Project Description

TP05: Role of myeloid cells in the liver for antiviral immunity

Different liver cell populations contribute to the unique hepatic immune regulation and to the liver´s function as lymphoid organ. Mechanisms that determine persistent infection of hepatitis B virus (HBV) or clearance of HBV infection are not known in sufficient detail. We will (i) characterize the role of liver-resident and recruited myeloid cells for hepatic immune surveillance and generation of HBV-specific immunity, (ii) investigate the immune stimulatory and organ-protective roles of myeloid cells during antiviral immunity in the liver, (iii) characterize the molecular mechanisms determining such functional plasticity of myeloid cells by employing immune competent models and (iv) translate key findings from preclinical models to patients to develop innovative immune therapies against persistent HBV infections.
Yuan D, Huang S, Berger E, Liu L, Gross N, Heinzmann F, Ringelhan M, Connor TO, Stadler M, Meister M, Weber J, Öllinger R, Simonavicius N, Reisinger F, Hartmann D, Meyer R, Reich M, Seehawer M, Leone V, Höchst B, Wohlleber D, Jörs S, Prinz M, Spalding D, Protzer U, Luedde T, Terracciano L, Matter M, Longerich T, Knolle P, Ried T, Keitel V, Geisler F, Unger K, Cinnamon E, Pikarsky E, Hüser N, Davis RJ, Tschaharganeh DF, Rad R, Weber A, Zender L, Haller D, Heikenwalder M. 2017. Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS. Cancer Cell. 31(6):771-789.e6. doi: 10.1016/j.ccell.2017.05.006.
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Protzer U, Knolle P. 2016. "To Be or Not to Be": Immune Tolerance in Chronic Hepatitis B. Gastroenterology. 151(5):805-806. doi: 10.1053/j.gastro.2016.09.038
Böttcher JP, Beyer M, Meissner F, Abdullah Z, Sander J, Höchst B, Eickhoff S, Rieckmann JC, Russo C, Bauer T, Flecken T, Giesen D, Engel D, Jung S, Busch DH, Protzer U, Thimme R, Mann M, Kurts C, Schultze JL, Kastenmüller W, Knolle PA. Nat Commun. 2015 Sep 25;6:8306. doi: 10.1038/ncomms9306
Böttcher JP, Schanz O , Garbers C, Zaremba A, Hegenbarth S, Kurts C, Beyer M, Schultze JL, Kastenmuller W, Rose-John S, Knolle PA. 2014. IL-6 trans-Signalling-Dependent Rapid Development of Cytotoxic CD8(+) T Cell Function. Cell reports 8: 1318-1327.
Böttcher JP, Schanz O, Wohlleber D, Abdullah Z, Debey-Pascher S, Staratschek-Jox A, Hochst B, Hegenbarth S, Grell J, Limmer A, Atreya I, Neurath MF, Busch DH, Schmitt E, van Endert P, Kolanus W, Kurts C, Schultze JL, Diehl L, Knolle PA. 2013. Liver-Primed Memory T Cells Generated under Noninflammatory Conditions Provide Anti-infectious Immunity. Cell reports 3: 779-795.
Diehl L, Schurich A, Grochtmann R, Hegenbarth S, Chen L, Knolle PA. 2008. Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance. Hepatology 47: 296-305.
Huang LR, Gabel YA, Graf S, Arzberger S, Kurts C, Heikenwalder M, Knolle PA, Protzer U. 2012. Transfer of HBV genomes using low doses of adenovirus vectors leads to persistent infection in immune competent mice. Gastroenterology 142: 1447-1450 e1443.
Huang LR, Wohlleber D, Reisinger F, Jenne CN, Cheng RL, Abdullah Z. Schildberg FA, Odenthal M, Dienes HP, van Rooijen N, Schmitt E, Garbi N, Croft M, Kurts C, Kubes P, Protzer U, Heikenwalder M, Knolle PA. 2013. Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection. Nat Immunol 14: 574-583.
Kern M, Popov A, Scholz K, Schumak B, Djandji D, Limmer A, Eggle D, Sacher T, Zawatzky R, Holtappels R, Reddehase MJ, Hartmann G, Debey-Pascher S, Diehl L, Kalinke U, Koszinowski U, Schultze J, Knolle PA. 2010. Virally infected mouse liver endothelial cells trigger CD8+ T-cell immunity. Gastroenterology 138: 336-346.
Protzer,U. Maini MK, Knolle PA. 2012. Living in the liver: hepatic infections. Nat Rev Immunol 12: 201- 213.
Schurich A, Bottcher JP, Burgdorf S. Penzler P, Hegenbarth S, Kern M, Dolf A, Endl E, Schultze J, Wiertz, E, Stabenow D, Kurts C, Knolle PA. 2009. Distinct kinetics and dynamics of cross-presentation in liver sinusoidal endothelial cells compared to dendritic cells. Hepatology 50: 909-919.
Thomson AW, Knolle PA. 2010. Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol 10: 753-766.