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AG Utermöhlen
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AG Utermöhlen

Group Leader: Prof. Dr. Olaf Utermöhlen
Phone: +49 221 478-32023 [Email protection active, please enable JavaScript.]

Selected recent publications

Co-workers:
Andrew Berdel (-32213/32216 )
Ulrike Karow (-32213 [Email protection active, please enable JavaScript.])
Arlette Paillard (-32213 )
Pailin Pohgratahakul (-32213)

Research topic:
Innate and adaptive immunity in vivo

Brief description in German:
Das Ziel der Arbeitsgruppe ist es, die komplexen Wechselwirkungen zwischen Infektionserregern und dem Immunsystem des Wirtorganismus im Verlauf von Infektionserkrankungen besser zu verstehen.

Wir identifizieren und charakterisieren molekulare Mechanismen, die zur Kontrolle und Elimination der infektiösen Mikroorganismen aber auch zur immunpathologischen Schädigung der Gewebe und Organe des Wirtes beitragen können. Basierend auf dem Verständnis derartiger molekularer Mechanismen möchten wir Möglichkeiten aufzeigen für innovative antimikrobielle oder immunmodulatorische Therapiekonzepte für bisher nicht oder nur ungenügend behandelbarer Infektionserkrankungen.

Das Immunsystem untescheidet grundsätzlich zwischen "fremden" und "eigenen" beziehungsweise "gefährlichen" und "harmlosen" Strukturen. Prinzipiell können Zellen des Immunsystem deshalb auch Tumore erkennen, die im Laufe ihrer Entstehung „fremde“ oder „gefährliche“ Strukturen entwickelt haben.

Häufig sind die Reaktionen gegen diese Merkmale von Tumoren allerdings sehr schwach ausgeprägt. Deshalb ist es das zweite wichtige Ziel der Arbeitsgruppe, immunregulatorische Mechanismen zu identifizieren, die zur Verstärkung der Immunreaktionen gegen Tumore geeignet sind, um hieraus Konzepte für die verlässliche und nachhaltige Immuntherapie von Tumoren zu entwickeln.

 

Infections with pathogenic microbes trigger in mammalian host organisms complex reactions of resident cells of the affected tissues and organs themselves and of the migratory cells of the innate and adaptive immune system.

The major goal of our research is to improve our understanding of the complex interactions between microbes and hosts that – viewed from the host´s side - are aimed at eliminating the invading microbes but which may also lead to immunpathologic host damage. Beyond an improved understanding of these physiologic and immunopathologic reactions, we aim at delineating novel approaches for antimicrobial and/or immunomodulatory therapies.

Within the frame of the DFG-supported Collaborative Research Center (CRC) 670, "Cell-autonomous immunity", we study the roles of acid sphingomyelinase (ASMase) and of riboflavinkinase (RFK) on the cell-autonomous defence of macrophages against infection with the facultative intracellular bacterium Listeria monocytogenes.

For the activity of ASMase, i.e. the hydrolysis of the membrane lipid sphingomyelin into phosphorylcholine and ceramide, we identified a novel function: enhanding the surfce tension of of the membranes of phagosomes and lysosomes. Thereby, ASMase enhances the efficacy of phagolysosomal fusion – which translates into rapid and effective antibacterial activity of single cells (Utermöhlen et al. 2003, Schramm et al. 2008).

The corresponding effect of ASMase activity on the surface tension of the membrane of cytotoxic granules in CD8+ cytotoxic T lymphocytes (CTL) enables highly effective directional secretion of cytotoxic effector molecules at the immunologic synapse, i.e. the contact site of CD8+ CTL with virus-infected target cells, (Herz et al. 2009).

We have contributed to identifying riboflavinkinase, the enzyme converting riboflavin/vitamin B2 into flavinmononucleotide (FMN), as a molecule directly linking the tumor necrosis factor (TNF) receptor I to the phagocyte NADPH oxidase (Yazdanpanah et al. 2009). Thereby, the longlasting enigma, how TNF-stimulated production of reactive oxygen species (ROS), was solved.

Currently, we are further characterizing the ASMase- and RFK-dependent molecular mechanisms of defence against various pathogens.

