Das intrahepatische T-Zell-Profil und dessen Polarisierung in der Entwicklung und Progression der nicht-alkoholischen Steatohepatitis (NASH)

• Antragstellerin: Dr. Hannah Drescher
• Fachliche Zuordnung: Gastroenterologie
• Förderung: Förderung von 2019 bis 2022
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 425970635

• Erstellungsjahr: 2023

Zusammenfassung der Projektergebnisse

Hepatic inflammation and immune cell dysregulation are key features of NASH progression. There is clear evidence in both mouse and human studies that show the critical role of immune cell infiltration and immune modulatory polarization in the progression from simple steatosis to NASH and fibrosis. We and others could show that the imbalance of multiple immune cell types within the pathologically changed hepatic microenvironment in NASH are implicated in the development of chronic hepatitis and the progression of fibrosis. However, very little is known about how immune cell infiltration and polarization in NASH is regulated, because of the lack of human tissue samples and technical challenges in analyzing parenchymal and non-parenchymal immune cell populations all at once. Our study is the first one to use CASH as a human NAFLD/NASH model which will contribute important insight into the pathogenesis of NAFLD/NASH and will help to better understand mechanisms of early disease development. This will lead future studies on novel pathways and potential biomarkers in NASH and will help to significantly improve and modify existing mouse models to better reflect human disease.

Projektbezogene Publikationen (Auswahl)

• Current Status in Testing for Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH). Cells, 8(8), 845.
  Drescher, Hannah; Weiskirchen, Sabine & Weiskirchen, Ralf
  
• Platelet Factor 4 Attenuates Experimental Acute Liver Injury in Mice. Frontiers in Physiology, 10 (2019, 3, 26).
  Drescher, Hannah K.; Brandt, Elisa F.; Fischer, Petra; Dreschers, Stephan; Schwendener, Reto A.; Kowalska, M. Anna; Canbay, Ali; Wasmuth, Hermann E.; Weiskirchen, Ralf; Trautwein, Christian; Berres, Marie-Luise; Kroy, Daniela C. & Sahin, Hacer
  
• Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nature Medicine, 25(4), 641-655.
  Malehmir, Mohsen; Pfister, Dominik; Gallage, Suchira; Szydlowska, Marta; Inverso, Donato; Kotsiliti, Elena; Leone, Valentina; Peiseler, Moritz; Surewaard, Bas G. J.; Rath, Dominik; Ali, Adnan; Wolf, Monika Julia; Drescher, Hannah; Healy, Marc E.; Dauch, Daniel; Kroy, Daniela; Krenkel, Oliver; Kohlhepp, Marlene; Engleitner, Thomas; ... & Heikenwalder, Mathias
  
• The Influence of Different Fat Sources on Steatohepatitis and Fibrosis Development in the Western Diet Mouse Model of Non-alcoholic Steatohepatitis (NASH). Frontiers in Physiology, 10 (2019, 6, 25).
  Drescher, Hannah K.; Weiskirchen, Ralf; Fülöp, Annabelle; Hopf, Carsten; de San Román Estibaliz, González; Huesgen, Pitter F.; de Bruin, Alain; Bongiovanni, Laura; Christ, Annette; Tolba, René; Trautwein, Christian & Kroy, Daniela C.
  
• The Inhibitory T Cell Receptors PD1 and 2B4 Are Differentially Regulated on CD4 and CD8 T Cells in a Mouse Model of Non-alcoholic Steatohepatitis. Frontiers in Pharmacology, 10 (2019, 3, 13).
  Hansel, Cordula; Erschfeld, Stephanie; Baues, Maike; Lammers, Twan; Weiskirchen, Ralf; Trautwein, Christian; Kroy, Daniela C. & Drescher, Hannah K.
  
• Intrahepatic TH17/TReg Cells in Homeostasis and Disease—It’s All About the Balance. Frontiers in Pharmacology, 11 (2020, 10, 2).
  Drescher, Hannah K.; Bartsch, Lea M.; Weiskirchen, Sabine & Weiskirchen, Ralf
  
• L-Selectin/CD62L Is a Key Driver of Non-Alcoholic Steatohepatitis in Mice and Men. Cells, 9(5), 1106.
  Drescher, Hannah K.; Schippers, Angela; Rosenhain, Stefanie; Gremse, Felix; Bongiovanni, Laura; de Bruin, Alain; Eswaran, Sreepradha; Gallage, Suchira U.; Pfister, Dominik; Szydlowska, Marta; Heikenwalder, Mathias; Weiskirchen, Sabine; Wagner, Norbert; Trautwein, Christian; Weiskirchen, Ralf & Kroy, Daniela C.
  
