 40 7410 - 59038

    Principal Investigator (PI)

    Prof. Dr. med. Samuel Huber

    Postdocs:

    Dr. rer. nat. Tanja Bedke

    Anastasios Giannou, MD, Ph.D.

    Dr. med. Sina Hübener

    Dr. med. Francis Huber

    Dr. rer. nat. Penelope Pelczar

    Babett Steglich, Ph.D. (auch AG Gagliani )

    Andres Pablo Machicote, Ph.D.

    Dr. rer. nat. Antonella Fazio

    Lis Noelia Velasquez, Ph.D.

    Dr. rer. nat. Shiwa Soukou-Wargalla

    Dr. med. Can Ergen-Behr

    Ph.D. - and MD-candidates:

    Franziska Bertram, cand. med.

    Marius Böttcher, MD

    Jan Kempski, cand. med.

    Mikolaj Nawrocki, cand. med.

    Morsal Sabihi, M. Sc.

    Mustafa Shiri, M.Sc.

    Friederike Stumme, M.Sc.

    Beibei Liu, cand. med.

    Rongrong Jia, cand. med.

    Tao Zhang, cand. med.

    Loreen Heuer, cand. med.

    Lennart Bauditz, cand. med.

    Anissa Franke, cand. med.

    Philipa Loose, cand. med.

    Technician:

    Cathleen Haueis, BTA

    Sandra Wende, BTA

    Verantwortlich für den Inhalt
    Autor: Dr. rer. nat. Antonella Fazio
    Erstellung: 11.06.2015
    Letzte Änderung: 16.06.2021
  • Endogene Alarmsignale in Regulation von Immunantworten

    Entzündliche Prozesse sind Bestandteil der komplexen immunologischen Antwort eines Organismus auf sterile oder infektiöse Schädigung vaskularisierter Gewebe. Während die entzündungsfördernden Funktionen von inflammatorischen Zytokinen und Chemokinen in vielen Geweben gut untersucht und belegt sind, bleibt ungeklärt, auf welche Weise geschädigte Zellen diese Signalkaskaden auslösen und wie die resultierenden Entzündungsreaktionen reguliert werden. Es wird angenommen, dass in prinzipiell jedem Organ gestresste oder zerfallende Zellen Bestandteile freisetzen können, die über spezifische, evolutionär konservierte Rezeptorsysteme entzündliche Kaskaden und regenerative Prozesse in Gang setzen. Diese zellulären Bestandteile werden als "damage-associated molecular patterns" (DAMPs) oder "Alarmine" bezeichnet. Im Gegensatz dazu gelten klassischerweise molekulare Bestandteile von Pathogenen (z.B. Lipopolysaccharid, LPS) als Auslöser infektassoziierter Entzündungen und werden dementsprechend als "pathogen-associated molecular patterns" (PAMPs) bezeichnet. Diese ursprünglich fast paradigmatische konzeptuelle Unterscheidung zwischen sterilen und infektiösen Entzündungsmechanismen weicht indes zunehmend einem Verständnis, in dem Parenchymzellen, Entzündungszellen und gegebenenfalls exogene Pathogene in ein komplexes Zusammenspiel dynamischer gegenseitiger Beeinflussung treten.

    Wir haben gezeigt, dass das ubiquitär exprimierte körpereigene Alarmin High-mobility group box 1 (HMGB1) im Zusammenspiel mit seinem Hauptrezeptor RAGE essenziell für die Rekrutierung von Entzündungszellen nach steriler nekrotischer Gewebsschädigung ist, und dass diese Entzündungszellen aktiv zur Gewebsschädigung beitragen. Der evolutionäre Vorteil dieses Mechanismus könnte in einem "Präventivschlag" gegen mikrobielle Besiedelung von Wundflächen liegen, der um den Preis einer zunächst verstärkten Gewebsschädigung erkauft wird. Der Fokus unserer Arbeitsgruppe liegt daher auf der Rolle körpereigener Alarmsignale in der Initiation und Unterhaltung entzündlicher Prozesse im Rahmen von infektiösen Erkrankungen, die in sehr unterschiedlichem Ausmaß mit qualitativ und quantitativ heterogenen Zell- und Organschädigungen einhergehen. Neben der Aufklärung relevanter zellulärer Effektoren dieser endogenen Schiene der Immunaktivierung befassen wir uns mit der Frage, inwiefern körpereigene Botenstoffe als immunologisches Adjuvans in der Ausbildung einer adaptiven Immunantwort benötigt werden.

    Mitarbeiter

    Dr. Peter Hübener, Oberarzt

    Elisabeth Zierz, M.Sc.

    Irke Wassmann, M.Sc.

    Ausgewählte Publikationen

    Volmari A*, Foelsch K*, Zierz E1, Yan K, Qi M, Bartels K, Kondratowicz S, Boettcher M, Reimers D, Nishibori M, Liu K, Schwabe RF, Lohse AW, Huber S, Mittruecker HW, Huebener P. Leukocyte-derived High-mobility group box 1 governs hepatic immune responses against Listeria monocytogenes. Hepatology Communications 2021 doi: https://doi.org/10.1101/797902

    Hoste E, Maueröder C, van Hove L, Catrysse L, Vikkula HK, Sze M, Maes B, Karjosukarso D, Martens L, Gonçalves A, Parthoens E, Roelandt R, Declercq W, Fuentes I, Palisson F, Gonzalez S, Salas-Alanis JC, Boon L, Huebener P, Mulder KW, Ravichandran K, Saeys Y, Schwabe RF, van Loo G. Epithelial HMGB1 Delays Skin Wound Healing and Drives Tumor Initiation by Priming Neutrophils for NET Formation. Cell Rep 2019;29:2689-2701.e4.

    Hernandez C*, Huebener P*, Pradere JP, Antoine DJ, Friedman RA, Schwabe RF. HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis. J Clin Invest 2018;128:2436-51.

    Kleinschmidt D, Giannou AD, McGee HM, Kempski J, Steglich B, Huber FJ, Ernst TM, Shiri AM, Wegscheid C, Tasika E, Hübener P, Huber P, Bedke T, Steffens N, Agalioti T, Fuchs T, Noll J, Lotter H, Tiegs G, Lohse AW, Axelrod J, Galun E, Flavell RA, Gagliani N, Huber S. A Protective Function of IL-22BP in Ischemia Reperfusion and Acetaminophen-Induced Liver Injury. J Immunol 2017;199:4078-90.

    Hernandez C*, Hübener P*, Schwabe RF. Damage-associated molecular patterns in cancer a double-edged sword. Oncogene 2016;35:5931-41.

    Karimi K, Keßler T, Thiele K, Ramisch K, Erhardt A, Hübener P, Barikbin R, Arck P, Tiegs G. Prenatal acetaminophen induces liver toxicity in dams, reduces fetal liver stem cells, and increases airway inflammation in adult offspring. J Hepatol 2015;62:1085-91.

    Hübener P, Gwak GY, Schwabe RF. Comment on: HMGB1-dependent and -independent autophagy. Autophagy 2015;11:1187-88.

    Hübener P*, Gwak GY*, Pradere JP, …, Goldberg IJ, Czaja MJ, Schwabe RF. High-mobility group box 1 is dispensable for autophagy, mitochondrial quality control, and organ function in vivo. CellMetab 2014;19:539-47.

    Hübener P*, Pradere JP*, Hernandez C*, Gwak GY, Caviglia JM, Mu X, Loike JD, Jenkins RE, Antoine DJ, Schwabe RF. The HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis. J Clin Invest 2015;125:539-50.

    *equally contributing authors

    Verantwortlich für den Inhalt
    Autor: Dr. Peter Hübener
    Erstellung: 11.06.2015
    Letzte Änderung: 16.07.2021
  • General Information

    In this lab we like studying the basic aspects of T cell biology, adaptation to environmental changes, and ultimately, how T cells either mediate physiological responses to pathogens or pathological tissue damaging processes. We combine different scientific methods and expertise to study the transcriptional and epigenetic regulation of key cytokine genes and the cellular trajectory and function of T cells in different non lymphoid tissues. We also make use of several mouse models of infections and diseases. Finally, we use system biology approaches and human samples to test the clinical relevance of our basic discoveries to provide the first step towards better therapies for human diseases.

    Key technologies available in the lab:

    • Conditional KO mouse models
    • Cytokine reporter mouse models
    • Fate mapping mouse models
    • In vivo and in vitro Cas9
    • Germ-free facility
    • Single Cell RNA/TCR/CITE seq
    • System biology in collaboration with Prof. S. Bonn


    Principal Investigator (PI) -
    Prof. Nicola Gagliani Ph.D.

    Contact profil - Prof. Nicola Gagliani Ph.D.
    More information - Research Portal UKE


    PostDocs:

    Theodora Agalioti Ph.D.
    Babett Steglich Ph.D. (part also of AG Prof. S. Huber)
    Franzisca Muscate Ph.D.
    Francesco Siracusa Ph.D.
    Filippo Cortesi Ph.D.
    Yogesh Kumar Ph.D.

    Clinician Scientists:

    Anna Wostemeier MD
    Jenny Krause MD
    Jonas Wagner MD
    Joseph Tintelnot MD

    Ph.D. students:
    Yang Xu MD
    Guido Rattay

    Technicians:
    Petra Market MTA
    Ayob Aleko MTA

    Management & Communication:
    Dana Klatt

    Project TitleFunding sourcePeriodRole of the PI
    Understanding the role of the
    microbiota and microbiota
    derived metabolites in therapy
    resistance of pancreatic
    cancer
    Deutsche Krebshilfe2021-2024Co-Pi
    Interactions between Metabolism
    and inflammation
    LFF joint2020-2023Co-PI
    Leber und AutoimmunitätLFF2020-2023PI
    Tissue resident memory
    T cells in glomerulonephritis
    DFG, CRC 1192/2,2020-2023Co-PI
    Immunology IncubatorRoche2021-2023PI
    Extracellular ATP to adenosine
    axis in the biology of regulatory
    and effector T cells.
    DFG, CRC13282018-2022Co-PI
    Analysis of the molecular and
    functional heterogeneity of
    Foxp3Neg IL-10-producing T cells.
    DFG, GA 2441/3-12019-2022Co-PI
    Inflammatory processes in the
    development of
    cholangiocarcinoma in Primary
    Sclerosing Cholangitis – Do the
    T cells play a role?
    DFG, CRU 3062019-2022PI
    Diet during pregnancy and
    maternal obesity: effects on the
    function of maternal TH17 and
    Treg cells and on subsequent
    offspring health.
    DFG, CRU 2962018-2022Co-PI
    Progression from NAFLD to NASH:
    Miscommunication between the
    intestinal microbiota and the CD4
    T cells as a potential cause
    DFG, CRC 841/32018-2022PI
    DietNamicERC, StG2016-2022PI
  • General information and list of ongoing projects

    The AG Schulze zur Wiesch aims to understand the immunological control and immunopathology of different chronic viral diseases like viral hepatitis and HIV. The focus of our translational investigations is the exact understanding and characterization of the virus-specific T cell response of these diseases and of individual patients (“from bed to bench”). The group consists of both biologists and PhD students as well as MDs and MD students. Funding is provided by a broad range of organizations (DFG SFB841+SFB1328), German Center for Infection (DZIF), EU and AmfAR, altogether reflecting the breadth of the different topics and diseases studied in this group in a collaborative way.