In our project within the Center for Molecular Medicine Cologne (ZMMK), We revealed that murine embryonic stem (ES) cells that give rise to teratoma and teratocarcinoma in syngeneic hosts express cytoprotective molecules, e.g. the serine protease inhibitor (serpin) SPI-6, a specific inhibitor of the proapoptotic granzyme B, and the lysosomal thiol cathepsin endoprotease cathepsin B, a specific inhibitor of the pore-forming perforin.

These cytoprotective molecules render ES cells highly resistant against lysis by CTL, although antigen-specific recognition of ES cells efficiently triggers degranulation of cytotoxic granules in CD8+ CTL (Abdullah et al., 2007). We have shown that after down-regulation of SPI-6 by RNA interference ES cells become fully susceptible to lysis by antigen-specific CD8+ CTL, thereby disproving the widely accepted assumption that murine ES cells are ignored by CD8+ T lymphocytes because of their low expression of MHC class I molecules.

Remarkably, expression of SPI-6 and cathepsin B does not render ES cells resistant against lysis by activated natural killer (NK) cells, which kill their target cells similar to CTL by perforin- and granzyme-dependent, granule-mediated cytolysis (Frenzel et al., 2008). To explain this differential killing of ES cells by CTL versus NK cells we currently study the differences in the usage of specific granzymes by CTL and NK cells.

Primarily, the immune system evolved out of the requirement to defend higher organisms against "foreign" microbial invaders. Many tumors may appear immunologically "foreign" due to expression of ectopic, fetal or mutated proteins. Therefore, the mechanisms distinguishing between "self" and "foreign" may also discriminate between healthy and tumorigenically transformed tissues.

Unfortunately, the spontaneous immune responses against such "endogenous foreign" tumor antigens are usually too weak to induce immune responses that result in eradication or at least control of the tumor cells. Therefore, a major focus of the group is to identify immunoregulatory mechanisms that enhance or prolong the usually weak CD8+ CTL response against tumor antigens in order to enable a reliable and lasting control of tumor cells by the immune system.

We have chosen a murine experimental system known for its notoriously weak CD8+ CTL response: the rejection of simian virus (SV) 40-transformed murine kidney sarcoma (mKSA) cells by SV40 large tumor antigen (TAg)-immunized BALB/c mice. BALB/c mice are considered to be low- or even non-responders with respect to the generation of TAg-specific CD8+ CTL, because hardly any TAg-specific CTL are detectable in the spleen and lymph nodes of TAg-immunized BALB/c mice.

However, within the peritoneal cavity of TAg-immune mice acutely rejecting intraperitoneally injected mKSA cells we detected a small population of tumor-associated TAg-specific CD8+ CTL that exert TAg-specific cytotoxic activity in primary ex vivo assays (Zerrahn et al., 1996).

In search for the mechanisms keeping the tumor antigen-specific CTL response so weak in BALB/c mice, we found that TAg-specific CD8+ CTL depend on the support of CD4+ T helper cells secreting the prototypic Th1 cytokines IL-2 and IFN-gamma over the whole course of the tumor cell rejection (Utermöhlen et al., 2001).

Remarkably, in parallel to Th1 cytokines, tumor-associated CD4+ T cells also secrete the typical Th2 cytokines IL-4 and IL-10 over the whole course of this immune response. We significantly increased the expression of the cytotoxic effector molecules granzyme A and B and, consequently, the TAg-specific cytotoxic activity of CD8+ TAg-specific CTL by neutralizing IL-4 as late as during the effector phase of mKSA cell rejection (Baschuk et al., 2007).

Within the CRC 832, "Molecular basis and modulation of cellular interactions in the tumor microenvironment", we investigate the effects of interleukin-10 (IL-10) on antigen-specific immune responses against tumors.

Selected recent  publications (2007 - date):

Project area: Infection immunity:

Tobias Sydor, Kristine von Bargen, Fong-Fu Hsu, Gitta Huth, Otto Holst, Jens Wohlmann, Ulrike Becken, Tobias Dykstra, Kristina Söhl, Buko Lindner, John F. Prescott, Ulrich E. Schaible, Olaf Utermöhlen, Albert Haas. Diversion of phagosome trafficking by pathogenic Rhodococcus equi depends on mycolic acid chain length. Cellular Microbiology 15(3):458-73.2013