• Mouse Models of Nonalcoholic Steatohepatitis: Head-to-Head Comparison of Dietary Models and Impact on Inflammation and Animal Welfare. Gastroenterology Research and Practice, 2020 (2020, 7, 13), 1-12.
  Kroh, Andreas; Ivanova, Vanina; Drescher, Hannah; Andruszkow, Julia; Longerich, Thomas; Nolting, Jochen; Eickhoff, Roman; Heise, D.; Rheinwalt, Karl P.; Neumann, Ulf P. & Ulmer, Florian T.
  
• Reevaluation of Lung Injury in TNF-Induced Shock: The Role of the Acid Sphingomyelinase. Mediators of Inflammation, 2020 (2020, 5, 1), 1-14.
  Reiss, Lucy K.; Raffetseder, Ute; Gibbert, Lydia; Drescher, Hannah K.; Streetz, Konrad L.; Schwarz, Agatha; Martin, Christian; Uhlig, Stefan & Adam, Dieter
  
• Tissue-Resident Memory T Cells in the Liver—Unique Characteristics of Local Specialists. Cells, 9(11), 2457.
  Bartsch, Lea M.; Damasio, Marcos P. S.; Subudhi, Sonu & Drescher, Hannah K.
  
• Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory. (2021, 4, 4). American Geophysical Union (AGU).
  Tonnerre, Pierre; Wolski, David; Subudhi, Sonu; Al-Jabban, Jihad; Hoogeveen, Ruben C.; Damasio, Marcos; Drescher, Hannah K.; Bartsch, Lea M.; Tully, Damien C.; Sen, Debattama R.; Bean, David J.; Brown, Joelle; Torres-Cornejo, Almudena; Robidoux, Maxwell; Kvistad, Daniel; Alatrakchi, Nadia; Cui, Ang; Lieb, David; Cheney, James A.; ... & Lauer, Georg M.
  
• Distinct Hepatic Gene‐Expression Patterns of NAFLD in Patients With Obesity. Hepatology Communications, 6(1), 77-89.
  Subudhi, Sonu; Drescher, Hannah K.; Dichtel, Laura E.; Bartsch, Lea M.; Chung, Raymond T.; Hutter, Matthew M.; Gee, Denise W.; Meireles, Ozanan R.; Witkowski, Elan R.; Gelrud, Louis; Masia, Ricard; Osganian, Stephanie A.; Gustafson, Jenna L.; Rwema, Steve; Bredella, Miriam A.; Bhatia, Sangeeta N.; Warren, Andrew; Miller, Karen K.; Lauer, Georg M. & Corey, Kathleen E.
  
• Flow Cytometry: A Blessing and a Curse. Biomedicines, 9(11), 1613.
  Drescher, Hannah; Weiskirchen, Sabine & Weiskirchen, Ralf
  
• Upregulation of Anti-Oxidative Stress Response Improves Metabolic Changes in L-Selectin-Deficient Mice but Does Not Prevent NAFLD Progression or Fecal Microbiota Shifts. International Journal of Molecular Sciences, 22(14), 7314.
  Eswaran, Sreepradha; Babbar, Anshu; Drescher, Hannah K.; Hitch, Thomas C. A.; Clavel, Thomas; Muschaweck, Moritz; Ritz, Thomas; Kroy, Daniela C.; Trautwein, Christian; Wagner, Norbert & Schippers, Angela
  
• Expression of IGF-1 receptor and GH receptor in hepatic tissue of patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Growth Hormone & IGF Research, 65, 101482.
  Osganian, Stephanie A.; Subudhi, Sonu; Masia, Ricard; Drescher, Hannah K.; Bartsch, Lea M.; Chicote, Mark L.; Chung, Raymond T.; Gee, Denise W.; Witkowski, Elan R.; Bredella, Miriam A.; Lauer, Georg M.; Corey, Kathleen E. & Dichtel, Laura E.
  
• Hepatitis B virus-specific CD4 T cell responses differentiate functional cure from chronic surface antigen+ infection. Journal of Hepatology, 77(5), 1276-1286.
  Hoogeveen, Ruben C.; Dijkstra, Suzan; Bartsch, Lea M.; Drescher, Hannah K.; Aneja, Jasneet; Robidoux, Maxwell P.; Cheney, James A.; Timm, Joerg; Gehring, Adam; de Sousa, Paulo Sergio Fonseca; Ximenez, Lya; Peliganga, Luis Baiao; Pitts, Anita; Evans, Fiona B.; Boonstra, André; Kim, Arthur Y.; Lewis-Ximenez, Lia L. & Lauer, Georg M.
  
• Molecular MRI quantification of extracellular aldehyde pairs for early detection of liver fibrogenesis and response to treatment. Science Translational Medicine, 14(663).
  Ning, Yingying; Zhou, Iris. Y.; Roberts, Jesse D.; Rotile, Nicholas J.; Akam, Eman; Barrett, Stephen C.; Sojoodi, Mozhdeh; Barr, Matthew N.; Punshon, Tracy; Pantazopoulos, Pamela; Drescher, Hannah K.; Jackson, Brian P.; Tanabe, Kenneth K. & Caravan, Peter