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5 results on '"Heide, Danijela"'

1. A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery

Author

Crouchet, Emilie, Bandiera, Simonetta, Fujiwara, Naoto, Li, Shen, El Saghire, Hussein, Fernández-Vaquero, Mirian, Riedl, Tobias, Sun, Xiaochen, Hirschfield, Hadassa, Jühling, Frank, Zhu, Shijia, Roehlen, Natascha, Ponsolles, Clara, Heydmann, Laura, Saviano, Antonio, Qian, Tongqi, Venkatesh, Anu, Lupberger, Joachim, Verrier, Eloi R., Sojoodi, Mozhdeh, Oudot, Marine A., Duong, François H. T., Masia, Ricard, Wei, Lan, Thumann, Christine, Durand, Sarah C., González-Motos, Victor, Heide, Danijela, Hetzer, Jenny, Nakagawa, Shigeki, Ono, Atsushi, Song, Won-Min, Higashi, Takaaki, Sanchez, Roberto, Kim, Rosa S., Bian, C. Billie, Kiani, Karun, Croonenborghs, Tom, Subramanian, Aravind, Chung, Raymond T., Straub, Beate K., Schuppan, Detlef, Ankavay, Maliki, Cocquerel, Laurence, Schaeffer, Evelyne, Goossens, Nicolas, Koh, Anna P., Mahajan, Milind, Nair, Venugopalan D., Gunasekaran, Ganesh, Schwartz, Myron E., Bardeesy, Nabeel, Shalek, Alex K., Rozenblatt-Rosen, Orit, Regev, Aviv, Felli, Emanuele, Pessaux, Patrick, Tanabe, Kenneth K., Heikenwälder, Mathias, Schuster, Catherine, Pochet, Nathalie, Zeisel, Mirjam B., Fuchs, Bryan C., Hoshida, Yujin, Baumert, Thomas F., Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Texas Southwestern Medical Center [Dallas], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Universität Heidelberg [Heidelberg] = Heidelberg University, Nouvel Hôpital Civil de Strasbourg, University Hospital Basel [Basel], Hiroshima University, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Kumamoto University, Broad Institute [Cambridge], Harvard University-Massachusetts Institute of Technology (MIT), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), University Medical Center of the Johannes Gutenberg-University Mainz, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Geneva University Hospital (HUG), Massachusetts Institute of Technology (MIT), Harvard University, This work was supported by ARC, Paris and Institut Hospitalo-Universitaire, Strasbourg (TheraHCC1.0 and 2.0 IHUARC IHU201301187 and IHUARC2019 to T.F.B.), the European Union (ERC-AdG-2014-671231-HEPCIR to T.F.B. and Y.H., EU H2020-667273-HEPCAR to T.F.B. and M.H., and INTERREG-IV-Rhin Supérieur-FEDER-Hepato-Regio-Net 2012 to T.F.B. and M.B.Z), ANRS, Paris (2013/108 and ECTZ103701 to T.F.B), NIH (DK099558 to Y. H., and CA233794 to Y.H. and T. F. B, CA140861 to B.C.F., and CA209940, R21CA209940, and R03AI131066 to N.P. and T.F.B.), Cancer Prevention and Research Institute of Texas (RR180016 to Y.H.), US Department of Defense (W81XWH-16-1-0363 to T.F.B. and Y.H.), the Irma T. Hirschl/Monique Weill-Caulier Trust (Y.H.), and the Foundation of the University of Strasbourg (HEPKIN to T. F. B. and Y. H.) and the Institut Universitaire de France (IUF, T.F.B.). M.H. is supported by an ERC CoG grant (HepatoMetaboPath) and EOS grant and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Project-ID 272983813—TRR 179, and Project-ID 314905040 SFB TR209. This work has been published under the framework of the LABEX ANR-10-LABX-0028_HEPSYS and Inserm Plan Cancer and benefits from funding from the state managed by the French National Research Agency as part of the Investments for the future program., ANR-10-LABX-0028,HepSys,Functional genomics of viral hepatitis and liver disease(2010), European Project: 671231,H2020,ERC-2014-ADG,HEPCIR(2016), European Project: 667273,H2020,H2020-PHC-2015-two-stage,HEP-CAR(2016), Cocquerel, Laurence, Functional genomics of viral hepatitis and liver disease - - HepSys2010 - ANR-10-LABX-0028 - LABX - VALID, Cell circuits as targets and biomarkers for liver disease and cancer prevention - HEPCIR - - H20202016-01-01 - 2020-12-31 - 671231 - VALID, Mechanisms underlying hepatocellular carcinoma pathogenesis and impact of co-morbidities. - HEP-CAR - - H20202016-01-01 - 2019-12-31 - 667273 - VALID, Universität Heidelberg [Heidelberg], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), Harvard University [Cambridge], Johannes Gutenberg - Universität Mainz (JGU), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)