Diana Corogeanu, Ruben Willmes, Martina Wolke, Georg Plum, Olaf Utermöhlen, Martin Krönke. Therapeutic concentrations of antibiotics inhibit Shiga toxin release from enterohemorrhagic E. coli O104:H4 from the 2011 German outbreak. BMC Microbiology 12:160-169. 2012

Oliver Liesenfeld, Iana Parvanova, Jens Zerrahn, Seong-Ji Han, Frederick Heinrich, Melba Muñoz, Frank Kaiser, Toni Aebischer, Torsten Buch, Ari Waisman, Gabriela Reichmann, Olaf Utermöhlen, Esther von Stebut, Friedericke D. von Loewenich, Christian Bogdan, Sabine Specht, Michael Saeftel, Achim Hoerauf, Maria M. Mota, Stephanie Könen-Waisman, Stefan H. Kaufmann, Jonahan C. Howard. The IFN-γ-inducible GTPase, Irga6, protects mice against Toxoplasma gondii but not against Plasmodium berghei and some other intracellular pathogens. PLoS One 6(6):e20568. 2011

Kristine von Bargen, Jens Wohlmann, Gregory Alan Taylor, Olaf Utermöhlen, Albert Haas. Nitric oxide-mediated intracellular growth restriction of pathogenic Rhodococcus equi can be prevented by iron. Infection and Immuninty 79(5):2098-111. 2011

Insa Joost , Susanne Jacob , Olaf Utermöhlen, Uwe Schubert, Joseph Patti, Mei-Fang Ong, Jürgen Groß, Christoph Justinger, Jörg Renno, Klaus Preissner, Markus Bischoff, Mathias Herrmann. Antibody response to the extracellular adherence protein (Eap) of Staphylococcus aureus in healthy and infected individuals. FEMS Immunol Med Microbiol 62(1): 23-31. 2011  doi: 10.1111/j.1574-695X.2011.00783.x.

Tobias Dykstra, Olaf Utermoehlen, Albert Haas. Defined particle ligands trigger specific defense mechanisms of macrophages. Innate Immunity 17(4):388-402. Epub 2010 Aug 3.

Benjamin Yazdanpanah, Katja Wiegmann, Vladimir Tchikov, Michael Schramm, Carola Pongratz, Andre Kleinridders, Hamid Kashkar, Olaf Utermöhlen, Oleg Krut, Jens C. Brüning, Stefan Schütze, Martin Krönke. Riboflavin Kinase couples TNF Receptor 1 to NADPH oxidase. Nature 460:1159-1163. 2009

Jasmin Herz, Julian Pardo, Hamid Kashkar, Michael Schramm, Erik Bos, Katja Wiegmann, Reinhard Wallich, Peter J. Peters, Elmon Schmelzer, Martin Krönke, Markus M. Simon, Olaf Utermöhlen. Acid sphingomyelinase is a critical regulator of cytotoxic granule secretion by primary T lymphocytes. Nature Immunology 10:761-768. 2009

Alexey Popov, Julia Driesen, Zeinab Abdullah, Claudia Wickenhauser, Marc Beyer, Svenja Debey-Pascher, Tomo Saric, Silke Kummer, Osamu Takikawa, Eugen Domann, Trinad Chakraborty, Martin Krönke, Olaf Utermöhlen, Joachim L. Schultze. Infection of myeloid dendritic cells with Listeria monocytogenes leads to the suppression of T cell function by multiple inhibitory mechanisms. Journal of Immunology 181:4976-4988. 2008

Maria A. Ermolaeva, Marie-Cecile Michallet, Nikoletta Papadopoulou, Olaf Utermöhlen, Ksanthi Kranidioti, George Kollias, Jürg Tschopp, Manolis Pasparakis. Role of TRADD in TNFR1-signaling and in TRIF-dependent inflammatory responses. Nature Immunology 9.:037-1046. 2008

Michael Schramm, Jasmin Herz, Albert Haas, Martin Krönke, Olaf Utermöhlen. Acid sphingomyelinase is required for efficient phago-lysosomal fusion. Cellular Microbiology 10:1839-1853. 2008

Monika Sakowicz-Burkiewicz, Gopala Nishanth, Ulrike Helmuth, Katrin Drögemüller, Dirk H. Busch, Olaf Utermöhlen, Michael Naumann, Martina Deckert, Dirk Schlüter. Protein kinase C- critically regulates the proliferation and survival of pathogen-specific T cells in murine listeriosis. Journal of Immunology 180:5601-5612. 2008