    We are employing a number of different state of the art methods like multicolor flow cytometry, intracellular cytokine staining, MHC class I +II tetramer staining, ELISpot-assays, PCR and cell cultures to understand the molecular mechanisms of viral chronicity in patient blood and tissue samples (eg. liver biopsies and intestinal mucosa). Overall, we see that the virus-specific immune response is blunted in many cases by expression of co-inhibitory molecules and pathways in patients with chronic disease and are trying to find novel avenues to re-invigorate the antiviral immune response.

    As translational immunological group we take part in several clinical vaccine and immune interventional studies.


    List of ongoing research projects:

    Autoimmunology-related projects:

    • The role of ectonucleotidases in patients with Graft-versus-Host disease (GvHD) and inflammatory bowel disease (IBD)

    HIV-related projects:HIV-related projects:

    • Icistem project
    • European HIV vaccine alliance
    • Studies of the viral reservoir in HIV infection / finding the needle in the haystack
    • Shock and kill strategy to eliminate latently infected cells
    • Gammadelta Regulatory T cells in HIV Infection
    Viral hepatitis-related projects:
    • Ex vivo characterization of coinhibitory molecules on MHC class II tetramer positive HCV-specific T cells in HCV infection
    Malaria-related projects:
    • Specific T cells in Malaria


  • General Information

    In our lab, we study the interaction among cancer, stroma and immune cells with the long-term aim of enabling future therapies to prevent or treat metastasis formation. Our team has expertise on cancer and related metastasis. By using transgenic mice combined with metastasis models and state-of-the art microsurgical techniques (e.g., trachea, lung, liver and intestine transplantation in mouse and rat models) we aim to understand how target metastasis organ microenvironment can be modulated to prevent or treat metastasis and to study complex cellular mechanisms directly in vivo, such as the emergence and function of tissue-resident immune cells. Finally, we use human samples isolated from patients suffering from metastasis in order to be able to translate our findings into the human condition.

    Key methods-technologies available in the lab:

    • Conditional Knock out mouse models
    • Culture of colon organoids carrying specific mutations
    • Forced models of liver and lung metastasis
    • Spontaneous models of liver and lung metastasis
    • Organ Transplantation (Orthotopic single left lung, liver, trachea and small intestine transplantation)
    • Models of liver and lung carcinogenesis
    • In vitro and in vivo transmigration assays of cancer cells
    • Extravasation assays
    • Isolation of lung and live endothelial cells and in vitro and in vivo endothelial assays
    • Germ-free facility
    • Single Cell RNA seq

    Figure 1. Graphical abstract summarizing the role of iNKT17 cell-derived IL-22 in regulating vascular endothelium and thereby promoting cancer cell extravasation and liver metastasis formation. Tissue resident iNKT17 cell derived IL-22 is promoting the early extravasation of CRC cancer cells into the liver parenchyma by increasing the permeability of the endothelium via ANPEP (Giannou et al., Immunity, 2023).

    Selected publications

    Giannou AD#, Kempski J#, Shiri AM#, Lücke J, Zhang T, Zhao L, Zazara DE, Cortesi F, Riecken K, Amezcua Vesely MC, Low JS, Xu H, Kaffe E, Garcia-Perez L, Agalioti T, Yamada Y, Jungraithmayr W, Zigmond E, Karstens KF, Steglich B, Wagner J, Konczalla L, Carambia A, Schulze K, von Felden J, May P, Briukhovetska D, Bedke T, Brockmann L, Starzonek S, Lange T, Koch C, Riethdorf S, Pelczar P, Böttcher M, Sabihi M, Huber FJ, Reeh M, Grass JK, Wahib R, Seese H, Stüben BO, Fard-Aghaie M, Duprée A, Scognamiglio P, Plitzko G, Meiners J, Soukou S, Wittek A, Manthey C, Maroulis IC, Arck PC, Perez D, Gao B, Zarogiannis SG, Strowig T, Pasqualini R, Arap W, Gosálvez JS, Kobold S, Prinz I, Guse AH, Tachezy M, Ghadban T, Heumann A, Li J, Melling N, Mann O, Izbicki JR, Pantel K, Schumacher U, Lohse AW, Flavell RA, Gagliani N, Huber S. Tissue resident iNKT17 cells facilitate cancer cell extravasation in liver metastasis via interleukin-22. Immunity 2023;56:125-142.e12. doi:10.1016/ j.immuni.2022.12.014.

    Tintelnot J, Xu Y, Lesker TR, Schönlein M, Konczalla L, Giannou AD, Pelczar P, Kylies D, Puelles VG, Bielecka AA, Peschka M, Cortesi F, Riecken K, Jung M, Amend L, Bröring TS, Trajkovic-Arsic M, Siveke JT, Renné T, Zhang D, Boeck S, Strowig T, Uzunoglu FG, Güngör C, Stein A, Izbicki JR, Bokemeyer C, Sinn M, Kimmelman AC, Huber S#, Gagliani N#. Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. Nature 2023; Mar;615(7950):168-174. doi: 10.1038/s41586-023-05728-y. Epub 2023 Feb 22.

    Giannou AD#, Kempski J#, Zhang T#, Lücke J#, Shiri AM, Zazara DE, Belios I, Machicote A, Seeger P, Agalioti T, Tintelnot J, Sagebiel A, Tomczak M, Bauditz L, Bedke T, Kocheise L, Mercanoglu B, Fard-Aghaie M, Giorgakis E, Lykoudis PM, Pikouli A, Grass JK, Wahib R, Bardenhagen J, Brunswig B, Heumann A, Ghadban T, Duprée A, Tachezy M, Melling N, Arck PC, Stringa P, Gentilini MV, Gondolesi GE, Nakano R, Thomson AW, Perez D, Li J, Mann O, Izbicki JR, Gagliani N, Maroulis IC#, Huber S#. IL-22BP controls the progression of liver metastasis in colorectal cancer. Front Oncol 2023; May 31;13:1170502. doi: 10.3389/fonc.2023.1170502. eCollection 2023.

    Lücke J#, Nawrocki M#, Schnell J, Meins N, Heinrich F, Zhang T, Bertram F, Sabihi M, Böttcher M, Blankenburg T, Pfaff M, Notz S, Kempski J, Reeh M, Wolter S, Mann O, Izbicki JR, Lütgehetmann M, Duprée A, Giannou AD#, Ondruschka B#, Huber S#. TNFα aggravates detrimental effects of SARS-CoV-2 infection in the liver. Front Immunol 2023; Mar 31;14:1151937. doi: 10.3389/fimmu.2023.1151937. eCollection 2023.

    Zhao L#, Giannou AD#, Xu Y#, Shiri AM, Liebold I, Steglich B, Bedke T, Zhang T, Lücke J, Scognamiglio P, Kempski J, Woestemeier A, Chen J, Agalioti T, Zazara DE, Lindner D, Janning M, Hennigs JK, Jagirdar RM, Kotsiou OS, Zarogiannis SG, Kobayashi Y, Izbicki JR, Ghosh S, Rothlin CV, Bosurgi L#, Huber S#, Gagliani N#. Efferocytosis fuels malignant pleural effusion through TIMP1. Sci Adv 2021;7:eabd6734. doi:10.1126/sciadv.abd6734.

    Zhao L#, Giannou AD#, Xu Y#, Shiri AM, Liebold I, Steglich B, Bedke T, Zhang T, Lücke J, Scognamiglio P, Kempski J, Woestemeier A, Chen J, Agalioti T, Zazara DE, Lindner D, Janning M, Hennigs JK, Jagirdar RM, Kotsiou OS, Zarogiannis SG, Kobayashi Y, Izbicki JR, Ghosh S, Rothlin CV, Bosurgi L#, Huber S#, Gagliani N#. Efferocytosis fuels malignant pleural effusion through TIMP1. Sci Adv 2021;7:eabd6734. doi:10.1126/sciadv.abd6734.

    Kempski J#, Giannou AD#, Riecken K, Zhao L, Steglich B, Lücke J, Garcia-Perez L, Karstens KF, Wöstemeier A, Nawrocki M, Pelczar P, Witkowski M, Nilsson S, Konczalla L, Shiri AM, Kempska J, Wahib R, Brockmann L, Huber P, Gnirck AC, Turner JE, Zazara DE, Arck PC, Stein A, Simon R, Daubmann A, Meiners J, Perez D, Strowig T, Koni P, Kruglov AA, Sauter G, Izbicki JR, Guse AH, Roesch T, Lohse AW, Flavell RA, Gagliani N#, Huber S#. IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans. Gastroenterology 2020;159:1417-30. doi:10.1053/j.gastro.2020.06.033. Epub 2020 Jun 22.

    Kanellakis NI#, Giannou AD#, Pepe MAA#, Agalioti T, Zazara DE, Giopanou I, Psallidas I, Spella M, Marazioti A, Arendt KAM, Lamort AS, Champeris Tsaniras S, Taraviras S, Papadaki H, Lilis I#, Stathopoulos GT#. Tobacco chemical-induced mouse lung adenocarcinoma cell lines pin the prolactin orthologue proliferin as a lung tumour promoter. Carcinogenesis 2019;Nov 25;40(11):1352-1362. doi:10.1093/carcin/bgz047.

    Kleinschmidt D#, Giannou AD#, McGee HM, Kempski J, Steglich B, Huber FJ, Ernst TM, Shiri AM, Wegscheid C, Tasika E, Hübener P, Huber P, Bedke T, Steffens N, Agalioti T, Fuchs T, Noll J, Lotter H, Tiegs G, Lohse AW, Axelrod JH, Galun E, Flavell RA, Gagliani N, Huber S. A Protective Function of IL-22BP in Ischemia Reperfusion and Acetaminophen-Induced Liver Injury. J Immunol 2017;199:4078-90. doi:10.4049/jimmunol.1700587. Epub 2017 Nov 6.