Subjects
Liver Cirrhosis, Male, Carcinoma, Hepatocellular, Hepatocellular carcinoma, Carcinogenesis, Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hepacivirus, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Chemoprevention, Models, Biological, Article, Cohort Studies, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Drug Discovery, Cancer genomics, Cyclic AMP, Animals, Humans, Cyclic AMP Response Element-Binding Protein, Immunologic Surveillance, Liver diseases, Nizatidine, Inflammation, Mice, Knockout, Macrophages, Liver Neoplasms, Prognosis, Hepatitis C, Computational biology and bioinformatics, Gene Expression Regulation, Neoplastic, Disease Models, Animal, Mechanisms of disease, HEK293 Cells, Liver, Hepatocytes, Transcriptome, Signal Transduction
Abstract

Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2+, CLEC5Ahigh, MARCOlow liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention., Drug and target discovery for advanced liver disease are hampered by a lack of suitable models for clinical translation. Here the authors present a human liver cell-based system modeling a clinical prognostic signature allowing to propose nizatidine for treatment of advanced liver fibrosis and hepatocellular carcinoma prevention.

Published
2021
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2. HIF1α-mediated RelB/APOBEC3B downregulation allows Hepatitis B Virus persistence

Author

Riedl, Tobias, Faure-Dupuy, Suzanne, Rolland, Maude, Schuehle, Svenja, Hizir, Zohier, Calderazzo, Silvia, Zhuang, Xiaodong, Wettengel, Jochen, Lopez, Martin Alexander, Barnault, Romain, Mirakaj, Valbona, Prokosch, Sandra, Heide, Danijela, Leuchtenbergeg, Corinna, Schneider, Martin, Heßling, Bernd, Stottmeier, Benjamin, Wessbecher, Isabel, Schirmacher, Peter, Mckeating, Jane, Protzer, Ulrike, Durantel, David, Lucifora, Julie, Dejardin, Emmanuel, Heikenwalder, Mathias, Faure‐Dupuy, Suzanne, and Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Hepatitis B virus, reservoir, Down-Regulation, Article, NF-κB, Cell Line, Minor Histocompatibility Antigens, Mice, Hepatitis B, Chronic, Lymphotoxin beta Receptor, Cytidine Deaminase, Animals, Humans, RNA, Messenger, HIF1α, Hypoxia, Microbial Viability, Transcription Factor RelB, Hypoxia-Inducible Factor 1, alpha Subunit, Hif1α, Hepatitis B Virus, Nf-κb, Cccdna, Reservoir, Amino Acids, Dicarboxylic, Liver, Gene Knockdown Techniques, cccDNA, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, DNA, Circular
Abstract

Therapeutic strategies against HBV focus, among others, on the activation of the immune system to enable the infected host to eliminate HBV. Hypoxia-inducible factor 1 alpha (HIF1α) stabilization has been associated with impaired immune responses. HBV pathogenesis triggers chronic hepatitis-related scaring, leading inter alia to modulation of liver oxygenation and transient immune activation, both factors playing a role in HIF1α stabilization.We addressed whether HIF1α interferes with immune-mediated induction of the cytidine deaminase, apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B; A3B), and subsequent covalently closed circular DNA (cccDNA) decay. Liver biopsies of chronic HBV (CHB) patients were analyzed by immunohistochemistry and in situ hybridization. The effect of HIF1α induction/stabilization on differentiated HepaRG or mice ± HBV ± LTβR-agonist (BS1) was assessed in vitro and in vivo. Induction of A3B and subsequent effects were analyzed by RT-qPCR, immunoblotting, chromatin immunoprecipitation, immunocytochemistry, and mass spectrometry. Analyzing CHB highlighted that areas with high HIF1α levels and low A3B expression correlated with high HBcAg, potentially representing a reservoir for HBV survival in immune-active patients. In vitro, HIF1α stabilization strongly impaired A3B expression and anti-HBV effect. Interestingly, HIF1α knockdown was sufficient to rescue the inhibition of A3B up-regulation and -mediated antiviral effects, whereas HIF2α knockdown had no effect. HIF1α stabilization decreased the level of v-rel reticuloendotheliosis viral oncogene homolog B protein, but not its mRNA, which was confirmed in vivo. Noteworthy, this function of HIF1α was independent of its partner, aryl hydrocarbon receptor nuclear translocator.In conclusion, inhibiting HIF1α expression or stabilization represents an anti-HBV strategy in the context of immune-mediated A3B induction. High HIF1α, mediated by hypoxia or inflammation, offers a reservoir for HBV survival in vivo and should be considered as a restricting factor in the development of immune therapies.