Bianca Schneider, Christian Schueller, Olaf Utermöhlen, Albert Haas. Lipid microdomain-dependent macropinocytosis determines compartmentation of Afipis felis. Traffic 8:226-240. 2007

Roland C. Zahn, Ina Schelp, Olaf Utermöhlen, Dorothee von Laer. A-to-G Hypermutation in the Genome of Lymphocytic Choriomeningitis Virus. Journal of Virology 81:457-64. 2007

Project area: Stem cell immunology:

Lukas P. Frenzel, Zeinab Abdullah, Anja K. Kriegeskorte, Rebecca Dieterich, Nadin Lange, Dirk H. Busch, Martin Krönke, Olaf Utermöhlen, Jürgen Hescheler, and Tomo Šaric. Role of NKG2D-ligands and ICAM-1 in NK cell-mediated lysis of murine embryonic stem cells and embryonic stem cell-derived cardiomyocytes. Stem cells 27:307-316. 2009

Zeinab Abdullah, Tomo Saric, Hamid Kashkar, Nikola Baschuk, Benjamin Yazadanpanah, Bernd Fleischmann, Jürgen Hescheler, Martin Krönke, Olaf Utermöhlen. Serpin-6 expression protects embryonic stem cells from lysis by antigen-specific CTL. Journal of Immunology. 178:3390-3399. 2007

Project area: Tumor immunology:

Nikola Baschuk, Olaf Utermöhlen, Roland Gugel, Gabriel Warnecke, Ulrike Karow, Daniela Paulsen, Frank Brombacher, Martin Krönke, Wolfgang Deppert. Interleukin-4 impairs granzyme-mediated cytotoxicity of Simian virus 40 large tumor antigen-specific CTL in BALB/c mice. Cancer Immunology and Immunotherapy. 56:1625-1636. 2007

Hamid Kashkar, Jens-Michael Seeger, Andreas Hombach, Anke Deggerich, Benjamin Yazdanpanah, Olaf Utermöhlen, Gerd Heimlich, Hinrich Abken, Martin Krönke. XIAP targeting sensitizes Hodgkin´s Lymphoma cells for cytolytic T cell attack. Blood 108:3434-3440. 2006

Further cooperative projects:

Brunn A, Utermöhlen O, Mihelcic M, Sánchez-Ruiz M, Carstov M, Blau T, Ustinova I, Penfold M, Montesinos-Rongen M, Deckert M. Differential Effects of CXCR4-CXCL12- and CXCR7-CXCL12-mediated Immune Reactions on Murine P0106-125 -induced Experimental Autoimmune Neuritis. Neuropathol Appl Neurobiol. 2013 Mar 4. doi: 10.1111/nan.12039. [Epub ahead of print]

Denise Tischner, Jennifer Theiss, Anna Karabinskaya, Jens van den Brandt, Sybille D. Reichardt, Ulrike Karow, Marco J. Herold, Fred Lühder, Olaf Utermöhlen, Holger M. Reichardt. Acid Sphingomyelinase is required for protection of activated T cells against glucocorticoid-induced cell death. Journal of Immunology 187:4509-16. 2011

Anna Brunn, Olaf Utermöhlen, Monica Sánchez Ruiz, Manuel Montesinos-Rongen, Tobias Blau, Dirk Schlüter, Martina Deckert. Accelerated onset but reduced disease activity in murine P0106-125-induced experimental autoimmune neuritis in the absence of B cells. Acta Neuropathologica 120:667-81. 2010

Anna Brunn, Olaf Utermöhlen, Mariana Carstov, Monica Sánchez Ruiz, Hrvoje Miletic, Dirk Schlüter, Martina Deckert. CD4 T Cells mediate Axonal Damage and Spinal Cord Motor Neuron Apoptosis in Murine P0106-125-induced Experimental Autoimmune Neuritis. American Journal of Pathology 173:93-105. 2008

Sabine A. Eming, Sabine Werner, Philippe Bugnon, Claudia Wickenhauser, Lisa Siewe, Olaf Utermöhlen, Jeffrey M. Davidson, Thomas Krieg, Axel Roers. Accelerated wound closure in mice deficient for interleukin-10. American Journal of Pathology 170:188-202. 2007

 

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