    Agalioti T#, Giannou AD#, Krontira AC#, Kanellakis NI, Kati D, Vreka M, Pepe M, Spella M, Lilis I, Zazara DE, Nikolouli E, Spiropoulou N, Papadakis A, Papadia K, Voulgaridis A, Harokopos V, Stamou P, Meiners S, Eickelberg O, Snyder LA, Antimisiaris SG, Kardamakis D, Psallidas I, Marazioti A, Stathopoulos GT. Mutant KRAS promotes malignant pleural effusion formation. Nat Commun 2017;8:15205. doi:10.1038/ncomms15205.

    Giannou AD#, Marazioti A#, Kanellakis NI#, Giopanou I#, Lilis I, Zazara DE, Ntaliarda G, Kati D, Armenis V, Giotopoulou GA, Krontira AC, Lianou M, Agalioti T, Vreka M, Papageorgopoulou M, Fouzas S, Kardamakis D, Psallidas I, Spella M#, Stathopoulos GT#. NRAS destines tumor cells to the lungs. EMBO Mol Med 2017;9:672-86. doi:10.15252/emmm.201606978.

    Giannou AD, Marazioti A, Spella M, Kanellakis NI, Apostolopoulou H, Psallidas I, Prijovich ZM, Vreka M, Zazara DE, Lilis I, Papaleonidopoulos V, Kairi CA, Patmanidi AL, Giopanou I, Spiropoulou N, Harokopos V, Aidinis V, Spyratos D, Teliousi S, Papadaki H, Taraviras S, Snyder LA, Eickelberg O, Kardamakis D, Iwakura Y, Feyerabend TB, Rodewald HR, Kalomenidis I, Blackwell TS, Agalioti T, Stathopoulos GT. Mast cells mediate malignant pleural effusion formation. J Clin Invest. 2015 Jun;125(6):2317-34. doi: 10.1172/JCI79840. Epub 2015 Apr 27.

    #equally contributing authors

    Principal Investigator

    Anastasios Giannou, NP, MD, MSc, PhD.

    PostDoc

    • Tao Zhang, MD

    Clinician Scientists

    • Jöran Lücke
    • Philipp Seeger

    PhD students

    • Siwen Zhang
    • Eleftherios Papazoglou

    MD students

    • Lennart Bauditz, cand. med.

    Technician

    • Tom Blankenburg, MTA

    Funding Giannou

    Funding

    Anastasios Giannou is funded by: Deutsche Krebshilfe, DFG (RU 5068), Erich und Gertrud Roggenbuck-Stiftung, Else Kröner Fresenius Stiftung, Fritz Thyssen Stiftung, German Academic Exchange Service (DAAD), Hamburger Krebsgesellschaft e.V., JUNG-Stiftung, Monika Kutzner Stiftung, UKE, Werner-Otto-Stiftung (alphabethical order).

    Verantwortlich für den Inhalt
    Autor: Anastasios Giannou
    Erstellung: 05.10.2023
    Letzte Änderung: 06.10.2023
  • General information

    Our laboratory focuses on studying the mechanisms that regulate macrophage responses during infections or in response to sterile damage. Specifically, our work centers on dissecting the impact of phagocytosis of dying cells, a key function carried out by macrophages in every tissue of our body, on their capacity to trigger tissue remodeling. Our data indeed indicate that phagocytosis of dying cells by macrophages is not merely a cleaning process but significantly influences macrophage behavior. Based on these findings, we are examining tissue-specific factors contributing to the transcriptional and functional heterogeneity of phagocytic macrophages in various contexts, including homeostasis, infection with the parasite Schistosoma mansoni, and in murine models of colitis, inflammation-driven cancer, autoimmune liver diseases and upon metabolic challenges. In all of these scenarios, we have access to human tissues to implement our discoveries, thanks to our affiliation with the I. Department of Medicine at the UKE and our guest associate position at the Bernhard Notch Institute for Tropical Medicine.

    By delving deep into the mechanisms of how macrophages engage in phagocytosis and the resulting implications on tissue homeostasis, immune responses, and disease progression, we aim to contribute to the development of innovative strategies that can improve the treatment and management of various diseases.

    List of ongoing research projects

    • The impact of apoptotic cell nature on macrophage function
    • Phagocytic macrophage control of cholangitis progression
    • The paradoxical role of IL-23 released by phagocytic macrophages in the damaged liver
    • Dying cell-derived extracellular vesicles and their impact on macrophage behavior
    • Lipid processing and phagocytic capacity of adipose tissue macrophages

    Selected Publications

    Staufer T, Körnig C, Liu B, Liu Y, Lanzloth C, Schmutzler O, Bedke T, Machicote A, Parak WJ, Feliu N, Bosurgi L, Huber S, Grüner F. Enabling X-ray fluorescence imaging for in vivo immune cell tracking. Sci Rep 2023 Jul 17;13(1):11505.

    Dörk R, Pelczar P, Shiri AM, Volmari A, Zierz E, Giannou A, Böttcher M, Bosurgi L, Huber S, Manthey CF. Myeloid cell specific deletion of PDGFR-α promotes dysbiotic intestinal microbiota and thus increased colitis susceptibility. J Crohns Colitis 2023 Jun 28;jjad103.

    Liebold I, Meyer S, Heine M, Kuhl A, Witt J, Eissing L, Fischer AW, Koop AC, Kluwe J, Wiesch JSZ, Wehmeyer M, Knippschild U, Scheja L, Heeren J, Bosurgi L#, Worthmann A#. TREM2 Regulates the Removal of Apoptotic Cells and Inflammatory Processes during the Progression of NAFLD. Cells. 2023 Jan 17;12(3):341.

    Zhao L*, Giannou AD*, Xu Y*, Shiri AM, Liebold I, Steglich B, Bedke T, Zhang T, Lücke J, Scognamiglio P, Kempski J, Woestemeier A, Chen J, Agalioti T, Zazara DE, Lindner D, Janning M, Hennigs JK, Jagirdar RM, Kotsiou OS, Zarogiannis SG, Kobayashi Y, Izbicki JR, Ghosh S, Rothlin CV, Bosurgi L#, Huber S#, Gagliani N#. Efferocytosis fuels malignant pleural effusion through TIMP1. Sci Adv. 2021 Aug 13; 7(33):eabd6734.

    Liebold I, Jawazneh AA, Hamley M, Bosurgi L. Apoptotic cell signals and heterogeneity in macrophage function: Fine-tuning for a healthy liver. Semin Cell Dev Biol. 2021 Nov;119:72-81.

    Zhao Y*, Kilian C*, Turner JE*, Bosurgi L*, Roedl K*, Bartsch P, Gnirck AC, Cortesi F, Schultheiß C, Hellmig M, Enk LUB, Hausmann F, Borchers A, Wong MN, Paust HJ, Siracusa F, Scheibel N, Herrmann M, Rosati E, Bacher P, Kylies D, Jarczak D, Lütgehetmann M, Pfefferle S, Steurer S, Zur-Wiesch JS, Puelles VG, Sperhake JP, Addo MM, Lohse AW, Binder M, Huber S, Huber TB, Kluge S, Bonn S, Panzer U, Gagliani N#, Krebs CF#. Clonal expansion and activation of tissue-resident memory-like Th17 cells expressing GM-CSF in the lungs of severe COVID-19 patients. Sci Immunol 2021; 6:eabf6692.

    de Freitas E Silva R, Gálvez RI, Pereira VRA, de Brito MEF, Choy SL, Lotter H, Bosurgi L, Jacobs T. Programmed Cell Death Ligand (PD-L)-1 Contributes to the Regulation of CD4 + T Effector and Regulatory T Cells in Cutaneous Leishmaniasis. Front Immunol. 2020 Oct 22; 11:574491.

    Bosurgi L*, Hughes LD*, Rothlin CV, Ghosh S. Death begets a new beginning. Immunol Rev. 2017 Nov;280(1):8-25.

    Bosurgi L, Cao YG, Cabeza-Cabrerizo M, Tucci A, Hughes LD, Kong Y, Weinstein JS, Licona-Limon P, Schmid ET, Pelorosso F, Gagliani N, Craft JE, Flavell RA, Ghosh S, Rothlin CV. Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells. Science. 2017; 356(6342):1072-1076.

    Spadaro O, Camell CD, Bosurgi L, Nguyen KY, Youm YH, Rothlin CV, Dixit VD. IGF1 Shapes Macrophage Activation in Response to Immunometabolic Challenge. Cell Rep. 2017 Apr 11;19(2):225-234.

    *equally contributing authors

    Principal Investigator

    Lidia Bosurgi, PhD

    PostDoc

    Dr. rer. nat. Imke Liebold

    PhD students

    • Stephanie Leyk, Ph.D. candidate
    • Simon Meyer, Ph.D. candidate
    • Clarissa Lanzloth, Ph.D. candidate

    Previous lab members

    • Dr. rer. nat. Madeleine Hamley
    • Dr. rer. nat. Amirah Al Jawazneh
    • Dr. med. Felix Piecha, Clinician Scientist
    • Benjamin Kruft, MSc

    Verantwortlich für den Inhalt
    Autorin: Lidia Bosurgi
    Erstellung: 06.10.2023
    Letzte Änderung: 06.10.2023
  • General Information

    Motivation

    The number of people suffering from severe obesity is increasing rapidly worldwide.According to the German Obesity Society, 67% of men and 53% of women in Germany are already overweight. We want to understand when obesity becomes pathological and how the physiological processes in adipose tissue can be utilised to protect people from metabolic diseases or chronic inflammation, such as diabetes mellitus or Crohn's disease. This is because obesity inflammation is not only restricted to adipose tissue - the intestines and liver also become inflamed over time. Our mission is to understand this process using systems biology methods and to help affected people.

    Technology and Team

    Our methodological approach is highly interdisciplinary and combines technologies from molecular and cell biology, computer-aided analyses, animal experiments and clinical research. Accordingly, our team combines expertise from the fields of basic biological research, translational immunology, medicine, applied mathematics and computer science as well as software development, data science and artificial intelligence. Values for good scientific practice, mutual respect, tolerance and open science are also important to us.

    The methodology at the Adlung Lab involves functional experiments, mouse models, patient data, organoid cultures, computational modelling and omics technologies.

