title: Dual Role of the Adaptive Immune System in Liver Injury and Hepatocellular Carcinoma Development.
abstract: Hepatocellular carcinoma (HCC) represents a classic example of inflammation-linked cancer. To characterize the role of the immune system in hepatic injury and tumor development, we comparatively studied the extent of liver disease and hepatocarcinogenesis in immunocompromised versus immunocompetent Fah-deficient mice. Strikingly, chronic liver injury and tumor development were markedly suppressed in alymphoid Fah(-/-) mice despite an overall increased mortality. Mechanistically, we show that CD8(+) T cells and lymphotoxin β are central mediators of HCC formation. Antibody-mediated depletion of CD8(+) T cells as well as pharmacological inhibition of the lymphotoxin-β receptor markedly delays tumor development in mice with chronic liver injury. Thus, our study unveils distinct functions of the immune system, which are required for liver regeneration, survival, and hepatocarcinogenesis.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Endig
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Laura Elisa
authors.initials: LE
authors.lastname: Buitrago-Molina
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Marhenke
authors.affiliation: Institute of Virology, Technische Universität München, Helmholtz Zentrum Muenchen, 85764 Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Reisinger
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Saborowski
authors.affiliation: Department of Cardiology, Philipps University Marburg, 35037 Marburg, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Schütt
authors.affiliation: Department of Nephrology and Hypertension, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Limbourg
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Könecke
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Schreder
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Michael
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Ana Clara
authors.initials: AC
authors.lastname: Misslitz
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, 8091 Zürich, Switzerland.
authors.forename: Marc Eammonn
authors.initials: ME
authors.lastname: Healy
authors.affiliation: Department of Cell Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.affiliation: ZIEL Institute for Food and Health, Technische Universität München, 85764 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Clavel
authors.affiliation: ZIEL Institute for Food and Health, Technische Universität München, 85764 Munich, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Haller
authors.affiliation: Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, 85764 Munich, Germany.
authors.forename: Kristian
authors.initials: K
authors.lastname: Unger
authors.affiliation: Department of Pathology, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Milton
authors.initials: M
authors.lastname: Finegold
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, 8091 Zürich, Switzerland.
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.affiliation: Institute of Pathology, Aachen University Hospital, 52074 Aachen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.affiliation: Department of Cardiology, Philipps University Marburg, 35037 Marburg, Germany; Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg, 69121 Heidelberg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwälder
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany. Electronic address: vogel.arndt@mh-hannover.de.
authors.forename: Arndt
authors.initials: A
authors.lastname: Vogel
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D063646:Carcinogenesis / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000473:pathology; D006801:Humans; D006867:Hydrolases / Q000276:immunology; D008107:Liver Diseases / Q000276:immunology* / Q000473:pathology; D008113:Liver Neoplasms / Q000276:immunology* / Q000473:pathology; D008115:Liver Regeneration / Q000276:immunology; D053308:Lymphotoxin-beta / Q000276:immunology; D051379:Mice
chemical_list: C505886:LTB protein, human; C505887:Ltb protein, mouse; D053308:Lymphotoxin-beta; D006867:Hydrolases; C020156:fumarylacetoacetase