Published
2021
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3. NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Author

Pfister, Dominik, Núñez, Nicolás Gonzalo, Pinyol, Roser, Govaere, Olivier, Pinter, Matthias, Szydlowska, Marta, Gupta, Revant, Qiu, Mengjie, Deczkowska, Aleksandra, Weiner, Assaf, Müller, Florian, Sinha, Ankit, Friebel, Ekaterina, Engleitner, Thomas, Lenggenhager, Daniela, Moncsek, Anja, Heide, Danijela, Stirm, Kristin, Kosla, Jan, Kotsiliti, Eleni, Leone, Valentina, Dudek, Michael, Yousuf, Suhail, Inverso, Donato, Singh, Indrabahadur, Teijeiro, Ana, Castet, Florian, Montironi, Carla, Haber, Philipp K, Tiniakos, Dina, Bedossa, Pierre, Cockell, Simon, Younes, Ramy, Vacca, Michele, Marra, Fabio, Schattenberg, Jörn M, Allison, Michael, Bugianesi, Elisabetta, Ratziu, Vlad, Pressiani, Tiziana, D'Alessio, Antonio, Personeni, Nicola, Rimassa, Lorenza, Daly, Ann K, Scheiner, Bernhard, Pomej, Katharina, Kirstein, Martha M, Vogel, Arndt, Peck-Radosavljevic, Markus, Hucke, Florian, Finkelmeier, Fabian, Waidmann, Oliver, Trojan, Jörg, Schulze, Kornelius, Wege, Henning, Koch, Sandra, Weinmann, Arndt, Bueter, Marco, Rössler, Fabian, Siebenhüner, Alexander, De Dosso, Sara, Mallm, Jan-Philipp, Umansky, Viktor, Jugold, Manfred, Luedde, Tom, Schietinger, Andrea, Schirmacher, Peter, Emu, Brinda, Augustin, Hellmut G, Billeter, Adrian, Müller-Stich, Beat, Kikuchi, Hiroto, Duda, Dan G, Kütting, Fabian, Waldschmidt, Dirk-Thomas, Ebert, Matthias Philip, Rahbari, Nuh, Mei, Henrik E, Schulz, Axel Ronald, Ringelhan, Marc, Malek, Nisar, Spahn, Stephan, Bitzer, Michael, Ruiz De Galarreta, Marina, Lujambio, Amaia, Dufour, Jean-Francois, Marron, Thomas U, Kaseb, Ahmed, Kudo, Masatoshi, Huang, Yi-Hsiang, Djouder, Nabil, Wolter, Katharina, Zender, Lars, Marche, Parice N, Decaens, Thomas, Pinato, David J, Rad, Roland, Mertens, Joachim C, Weber, Achim, Unger, Kristian, Meissner, Felix, Roth, Susanne, Jilkova, Zuzana Macek, Claassen, Manfred, Anstee, Quentin M, Amit, Ido, Knolle, Percy, Becher, Burkhard, Llovet, Josep M, and Heikenwalder, Mathias

Subjects
Male, Carcinoma, Hepatocellular, Carcinogenesis, Tumor Necrosis Factor-alpha, Liver Neoplasms, Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, digestive system diseases, B7-H1 Antigen, 3. Good health, Mice, Liver, Non-alcoholic Fatty Liver Disease, Disease Progression, Animals, Humans, Immunotherapy
Abstract