    Selected publications

    Kilian C#, Ulrich H#, Zouboulis V, Sprezyna P, Schreiber J, Landsberger T, Büttner M, Biton M, Villablanca EJ, Huber S, Adlung L. "Longitudinal single-cell data informs deterministic modelling of inflammatory bowel disease”. Biorxiv 2023. doi: 10.1101/2023.10.27.561846.

    Adlung L. "Cell and Molecular Biology for Non-Biologists". Springer Berlin Heidelberg 2022. doi: 10.1007/978-3-662-65357-9.

    Adlung L#, Stapor P#, Tönsing C#, Schmiester L, Schwarzmüller LE, Postawa L, Wang D, Timmer J, Klingmüller U, Hasenauer J, Schilling M. "Cell-to-cell variability in JAK2/STAT5 pathway components and cytoplasmic volumes defines survival threshold in erythroid progenitor cells". Cell Rep 2021 Aug 10;36(6):109507. doi: 10.1016/j.celrep.2021.109507.

    Adlung L#, Cohen Y#, Mor U#, Elinav E. "Machine learning in clinical decision making". Med 2021 Jun 11;2(6):642-665. doi: 10.1016/j.medj.2021.04.006.

    Jaitin DA#, Adlung L#, Thaiss CA#, Weiner A#, Li B#, Descamps H, Lundgren P, Bleriot C, Liu Z, Deczkowska A, Keren-Shaul H, David E, Zmora N, Eldar SM, Subezky N, Shibolet O, Hill DA, Lazar MA, Colonna M, Ginhoux F, Shapiro H, Elinav E, Amit I. "Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner". Cell 2019 Jul 25;178(3):686-698.e14. doi: 10.1016/j.cell.2019.05.054.

    # equal contribution

    Funding

    • German Research Foundation (DFG)
    • Behörde für Wissenschaft, Forschung, Gleichstellung und Bezirke (BWFGB) der Freien und Hansestadt Hamburg – Hamburg Innovation (HI)
    • German Scholars Organization and the Klaus Tschira Foundation
    • Porsche Zentren in Hamburg X HSV/FutureDock

    Principal Investigator

    Dr. rer. nat. Lorenz Adlung

    Postdoc

    Dr. rer. nat. Hanna Ulrich

    Clinician Scientists

    Dr. med. Christoph Kilian

    Lab Manager

    Paulina Sprezyna

    MD students

    Omar Homayon (cand. med.)

    Viktor Zouboulis

    Verantwortlich für den Inhalt
    Autor: Dr. rer. nat. Lorenz Adlung
    Erstellung: 05.12.2023
    Letzte Änderung: 19.12.2023


Infektionsimmunologie

  • General information and list of ongoing projects

    General information:

    We study how nonclassical HLA-I molecules affect antiviral responses and HIV-induced inflammation of the central nervous system in 3D-organoid models and with functional analysis of human immune cell subsets.

    By presenting viral protein on the surface of infected cells, classical Human leukocyte antigen class I (HLA-I) molecules activate antiviral responses while maintaining self-tolerance under healthy conditions. Nonclassical HLA-I molecules (HLA-F, HLA-E and HLA-G) shape innate and adaptive immune responses in mechanisms distinct from antigen presentation. We study how nonclassical HLA-I molecules are regulated under inflammatory conditions and during viral infection, focusing on the Human Immunodeficiency Virus (HIV). We further investigate how nonclassical HLA-I molecules modulate the function of cytotoxic effector cells such as natural killer cells and CD8+ T cells in the peripheral blood and in the highly tolerogenic environment of the liver. Here, tolerance mechanisms can result in ineffective antiviral and antitumor immune responses, but are essential to prevent autoimmune liver disease. For our studies, we focus on human culture systems such as 3D-hepatic organoid models and functional investigation of human immune cell subsets from patient cohorts and healthy individuals.

    Ongoing immune inflammation predisposes HIV-1 infected individuals to the development of HIV-1 associated neurodegeneration. As a second line of research, we investigate inflammation in the central nervous system driven by HIV-1 infection. HIV-1 infection of macrophages and microglia is studied in human induced pluripotent stem cell-derived cerebral organoids. This neuro-immune 3D-culture model consists of neurons and glial cells and enables us to investigate the direct link between activated microglia and neuronal damage.

    List of ongoing research projects:

    • Natural killer cell regulation of T cells in HIV-1 infection
    • Microglia in HIV-1 associated neurodegeneration
    • The role of HLA-F in liver inflammation and infection
    • Nonclassical HLA-I (HLA-F and HLA-E)-dependent immune responses in HIV-1

    Group Members:

    • Dr. Leonore Mensching (Post-Doc)
    • Sébastien Brias (PhD student)
    • Timo Trenkner (PhD student)
    • Janet I. Akko (cand. med.)
    • Thomas van Stigt Thans (cand. med.)
    • Maya Beiersdorfer (cand. med.)

    Selected Publications:

    2021

    Koyro TF, Kraus E, Lunemann S, Hölzemer A, Wulf S, Jung J, Fittje P, Henseling F, Körner C, Huber TB, Grundhoff A, Wiech T, Panzer U, Fischer N, Altfeld M. Upregulation of HLA-F expression by BK polyomavirus infection induces immune recognition by KIR3DS1-positive natural killer cells. Kidney Int 2021;99:1140-8.

    Graf LM, Rosenkranz SC, Hölzemer A, Hagel C, Goebell E, Jordan S, Friese MA, Addo MM, Schulze Zur Wiesch J, Beisel C. Clinical Presentation and Disease Course of 37 Consecutive Cases of Progressive Multifocal Leukoencephalopathy (PML) at a German Tertiary-Care Hospital: A Retrospective Observational Study. Front Neurol 2021;12:632535.

    2019

    van Stigt Thans T*, Akko JI*, Niehrs A, Garcia-Beltran WF, Richert L, Stürzel CM, Ford CT, Li H, Ochsenbauer C, Kappes JC, Hahn BH, Kirchhoff F, Martrus G, Sauter D, Altfeld M, Hölzemer A. Primary HIV-1 Strains Use Nef To Downmodulate HLA-E Surface Expression. J Virol 2019;93:e00719-19.

    Niehrs A, Garcia-Beltran WF, Norman PJ, Watson GM, Hölzemer A, Chapel A, Richert L, Pommerening-Röser A, Körner C, Ozawa M, Martrus G, Rossjohn J, Lee JH, Berry R, Carrington M, Altfeld M. A subset of HLA-DP molecules serve as ligands for the natural cytotoxicity receptor NKp44. Nat Immunol 2019;20:1129-37.

    2018

    Lunemann S, Schöbel A, Kah J, Fittje P, Hölzemer A, Langeneckert AE, Hess LU, Poch T, Martrus G, Garcia-Beltran WF, Körner C, Ziegler AE, Richert L, Oldhafer KJ, Schulze Zur Wiesch J, Schramm C, Dandri M, Herker E, Altfeld M. Interactions Between KIR3DS1 and HLA-F Activate Natural Killer Cells to Control HCV Replication in Cell Culture. Gastroenterology 2018;155:1366-71.

    2017

    Hölzemer A, Garcia-Beltran WF, Altfeld M. Natural Killer Cell Interactions with Classical and Non-Classical Human Leukocyte Antigen Class I in HIV-1 Infection. Front Immunol 2017;8:1496.

    Körner C, Simoneau CR, Schommers P, Granoff M, Ziegler M, Hölzemer A, Lunemann S, Chukwukelu J, Corleis B, Naranbhai V, Kwon DS, Scully EP, Jost S, Kirchhoff F, Carrington M, Altfeld M. HIV-1-Mediated Downmodulation of HLA-C Impacts Target Cell Recognition and Antiviral Activity of NK Cells. Cell Host Microbe 2017;22:111-9.e4.

    Dulberger CL, McMurtrey CP, Hölzemer A, Neu KE, Liu V, Steinbach AM, Garcia- Beltran WF, Sulak M, Jabri B, Lynch VJ, Altfeld M, Hildebrand WH, Adams EJ. Human Leukocyte Antigen F Presents Peptides and Regulates Immunity through Interactions with NK Cell Receptors. Immunity. 2017;46:1018-29.e7.

    2016

    Lunemann S, Martrus G, Hölzemer A, Chapel A, Ziegler M, Körner C, Garcia Beltran W, Carrington M, Wedemeyer H, Altfeld M. Sequence variations in HCV core-derived epitopes alter binding of KIR2DL3 to HLA-C∗03:04 and modulate NK cell function. J Hepatol 2016;65:252-8.

    Garcia-Beltran WF, Hölzemer A, Martrus G, Chung AW, Pacheco Y, Simoneau CR, Rucevic M, Lamothe-Molina PA, Pertel T, Kim TE, Dugan H, Alter G, Dechanet- Merville J, Jost S, Carrington M, Altfeld M. Open conformers of HLA-F are high- affinity ligands of the activating NK-cell receptor KIR3DS1. Nat Immunol 2016;17:1067-74.

    2015

    Hölzemer A*, Thobakgale CF*, Jimenez Cruz CA, Garcia-Beltran WF, Carlson JM, van Teijlingen NH, Mann JK, Jaggernath M, Kang SG, Körner C, Chung AW, Schafer JL, Evans DT, Alter G, Walker BD, Goulder PJ, Carrington M, Hartmann P, Pertel T, Zhou R, Ndung'u T, Altfeld M. Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa. PLoS Med 2015;12:e1001900; discussion e1001900.

    2014

    van Teijlingen NH*, Hölzemer A*, Körner C, García-Beltrán WF, Schafer JL, Fadda L, Suscovich TJ, Brander C, Carrington M, Evans DT, van Baarle D, Altfeld M. Sequence variations in HIV-1 p24 Gag-derived epitopes can alter binding of KIR2DL2 to HLA-C*03:04 and modulate primary natural killer cell function. AIDS 2014;28:1399-408.

    *equally contributing authors

    Verantwortlich für den Inhalt
    Autor: Dr. med. Angelique Hölzemer
    Erstellung: 05.10.2020
    Letzte Änderung: 17.06.2021


Virushepatitis-Infektionen

  • Virushepatitis

    Häufigster und wichtigster Auslöser einer Leberschädigung sind Infektionserreger, wobei Hepatitisviren eine zentrale Rolle spielen. Weltweit sind fast 500 Millionen Menschen chronisch mit Hepatitis-B-, D- und C-Viren infiziert. Langfristig führt dies zu einem erhöhten Risiko, an Lebezirrhose und an einem hepatozellulären Karzinom zu erkranken. Das Forschungsfeld der viralen Hepatitis wurde durch das Fehlen geeigneter Zellkultursysteme und Tiermodelle stark limitiert. Unsere Arbeitsgruppe benutzt ein einzigartiges Transplantationsmodell, das auf der Repopulierung der Mausleber mit fremden Hepatozyten basiert. Als Empfängertiere dienen Mäuse, bei denen aufgrund eines leberzell-toxisch wirkenden Transgens (uPA: Uroplasminogenaktivator) endogene Maushepatozyten zu Grunde gehen. Dies ermöglicht eine fast komplette Rekonstitution der Mausleber mit menschlichen Leberzellen. Das dauerhafte Überleben der transplantierten Fremd-Hepatozyten wird durch das Einkreuzen immundefizienter Mäusen (SCID/beige oder SCID/IL2γr) erreicht, sodass keine Abstoßungsreaktionen stattfinden können. Diese "humanisierten" Mäuse können nun mit humanen Hepatitisviren (HBV, HDV, HCV und HEV) infiziert werden (Fig.1), worauf es zu einer persistierenden Virämie kommt, die der natürlichen viralen Infektion beim Menschen vergleichbar ist. Durch die Nutzung dieses Modells können wir erstmalig den kompletten Replikationszyklus dieser Viren in vivo untersuchen, sowie die Wirksamkeit verschiedener, sich in der Entwicklung befindlicher antiviraler Medikamente testen.

    Forschungsschwerpunkt

    • Präklinische Studien um verbesserte Behandlungsmethoden zu entwickeln (Testung neuer Medikamente)
    • Molekulare Mechanismen der HBV- und HDV-Persistenz
    • Interaktionen zwischen humanen hepatotropen Viren (HBV, HDV, HCV, HEV) und der humanen angeborenen Immunantwort (das heißt Interferon-Signalwege)

    Themenbereich HBV (Projektleiterin: Prof. Dr. Maura Dandri)

    Die bisherigen Heilungsraten durch antivirale Therapie mit Inhibitoren der HBV-Replikation (Nukleosidanaloga) oder mit Interferon sind leider gering. Ursächlich ist die fehlende direkte therapeutische Beeinflussbarkeit der im Zellkern von Hepatozyten vorliegenden Form des HBV-Virus, der sog. "covalently closed circular" DNA (cccDNA). Die cccDNA spielt eine zentrale Rolle im HBV-Replikationszyklus, indem sie als ständige Matrize zur Replikation neuer Viruspartikel dient. Mithilfe dieses Maussystems können nun neue antivirale Substanzen getestet werden. So wurde in Zusammenarbeit mit Prof. S. Urban (Heidelberg) der therapeutische Effekt einer Eintrittsblockade auf die HBV-Infektion untersucht und gezeigt, dass der Eintrittshemmer Myrcludex-B in der Lage ist, auch während einer bereits erfolgten Infektion die weitere Ausbreitung der Viren zu blockieren (Volz, J. Hepatology 2013). Das Projekt "Entry inhibition as a novel antiviral concept for hepatotropic viruses" wird vom BMBF (DZIF TTU-Hepatitis 05.804) gefördert. Die präklinische Testung neuerer antiviraler Substanzen in "humanisierten" Mäusen wird auch durch Kooperationen mit internationalen Institutionen und mit der Industrie durchgeführt.

    Im Rahmen des SFB841 (A5: Molecular mechanisms of HBV persistence in chronically infected uPA chimeric mice) untersuchen wir die molekularen Mechanismen der HBV-Persistenz. Insbesondere gehen wir der Frage nach, wodurch die Aktivität der HBV-Matrize, das cccDNA-Molekül, modifiziert wird und welche Rolle die intrahepatische angeborene Immunantwort spielt. Mithilfe innovativer molekularer Methoden und in Zusammenarbeit mit Prof. M. Levrero (Univ. Rome) und Prof. U. Protzer (München) konnten wir zeigen, wie bestimmte Faktoren und therapeutische Zytokine (z.B. IFNα) die Aktivität (Belloni et al.J. Clin.Invest. 2012; Allweiss et al. J. Hepatology 2014) und die Stabilität (Lucifora et al. Science 2014) des viralen cccDNA Minichromosoms beeinflussen können. Beides hat zur Folge, dass die DNA teilweise stillgelegt oder sogar degradiert wird. Um die Interaktionen zwischen angeborener und adaptiver Immunantwort zu untersuchen, sollen uPA Mäuse auch partiell mit humanen Immunzellen rekonstituiert werden. Wir sind fest überzeugt, dass ein besseres Verständnis der HBV-Wirts-Interaktionen die Entwicklung wesentlich effektiverer Therapien ermöglich wird.

    Themenbereich HDV (Projektleiter/in: Dr. Marc Lütgehetmann und Prof. Dr. Maura Dandri)

    Von den 300 Millionen Menschen, die weltweit chronisch mit HBV infiziert sind, haben circa 5% ebenfalls eine Infektion mit dem Hepatitis-D-Virus (HDV). Weil HDV nur mit Hilfe des HBV-Oberflächenproteins die infizierten Zellen verlassen kann, kann es sich auch nur in Verbindung mit einer HBV-Infektion vermehren. Im chronischen Stadium einer HBV/HDV-Koinfektion zeigen die Betroffenen einen Krankheitsverlauf, der im Vergleich zu einer alleinigen HBV-Infektion schneller zur Leberzirrhose führen kann. Wir konnten zeigen, dass die chimären Lebern der HBV-infizierten Mäuse auch mit HDV superinfiziert oder ko-infiziert werden können (Lütgehetmann, Hepatology 2012). im Rahme des SFB841 (A8: Hepatitis-D-Virus-induzierte Pathogenese und Interaktion mit dem angeborenen Immunsystem) untersuchen wir Interaktionen zwischen HBV und HDV und dem humanen angeborenen Immunsystem sowie die virus-induzierte Pathogenese im Laufe einer Infektion mit HDV in humanisierten uPA-Mäusen.

    Kontakt, Ansprechpartner und Mitarbeiter

    Projektleiterin: Prof. Dr. rer. nat. Maura Dandri

    Dr. med. Marc Lütgehetmann

    Dr. rer. nat. Tassilo Volz

    Dr. rer. nat. Lena Allweiss

    Dr. rer. nat. Katja Giersch

    Dr. rer. nat. Janine Kah

    Dr. med. Jan-Hendrik Bockmann

    Oliver Daniel Bhadra, Medizin Student, Grad. Kolleg (GRK841)

    Sebastian Luft, Medizin Student, Grad. Kolleg (GRK841)

    Aktuelle Kooperationen mit anderen Institutionen/Hochschulen

    1) Prof. Dr. Stephan Urban, Department of Infectious Diseases, Molecular Virology, Universitätsklinikum Heidelberg

    2) Prof. Dr. Ulrike Protzer, Institute of Virology,Technische Universität München / Helmholtz Zentrum München

    3) Prof. Dr. med. Jörg Petersen, IFI Institut für interdisziplinäre Medizin an der Asklepiosklinik St. Georg, Hamburg

    4) PD Dr. Jörg-Matthias Pollok, Chirurgisches Zentrum, Universitätsklinikum Bonn

    5) PD Dr. Dieter Glebe, Institut für Medizinische Virologie, Justus-Liebig-Universität Gießen

    6) Prof. Antonio Bertoletti, Emerging Infectious Diseases Duke-Nus Graduate Medical School, Singapore Institute for Clinical Sciences (A*Star), Singapore

    7) Prof. Dr. Teresa Pollicino, Division of Clinical and Molecular Hepatology, University Hospital of Messina, Italy

    8) Prof. Dr. Massimo Levrero, Department of Internal Medicine - DMISM, Laboratory of Gene Expression, La Sapienza University, Rome, Italy

    9) Prof. Dr. John Murray, School of Mathematics and Statistics, Sydney University, Australien

    10) Prof. Dr. Maria Buti, Hepatitis Laboratory, Biochemistry Department Vall d'Hebron Hospital, Barcelona, Spain

    11) Prof. Camille Sureau, Laboratoire de Virologie Moléculaire, Institut National de la Transfusion Sanguine (INTS), Paris, France12.

    12) Prof. Dr. Thomas Baumert, Institut National de la Santé et de la Recherche Médicale, Unité 1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.

    Publikationen

    1. Giersch K, Allweiss L, Volz T, Helbig M, Bierwolf J, Lohse AW, Pollok JM, Petersen J, Dandri M, Lütgehetmann M. Hepatitis Delta co-infection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection. J Hepatol 2015 Mar 17 doi: 10.1016/j.jhep.2015.03.011. [Epub ahead of print]

    2. Mailly L, Xiao F, Lupberger J, Wilson GK, Aubert P, Duong FH, Calabrese D, Leboeuf C, Fofana I, Thumann C, Bandiera S, Lütgehetmann M, Volz T, Davis C, Harris HJ, Mee CJ, Girardi E, Chane-Woon-Ming B, Ericsson M, Fletcher N, Bartenschlager R, Pessaux P, Vercauteren K, Meuleman P, Villa P, Kaderali L, Pfeffer S, Heim MH, Neunlist M, Zeisel MB, Dandri M, McKeating JA, Robinet E, Baumert TF. Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody. Nat Biotechnol 2015 Mar 23. doi: 10.1038/nbt.3179. [Epub ahead of print]

    3. Oehler N, Volz T, Bhadra OD, Kah J, Allweiss L, Giersch K, Bierwolf J, Riecken K, Pollok JM, Lohse AW, Fehse B, Petersen J, Urban S, Lütgehetmann M, Heeren J, Dandri M. Binding of hepatitis B virus to its cellular receptor alters the expression profile of genes of bile acid metabolism. Hepatology 2014 Nov;60(5):1483-93

    4. Allweiss L, Volz T, Lütgehetmann M, Giersch K, Bornscheuer T, Lohse AW, Petersen J, Ma H, Klumpp K, Fletcher SP, Dandri M. Immune cell responses are not required to induce substantial hepatitis B virus antigen decline during pegylated interferon-alpha administration. J Hepatol 2014 Mar 60(3):500-7.

    5. Giersch K, Helbig M, Volz T, Allweiss L, Mancke LV, Lohse AW, Polywka S, Pollok JM, Petersen J, Taylor J, Dandri M, Lütgehetmann M. Persistent hepatitis D virus mono-infection in humanized mice is efficiently converted by hepatitis B virus to a productive co-infection. J Hepatol 2014 Mar; 60(3):538-44.