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

4. NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Author

Pfister, Dominik, Núñez, Nicolás Gonzalo, Pinyol, Roser, Govaere, Olivier, Pinter, Matthias, Szydlowska, Marta, Gupta, Revant, Qiu, Mengjie, Deczkowska, Aleksandra, Weiner, Assaf, Müller, Florian, Sinha, Ankit, Friebel, Ekaterina, Engleitner, Thomas, Lenggenhager, Daniela, Moncsek, Anja, Heide, Danijela, Stirm, Kristin, Kosla, Jan, Kotsiliti, Eleni, Leone, Valentina, Dudek, Michael, Yousuf, Suhail, Inverso, Donato, Singh, Indrabahadur, Teijeiro, Ana, Castet, Florian, Montironi, Carla, Haber, Philipp K, Tiniakos, Dina, Bedossa, Pierre, Cockell, Simon, Younes, Ramy, Vacca, Michele, Marra, Fabio, Schattenberg, Jörn M, Allison, Michael, Bugianesi, Elisabetta, Ratziu, Vlad, Pressiani, Tiziana, D'Alessio, Antonio, Personeni, Nicola, Rimassa, Lorenza, Daly, Ann K, Scheiner, Bernhard, Pomej, Katharina, Kirstein, Martha M, Vogel, Arndt, Peck-Radosavljevic, Markus, Hucke, Florian, Finkelmeier, Fabian, Waidmann, Oliver, Trojan, Jörg, Schulze, Kornelius, Wege, Henning, Koch, Sandra, Weinmann, Arndt, Bueter, Marco, Rössler, Fabian, Siebenhüner, Alexander, De Dosso, Sara, Mallm, Jan-Philipp, Umansky, Viktor, Jugold, Manfred, Luedde, Tom, Schietinger, Andrea, Schirmacher, Peter, Emu, Brinda, Augustin, Hellmut G, Billeter, Adrian, Müller-Stich, Beat, Kikuchi, Hiroto, Duda, Dan G, Kütting, Fabian, Waldschmidt, Dirk-Thomas, Ebert, Matthias Philip, Rahbari, Nuh, Mei, Henrik E, Schulz, Axel Ronald, Ringelhan, Marc, Malek, Nisar, Spahn, Stephan, Bitzer, Michael, Ruiz de Galarreta, Marina, Lujambio, Amaia, Dufour, Jean-François, Marron, Thomas U, Kaseb, Ahmed, Kudo, Masatoshi, Huang, Yi-Hsiang, Djouder, Nabil, Wolter, Katharina, Zender, Lars, Marche, Parice N, Decaens, Thomas, Pinato, David J, Rad, Roland, Mertens, Joachim C, Weber, Achim, Unger, Kristian, Meissner, Felix, Roth, Susanne, Jilkova, Zuzana Macek, Claassen, Manfred, Anstee, Quentin M, Amit, Ido, Knolle, Percy, Becher, Burkhard, Llovet, Josep M, and Heikenwalder, Mathias

Subjects
610 Medicine & health, digestive system diseases, 3. Good health
Abstract

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

5. Intercrypt sentinel macrophages tune antibacterial NF-κB responses in gut epithelial cells via TNF

Author

Hausmann, Annika, Felmy, Boas, Kunz, Leo, Kroon, Sanne, Berthold, Dorothée L., Ganz, Giverny, Sandu, Ioana, Nakamura, Toshihiro, Zangger, Nathan Sébastien, Zhang, Yang, Dolowschiak, Tamas, Fattinger, Stefan A., Furter, Markus, Müller-Hauser, Anna A., Barthel, Manja, Vlantis, Katerina, Wachsmuth, Laurens, Kisielow, Jan, Tortola, Luigi, Heide, Danijela, Heikenwälder, Mathias, Oxenius, Annette, Kopf, Manfred, Schroeder, Timm, Pasparakis, Manolis, Sellin, Mikael E., and Hardt, Wolf-Dietrich

Subjects
digestive system, 3. Good health
Abstract

Intestinal epithelial cell (IEC) NF-κB signaling regulates the balance between mucosal homeostasis and inflammation. It is not fully understood which signals tune this balance and how bacterial exposure elicits the process. Pure LPS induces epithelial NF-κB activation in vivo. However, we found that in mice, IECs do not respond directly to LPS. Instead, tissue-resident lamina propria intercrypt macrophages sense LPS via TLR4 and rapidly secrete TNF to elicit epithelial NF-κB signaling in their immediate neighborhood. This response pattern is relevant also during oral enteropathogen infection. The macrophage-TNF-IEC axis avoids responses to luminal microbiota LPS but enables crypt- or tissue-scale epithelial NF-κB responses in proportion to the microbial threat. Thereby, intercrypt macrophages fulfill important sentinel functions as first responders to Gram-negative microbes breaching the epithelial barrier. The tunability of this crypt response allows the induction of defense mechanisms at an appropriate scale according to the localization and intensity of microbial triggers., Journal of Experimental Medicine, 218 (11), ISSN:0022-1007, ISSN:1540-0069, ISSN:1540-9538

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