    6. Lucifora J, Xia Y, Reisinger F, Zhang K, Stadler D, Cheng X, Sprinzl MF, Koppensteiner H, Makowska Z, Volz T, Remouchamps C, Chou WM, Thasler WE, Hüser N, Durantel D, Liang TJ, Münk C, Heim MH, Browning JL, Dejardin E, Dandri M, Schindler M, Heikenwalder M, Protzer U. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA Science. 2014 Mar 14;343(6176):1221-8.

    7. Volz T, Allweiss L, M Barek MB, Warlich M, Lohse AW, Pollok JM, Alexandrov A, Urban S, Petersen J, Lütgehetmann M, Dandri M. The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus. J Hepatol. 2013; 58: 861-7.

    8. Belloni L, Allweiss L, Guerrieri F, Pediconi N, Volz T, Pollicino T, Petersen J, Raimondo G, Dandri M, Levrero M. IFNα inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome. J Clin Invest. 2012 Feb 1;122(2):529-37

    9. Lütgehetmann M, Mancke LV, Volz T, Helbig M, Allweiss L, Bornscheuer T, Pollok JM, Lohse AW, Petersen J, Urban S, Dandri M. Humanized chimeric uPA mouse model for the study of hepatitis B and D virus interactions and preclinical drug evaluation. Hepatology 2012 Mar;55(3):685-94.

    10. Lütgehetmann M, Bornscheuer T, Volz T, Allweiss L, Bockmann JH, Pollok JM, Lohse AW, Petersen J, Dandri M. Hepatitis B Virus Limits Response of Human Hepatocytes to Interferon alpha in Chimeric Mice. Gastroenterology. 2011 Jun;140(7):2074-83.

  • Hepatitis E

    Hepatitis E, eine Inflammation der Leber, wird durch das Hepatitis-E-Virus (HEV), welches weltweit vorkommt, ausgelöst. Mit in Deutschland 3.700 gemeldeten Fälle von Hepatitis E (2019) stellt diese nach der Hepatitis B und C die dritthäufigste gemeldete Virushepatitis dar. Die anti-HEV-Seroprävalenz in Deutschland liegt bei bis zu 20-30 %. HEV wird in Europa vor allem durch den Verzehr von unzureichend erhitztem Schweinefleisch übertragen, aber auch Bluttransfusionen haben bis Ende 2019 ein relevantes Risiko dargestellt. Seit Januar 2020 werden nun jedoch alle Blutspenden in Deutschland auf HEV getestet. Immunkompromittierte mit HEV-Kontakt haben ein Risiko von circa 50 %, eine chronische Hepatitis E zu entwickeln, was zu einer Leberzirrhose führen kann. HEV- Infektionen wurden zudem mit Erkrankungen verschiedenster Organsysteme, sogenannten extrahepatischen Manifestationen, in Verbindung gebracht.

    Forschungsschwerpunkte:

    ● Epidemiologie und Identifikation von Risikofaktoren der HEV-Infektion
    ● Klinischer und serologischer Verlauf
    ● Stellenwert und Pathophysiologie extrahepatischer Manifestationen sowie HEV-spezifische
    Antikörper und Immunantwort

    Themenbereich "Epidemiologie und klinischer Verlauf" (Projektleiter: Dr. Thomas Horvatits)

    HEV kommt weltweit vor. Der in Europa prädominierende Genotyp (GT) ist GT 3, und dieser wird vor allem durch Verzehr von Schweinefleisch oder durch Tierkontakte übertragen. In den Tropen und Subtropen werden GT 1 sowie GT 2 v. a. über kontaminiertes Trinkwasser übertragen. Basierend auf serologischen Daten ist von einer anti-HEV-IgG-Seroprävalenz von bis zu 20-30 % in unserer Region auszugehen. Zur Identifikation von Risikofaktoren einer HEV-Infektion führen wir epidemiologische Untersuchungen (standardisierte Fragebogenanalysen, Serologie, PCR-Untersuchung) an verschiedenen Kohorten (Patienten, Blutspender, Risikogruppen für HEV-Exposition) durch mit dem Ziel der Etablierung möglicher Präventionsstrategien.

    Themenbereich "Klinischer und serologischer Verlauf, spezifische Antikörper und Immunantwort" (Projektleiter: Dr. Thomas Horvatits, PD Dr. Sven Pischke)

    Zur Erfassung des klinischen Verlaufs und zur detaillierten Charakterisierung der HEV-Infektion führen wir observationelle Untersuchungen bei Patienten mit zugrundeliegender Lebererkrankung und bei immunkompromittierten Patienten durch, die ein erhöhtes Risiko haben, im Rahmen einer Hepatitis E ein akutes Leberversagen (ALF), ein Akut-auf-Chronisches Leberversagen (ACLF) oder eine chronische Hepatitis E zu entwickeln. Zudem beschäftigen wir uns mit therapeutischen Ansätzen für Patienten, welche auf die aktuell empfohlene (off-label-) Ribavirin-Therapie kein adäquates Ansprechen zeigen.

    Themenbereich "Extrahepatische Manifestationen und spezifische Immunantwort" (Projektleiter: PD Dr. Sven Pischke)

    HEV-Infektionen werden neben Leberentzündungen auch zunehmend mit anderen Erkrankungen diverser Organe assoziiert. Die Pathophysiologie sowie ein möglicher Kausalzusammenhang dieser „extrahepatischen Manifestationen“ ist noch weitestgehend ungeklärt. Deshalb erfassen wir die Relevanz extrahepatischer Manifestationen von HEV-Infektionen in standardisierter Art und Weise und untersuchen, inwieweit mutmaßliche extrahepatische Manifestationen wie das Guillain-Barré-Syndrom (GBS), die neuralgische Amyotrophie (NA), Myasthenia Gravis (MG), Glomerulonephritis (GN) und Psychosen mit einer überschießenden Immunantwort assoziiert sind.
    Die Schädigung der Leber wird mutmaßlich nicht nur durch das Hepatitis-E-Virus selbst, sondern durch eine starke Immunantwort (zytotoxische T-Zellen und Natürliche Killerzellen (NK-Zellen)) verursacht. Die Mechanismen dieser (überschießenden) Immunantwort sind bis dato nur unzureichend geklärt und daher Teil unserer Forschung.

    • Kontakt
      E-Mail

      Dr. Thomas Horvatits (t.horvatits@uke.de)

      PD Dr. Sven Pischke (s.pischke@uke.de)

    Verantwortlich für den Inhalt
    Autoren: Dr. Thomas Horvatits, PD Dr. Sven Pischke
    Erstellung: 05.03.2020
    Letzte Änderung: 05.03.2020


Lebertumoren

  • Hepatocarcinogenesis and molecular risk stratification

    Objective:

    Despite the revolution of personalized cancer care and immunotherapy in many other cancer entities, liver cancer has fallen behind regarding biomarker research and personalized medicine. Based on our previous work, our translational research group aims at delineating actionable mechanisms of liver cancer initiation and progression and at establishing molecular risk stratification algorithms. We have the ambitious goal to implement personalized cancer care in this devastating disease, including primary prevention strategies, early cancer detection, improving treatment allocation, and solving therapeutic resistance. We are working both on clinical and translational projects, including wet and dry bench work, and in close collaboration with local and international partners.

    Methods / data sets: ·

    • Large clinical database (~1,000 patients)
    • Large biobank of tissue and blood specimens
    • Liquid Biopsy technologies o
      • Circulating tumor DNA
      • Extracellular vesicles
      • Circulating tumor cells
    • Next-generation sequencing
      • RNAseq (bulk, small RNA, single-cell)
      • DNA mutation / methylation profiling ·
    • Tissue Microarray
    • Metabolomics, Tissue and Serum
    • Proteomics
    • Clinical trials (all phases)

    Principal Investigators:

    Dr. Kornelius Schulze, MD

    Dr. Johann von Felden, MD

    Clinician Scientists:

    Dr. Thorben Fründt, MD

    Dr. Ines Gil-Ibanez, MD

    Lorenz Kocheise, MD

    Vincent Jörg, MD

    associated:

    Dr. Jan Kempski, MD

    Dr. Rüdiger Schmitz, MD

    Selected publications:

    von Felden J, Garcia-Lezana T, Dogra N, Kozlova E, Ahsen ME, Craig AJ, Gifford S, Wunsch B, Smith JT, Kim S, Diaz JEL, Chen X, Labgaa I, Haber PK, Olsen R, Han D, Restrepo P, D’Avola D, Hernandez-Meza G, Allette K, Sebra R, Saberi B, Tabrizian P, Asgharpour A, Dieterich D, Llovet JM, Cordon-Cardo C, Tewari A, Schwartz M, Stolovitzky G, Losic B, Villanueva A. Unannotated small RNA clusters in circulating extracellular vesicles detect early stage liver cancer. Gut 2021.

    Pfister D, Núñez NG, Pinyol R, Govaere O, Pinter M, Szydlowska M, Gupta R, Qiu M, Deczkowska A, Weiner A, Müller F, Sinha A, Friebel E, Engleitner T, Lenggenhager D, Moncsek A, Heide D, Stirm K, Kosla J, Kotsiliti E, Leone V, Dudek M, Yousuf S, Inverso D, Singh I, Teijeiro A, Castet F, Montironi C, Haber PK, Tiniakos D, Bedossa P, Cockell S, Younes R, Vacca M, Marra F, Schattenberg JM, Allison M, Bugianesi E, Ratziu V, Pressiani T, D'Alessio A, Personeni N, Rimassa L, Daly AK, Scheiner B, Pomej K, Kirstein MM, Vogel A, Peck-Radosavljevic M, Hucke F, Finkelmeier F, Waidmann O, Trojan J, Schulze K., Wege H, Koch S, Weinmann A, Bueter M, Rössler F, Siebenhüner A, De Dosso S, Mallm JP, Umansky V, Jugold M, Luedde T, Schietinger A, Schirmacher P, Emu B, Augustin HG, Billeter A, Müller-Stich B, Kikuchi H, Duda DG, Kütting F, Waldschmidt DT, Ebert MP, Rahbari N, Mei HE, Schulz AR, Ringelhan M, Malek N, Spahn S, Bitzer M, Ruiz de Galarreta M, Lujambio A, Dufour JF, Marron TU, Kaseb A, Kudo M, Huang YH, Djouder N, Wolter K, Zender L, Marche PN, Decaens T, Pinato DJ, Rad R, Mertens JC, Weber A, Unger K, Meissner F, Roth S, Jilkova ZM, Claassen M, Anstee QM, Amit I, Knolle P, Becher B, Llovet JM, Heikenwalder M. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 2021;592:450-56.

    Labgaa I*, von Felden J*, Craig AJ, Martins-Filho SN, Villacorta-Martin C, Demartines N, Dormond O, D'Avola D, Villanueva A. Experimental Models of Liquid Biopsy in Hepatocellular Carcinoma Reveal Clone-Dependent Release of Circulating Tumor DNA. Hepatol Commun 2021;5:1095-1105.

    von Felden J, Craig AJ, Garcia-Lezana T, Labgaa I, Haber PK, D'Avola D, Asgharpour A, Dieterich D, Bonaccorso A, Torres-Martin M, Sia D, Sung MW, Tabrizian P, Schwartz M, Llovet JM, Villanueva A. Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma. Oncogene 2021;40:140-51.

    von Felden J, Garcia-Lezana T, Schulze K, Losic B, Villanueva A. Liquid biopsy in the clinical management of hepatocellular carcinoma. Gut 2020;69:2025-34.

    Craig AJ, von Felden J, Garcia-Lezana T, Sarcognato S, Villanueva A. Tumour evolution in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2020;17:139-52

    Hernandez-Meza G*, von Felden J*, Gonzalez-Kozlova EE, Garcia-Lezana T, Peix J, Portela A, Craig AJ, Sayols S, Schwartz M, Losic B, Mazzaferro V, Esteller M, Llovet JM, Villanueva A. DNA Methylation Profiling of Human Hepatocarcinogenesis. Hepatology 2020;10.1002/hep.31659.

    Krause J, von Felden J, Casar C, Fründt TW, Galaski J, Schmidt C, Jung C, Ittrich H, Weidemann SA, Krech T, Heumann A, Li J, Fischer L, Sauter G, Lohse AW, Wege H, Schulze K. Hepatocellular carcinoma: Intratumoral EpCAM-positive cancer stem cell heterogeneity identifies high-risk tumor subtype. BMC Cancer 2020;20:1130.

    von Felden J, Wege H, Schulze K. Elevated Aspartate Aminotransferase to Alanine Aminotransferase Ratio Predicts Poor Outcome in Hepatocellular Carcinoma. Hepatol Commun 2020;4:1382-83.

    Ruiz de Galarreta M, Bresnahan E*, Molina-Sánchez P*, Lindblad KE*, Maier B*, Sia D, Puigvehi M, Miguela V, Casanova-Acebes M, Dhainaut M, Villacorta-Martin C, Singhi AD, Moghe A, von Felden J, Tal Grinspan L, Wang S, Kamphorst AO, Monga SP, Brown BD, Villanueva A, Llovet JM, Merad M, Lujambio A. β-Catenin Activation Promotes Immune Escape and Resistance to Anti-PD-1 Therapy in Hepatocellular Carcinoma. Cancer Discov 2019;9:1124-41

    von Felden J, Alric L, Pischke S, Aitken C, Schlabe S, Spengler U, Giordani MT, Schnitzler P, Bettinger D, Thimme R, Xhaard A, Binder M, Ayuk F, Lohse AW, Cornelissen JJ, de Man RA, Mallet V. The burden of hepatitis E among patients with haematological malignancies: A retrospective European cohort study. J Hepatol 2019;71:465-72.

    Scheiner B, Kirstein MM, Hucke F, Finkelmeier F, Schulze K, von Felden J, Koch S, Schwabl P, Hinrichs JB, Waneck F, Waidmann O, Reiberger T, Müller C, Sieghart W, Trauner M, Weinmann A, Wege H, Trojan J, Peck-Radosavljevic M, Vogel A, Pinter M. Programmed cell death protein-1 (PD-1)-targeted immunotherapy in advanced hepatocellular carcinoma: efficacy and safety data from an international multicentre real-world cohort. Aliment Pharmacol Ther 2019;49:1323-33.

    von Felden J*, Schulze K*, Krech T, Ewald F, Nashan B, Pantel K, Lohse AW, Riethdorf S, Wege H. Circulating tumor cells as liquid biomarker for high HCC recurrence risk after curative liver resection. Oncotarget 2017;8:89978-87.

    Weismüller TJ, Trivedi PJ, Bergquist A, Imam M, Lenzen H, Ponsioen CY, Holm K, Gotthardt D, Färkkilä MA, Marschall HU, Thorburn D, Weersma RK, Fevery J, Mueller T, Chazouillères O, Schulze K, Lazaridis KN, Almer S, Pereira SP, Levy C, Mason A, Naess S, Bowlus CL, Floreani A, Halilbasic E, Yimam KK, Milkiewicz P, Beuers U, Huynh DK, Pares A, Manser CN, Dalekos GN, Eksteen B, Invernizzi P, Berg CP, Kirchner GI, Sarrazin C, Zimmer V, Fabris L, Braun F, Marzioni M, Juran BD, Said K, Rupp C, Jokelainen K, Benito de Valle M, Saffioti F, Cheung A, Trauner M, Schramm C, Chapman RW, Karlsen TH, Schrumpf E, Strassburg CP, Manns MP, Lindor KD, Hirschfield GM, Hansen BE, Boberg KM; International PSC Study Group. Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis. Gastroenterology 2017;152:1975-84.e8.

    Schulze K, Nault JC, Villanueva A. Genetic profiling of hepatocellular carcinoma using next-generation sequencing. J Hepatol 2016;65:1031-42.

    Zenouzi R, Weismüller TJ, Jørgensen KK, Bubenheim M, Lenzen H, Hübener P, Schulze K, Weiler-Normann C, Sebode M, Ehlken H, Pannicke N, Hartl J, Peiseler M, Hübener S, Karlsen TH, Boberg KM, Manns MP, Lohse AW, Schramm C. No Evidence That Azathioprine Increases Risk of Cholangiocarcinoma in Patients With Primary Sclerosing Cholangitis. Clin Gastroenterol Hepatol 2016;14:1806-12.

    Schulze K*, Imbeaud S*, Letouzé E*, Alexandrov LB, Calderaro J, Rebouissou S, Couchy G, Meiller C, Shinde J, Soysouvanh F, Calatayud AL, Pinyol R, Pelletier L, Balabaud C, Laurent A, Blanc JF, Mazzaferro V, Calvo F, Villanueva A, Nault JC, Bioulac-Sage P, Stratton MR, Llovet JM, Zucman-Rossi J. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet 2015;47:505-11.

    Schulze K, Gasch C, Staufer K, Nashan B, Lohse AW, Pantel K, Riethdorf S, Wege H. Presence of EpCAM-positive circulating tumor cells as biomarker for systemic disease strongly correlates to survival in patients with hepatocellular carcinoma. Int J Cancer 2013;133:2165-71.

    *equally contributing authors

    Verantwortlich für den Inhalt
    Autor: Dr. Kornelius Schulze; Dr. Johann von Felden
    Erstellung: 20.07.2021
    Letzte Änderung: 20.07.2021


NET

  • Tumormikroenvironment

    Forschungsschwerpunkte

    Der Forschungsschwerpunkt der AG Tumormikroenvironment liegt auf der Untersuchung des entzündlichen Tumorstromas bei Tumoren des gastro-intestinal Traktes. Das Tumorstroma setzt sich aus der extrazellulären Matrix, den Tumorstromazellen (Fibroblasten) und infiltrierenden Entzündungszellen zusammen. Ein Schwerpunkt der Untersuchungen ist der Einfluss der pathologisch erhöhten Matrixfestigkeit in Tumoren (Fibrose) auf die Tumorzellen. Es konnte hier bereits eine Stimulation von Wachstum, Ausprägung eines malignen mesenchymalen Phänotyps (EMT) und Verminderung des Chemotherapieansprechens für Tumorzellen in einer festen Matrixumgebung gezeigt werden. Die Entschlüsselung der zugrundeliegenden molekularen Mechanismen ist Gegenstand aktueller Forschungsarbeiten zu diesem Thema. Ein zweiter Schwerpunkt der Untersuchungen zum Tumorstroma betrifft die Kommunikation der Tumorfibroblasten und Tumor-assoziierten Makrophagen mit den Tumorzellen. Es interessiert uns hier welchen Einfluss die Stromazellen auf die Ausprägung eines malignen (mesenchymalen) Phänotyps und das Ansprechen auf Chemotherapie haben. Im Gegenzug wollen wir aber auch verstehen welchen Einfluss die Tumorzellen auf die Stromazellen haben und durch welche Mechanismen/Signalwege ein tumorfördernder Phänotyp in den Stromazellen induziert wird. Die Untersuchungen zum entzündlichen Tumorstroma werden an verschiedenen Tumorentitäten des gastro-intestinal Traktes durchgeführt – insbesondere interessieren uns das hepatozellulären Karzinom (HCC), das duktale Adenokarzinom des Pankreas und das Adenokarzinom des Ösophagus. Es besteht für diesen Forschungsschwerpunkt eine sehr enge Kooperation mit der Klinik für Allgemein-, Viszeral- und Thoraxchirurgie.

    Neben dem Tumorstroma bei gastro-intestinalen Karzinomen liegt ein weiterer Forschungsschwerpunkt auf der Untersuchung neuroendokriner Tumore. Aufgrund der Seltenheit dieser Tumorerkrankung ist bisher wenig über die Tumorbiologie bekannt, und es besteht ein dringender Bedarf neue Therapien zu entwickeln. Bisher waren die präklinischen Forschungsbemühungen durch die eingeschränkte Verfügbarkeit von gut-differenzierten neuroendokrinen Zelllinien limitiert. Durch die erfolgreiche Etablierung zweier neuer primärer Tumorzelllinien aus neuroendokrinen Tumoren des Pankreas in unserem Labor, haben wir die Möglichkeit an klinisch-relevanten Tumorzelllinien neue therapeutische Verfahren zu entwickeln und Untersuchungen zum Verständnis der Tumorbiologie dieser Tumore durchzuführen.

    Kontakt, Ansprechpartner und Mitarbeiter

    Leiter: Priv.-Doz. Dr. med. Schrader

    Martina Fahl (MTA)

    Corinna Rhotert (MTA)

    Publikationen

    Bacher M*, Schrader J*, Thompson N, Kuschela K, Gemsa D, Waeber G, Schlegel J. Up-regulation of macrophage migration inhibitory factor gene and protein expression in glial tumor cells during hypoxic and hypoglycemic stress indicates a critical role for angiogenesis in glioblastoma multiforme. Am J Pathol. 2003. 162(1):11-7. *equally contributed

    Schrader J, Rennekamp W, Niebergall U, Schoppet M, Jahr H, Brendel MD, Hörsch D, Hofbauer LC. Cytokine induced osteoprotegerin expression protects pancreatic beta cells through p38 MAP kinase signaling against cell death. Diabetologia. 2007. 50(6):1243-7.

    Benten D, Keller G, Quaas A, Schrader J, Gontarewicz A, Balabanov S, Braig M, Wege H, Moll J, Lohse AW, Brummendorf TH. Aurora kinase inhibitor PHA-739358 suppresses growth of hepatocellular carcinoma in vitro and in a xenograft mouse model. Neoplasia. 2009. 11(9):934-44.

    Schrader J, Deuster O, Rinn B, Schulz M, Kautz A, Dodel R, Meyer B, Al-Abed Y, Balakrishnan K, Reese JP, Bacher M. Restoration of contact inhibition in human glioblastoma cell lines after MIF knockdown. BMC Cancer. 2009. 28;9:464.

    Schrader J*, Gordon-Walker TT*, van Deemter M, Aucott RL, Quaas A, Walsh S, Benten D, Forbes SJ, Wells RG, Iredale JP. Matrix stiffness modulates proliferation, chemotherapeutic response and dormancy in hepatocellular carcinoma cells. Hepatology. 2011. 53(4):1192-205. *equally contributed

    Schrader J, Iredale J. The inflammatory microenvironment of HCC – The plot becomes complex. J Hepatol. 2011. 54(5):853-5.

    Lüth S*, Schrader J*, Zander S, Carambia A, Buchkremer J, Huber S, Reifenberg K, Yamamura KI, Schirmacher P, Lohse AW, Herkel J. Chronic inflammatory IFNgamma-signalling suppresses hepatocarcinogenesis in mice by sensitizing hepatocytes for apoptosis. Cancer Res. 2011. 71(11):3763-71. *equally contributed

    Fraedrich K, Schrader J, Ittrich H, Keller G, Gontarewicz A, Matzat V, Kromminga A, Pace A, Moll J, Bläker M, Lohse AW, Hörsch D, Brümmendorf TH, Benten D. Targeting aurora kinases with danusertib (PHA-739358) inhibits growth of liver metastases from gastroenteropancreatic neuroendocrine tumors in an orthotopic xenograft model. Clin Cancer Res. 2012;18(17):4621-32

    Schrader J. The role of MDSCs in hepatocellular carcinoma - in vivo veritas? J Hepatol. 2013;59(5):921-3.

    Schrader J, Niebel P, Rossi A, Archontidou-Aprin E, Hörsch D. Differential signaling by regulatory subunits of phosphoinositide-3-kinase influences cell survival in INS-1E insulinoma cells. Exp Clin Endocrinol Diabetes 2015;123(3): 118-25


Emerging Infections


Tropenmedizinische Forschung

  • Fall-Kontroll-Studie zu respiratorischen Erregern

    Respiratorische Infektionen gehören weltweit zu den häufigsten Ursachen für eine fieberhafte Erkrankung bei Kindern, insbesondere auch im tropischen Afrika. Aktuell wird zur Diagnostik bei schweren respiratorischen Erkrankungen, bei vorhandenen Möglichkeiten, meist eine Multiplex-PCR auf bis zu 15 verschiedene Erreger durchgeführt. Da entsprechende Erreger häufig auch bei Gesunden nachgewiesen werden können, ist die Bedeutung einer positiven Reaktion in diesen Untersuchungen häufig unklar.

    Um diese Frage zu klären, führen wir aktuell eine Fall-Kontroll-Studie in einem Krankenhaus in Ghana durch, bei der sowohl von Kindern, die sich wegen eines Atemwegsinfekts in stationärer Behandlung befinden, als auch von Kindern einer gesunden Kontrollgruppe Abstriche des Nasenrachenraumes angefertigt und diese auf insgesamt 20 mögliche bakterielle und virale Erreger untersucht werden. Durch den Vergleich der Prävalenz zwischen den Gruppen wird dann eine Aussage zur klinischen Relevanz der Erreger ermöglicht.

    Untersuchung der nosokomialen Transmission von Multiresistenten Gram-negativen Erregern

    Die weltweit zunehmende Bedeutung von multiresistenten bakteriellen Erregern ist unbestritten. Neben MRSA haben in den letzten Jahren gerade Resistenzen bei gram-negativen Erregern im Darm deutlich zugenommen, allerdings ist die Datenlage zur Prävalenz von Resistenzen in West Afrika sehr dürftig. Studien bei Reisenden zeigen eine vermehrte Akquisition von multiresistenten Erregern bei Reisen nach Asien und Afrika und Daten aus einer früheren Studie bei Kindern in Agogo (Ghana) zeigen eine Prävalenz von bis zu 80% extended spectrum beta lactamase (ESBL) produzierende Klebsiellen in
    Blutkulturen.

    Daher führen wir zur Zeit eine Studie in einem ghanaischen Krankenhaus durch, in der wir die Prävalenz und nosokomiale Transmission der Besiedelung mit ESBL- und Carbapenemase-produzierenden Bakterien untersuchen.

    Publikationen

    Association Between Malaria and Invasive non-typhoid Salmonella Infection in a Hospital Study – Accounting for Berkson’s Bias. Krumkamp , Kreuels B, Sarpong N, Gyau K, Foli G, Hogan B, Jaeger A, Reigl L, Zeeb H, Marks F, Adu-Sarkodie Y, May J. Clin Infect Dis 2015, In Press

    A case of severe Ebola virus infection complicated by gram-negative septicemia. Kreuels B, Wichmann D, Emmerich P, Schmidt-Chanasit J, de Heer G, Kluge S, Sow A, Renné T, Günther S, Lohse AW, Addo MM, Schmiedel S. N Engl J Med. 2014

    The causal effect of malaria on stunting: a Mendelian randomization and matching approach. Kang H*, Kreuels B*, Adjei O, Krumkamp R, May J, Small DS. Int J Epidemiol. 2013 *Equally contributed

  • Malaria immunology

    General information:

    In our group we investigate the adaptive immune response to Plasmodium falciparum malaria. We study the regulation of the T and B cell response, the development of immunological memory and the formation of protective immunity. Our ultimate goal is to find immunologic pathways that could be modulated to prevent malaria complications or to enhance vaccine efficacy. Studies are being conducted here in Hamburg and in Kumasi, Ghana.

    Malaria remains to be one of the deadliest infectious diseases worldwide with about 200 million cases and 400 000 deaths per year, most of them children below 5 years of age. The clinical picture of malaria varies, from severe, life-threatening disease to uncomplicated, febrile malaria or even asymptomatic infections. The host´s immune response is one of the important factors that determine the severity of malaria. A challenge in the immune response to malaria is the optimal balance between immune activation and immune suppression. Pro-inflammatory responses are important to clear the pathogen whereas anti-inflammatory responses are needed to protect the host from pathogenic effects of an overwhelming immune response. In our group we investigate the adaptive immune response to Plasmodium falciparum malaria. We focus on the following topics: 1) the regulation of the adaptive immune response and 2) the development of immunological memory and the formation of protective immunity.

    We aim to find out what role pro-inflammatory T cell responses play in the development of malaria complications and which pathways can protect from the development of severe malaria. In this context we explore the role regulatory T cell subsets, the induction of co-inhibitory molecules as well as the expansion of regulatory B cells. Additionally, we investigate how the activated pro- and anti-inflammatory pathways influence the formation and longevity of T and B cell memory.

    We use state-of-the-art cellular immunology methods such as multicolor flow cytometry staining, intracellular cytokine staining, ELISPOT, ELISA, cytometric bead assays, PCR and cell culture.

    Studies are being conducted here in Hamburg and at the Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR) in Kumasi, Ghana. We work with samples from adults with acute malaria or former residents from endemic areas in Hamburg as well as with children with acute malaria or asymptomatic infection in highly endemic areas in Ghana.

    List of ongoing research projects:

    • T cell regulation in acute Plasmodium falciparum malaria
    • CD4+ T cell memory in malaria
    • B cell regulation and B cell memory in malaria

    Group members:

    Dr med Maria Sophia Mackroth, PI
    Maren Sandkuhl, technician

    Selected publications:

    Kaminski LC, Riehn M, Abel A, Steeg C, Yar DD, Addai-Mensah O, Aminkiah F, Owusu Dabo E, Jacobs T, Mackroth MS. Cytotoxic T Cell-Derived Granzyme B Is Increased in Severe Plasmodium Falciparum Malaria. Front Immunol. 2019;10:2917.

    Rivera-Correa J, Mackroth MS, Jacobs T, Schulze Zur Wiesch J, Rolling T, Rodriguez A. Atypical memory B-cells are associated with Plasmodium falciparum anemia through anti-phosphatidylserine antibodies. Elife. 2019;8:e48309.

    Abel A, Steeg C, Aminkiah F, Addai-Mensah O, Addo M, Gagliani N, Casar C, Yar DD, Owusu-Dabo E, Jacobs T, Mackroth MS. Differential expression pattern of co-inhibitory molecules on CD4+ T cells in uncomplicated versus complicated malaria. Sci Rep. 2018;8:4789.

    Koblischke M, Mackroth MS, Schwaiger J, Fae I, Fischer G, Stiasny K, Heinz FX, Aberle JH. Protein structure shapes immunodominance in the CD4 T cell response to yellow fever vaccination. Sci Rep. 2017;7:8907.

    Mackroth MS, Abel A, Steeg C, Schulze Zur Wiesch J, Jacobs T. Acute Malaria Induces PD1+CTLA4+ Effector T Cells with Cell-Extrinsic Suppressor Function. PLoS Pathog. 2016;12:e1005909.

    Sellau J, Alvarado CF, Hoenow S, Mackroth MS, Kleinschmidt D, Huber S, Jacobs T. IL-22 dampens the T cell response in experimental malaria. Sci Rep. 2016;6:28058.

    Mackroth MS, Tappe D, Tannich E, Addo M, Rothe C. Rapid-Antigen Test Negative Malaria in a Traveler Returning From Thailand, Molecularly Diagnosed as Plasmodium knowlesi. Open Forum Infect Dis. 2016;3:ofw039.

Deutsche Leberstiftung 2023
European Reference Network for rare or low prevalence complex diseases //Network, Hepatological Diseases (ERN RARE-LIVER)
Logo ENETS - European Neuroendocrine Tumor Society
Signet - Deutsche Gesellschaft für Infektiologie e.V.
Signet - Deutsches Zentrum für Infektionsforschung