title: Transient Expression of Transgenic IL-12 in Mouse Liver Triggers Unremitting Inflammation Mimicking Human Autoimmune Hepatitis.
abstract: The etiopathogenesis of autoimmune hepatitis (AIH) remains poorly understood. In this study, we sought to develop an animal model of human AIH to gain insight into the immunological mechanisms driving this condition. C57BL/6 mice were i.v. injected with adeno-associated viral vectors encoding murine IL-12 or luciferase under the control of a liver-specific promoter. Organ histology, response to immunosuppressive therapy, and biochemical and immunological parameters, including Ag-specific humoral and cellular response, were analyzed. Mechanistic studies were carried out using genetically modified mice and depletion of lymphocyte subpopulations. Adeno-associated virus IL-12-treated mice developed histological, biochemical, and immunological changes resembling type 1 AIH, including marked and persistent liver mononuclear cell infiltration, hepatic fibrosis, hypergammaglobulinemia, anti-nuclear and anti-smooth muscle actin Abs, and disease remission with immunosuppressive drugs. Interestingly, transgenic IL-12 was short-lived, but endogenous IL-12 expression was induced, and both IL-12 and IFN-γ remained elevated during the entire study period. IFN-γ was identified as an essential mediator of liver damage, and CD4 and CD8 T cells but not NK, NKT, or B cells were essential executors of hepatic injury. Furthermore, both MHC class I and MHC class II expression was upregulated at the hepatocellular membrane, and induction of autoreactive liver-specific T cells was detected. Remarkably, although immunoregulatory mechanisms were activated, they only partially mitigated liver damage. Thus, low and transient expression of transgenic IL-12 in hepatocytes causes loss of tolerance to hepatocellular Ags, leading to chronic hepatitis resembling human AIH type 1. This model provides a practical tool to explore AIH pathogenesis and novel therapies.
authors: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra, 31008 Pamplona, Spain;
authors: Irene
authors: 0000-0002-9839-1411
authors: I
authors: Gil-Farina
authors: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra, 31008 Pamplona, Spain;
authors: Marianna
authors: 0000-0002-4460-6472
authors: M
authors: Di Scala
authors: Unidad de Investigación Mixta Hospital Universitario de Canarias-Universidad de La Laguna, Facultad de Medicina, Universidad de La Laguna, 38071 Santa Cruz de Tenerife, Spain; and.
authors: Eduardo
authors: E
authors: Salido
authors: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra, 31008 Pamplona, Spain;
authors: Esperanza
authors: 0000-0002-5985-3126
authors: E
authors: López-Franco
authors: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra, 31008 Pamplona, Spain;
authors: Estefania
authors: E
authors: Rodríguez-García
authors: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra, 31008 Pamplona, Spain;
authors: Mercedes
authors: M
authors: Blasi
authors: University Clinic of Navarra, University of Navarra, 31008 Pamplona, Spain.
authors: Juana
authors: J
authors: Merino
authors: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra, 31008 Pamplona, Spain;
authors: Rafael
authors: 0000-0002-9461-020X
authors: R
authors: Aldabe
authors: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra, 31008 Pamplona, Spain; University Clinic of Navarra, University of Navarra, 31008 Pamplona, Spain.
authors: Jesús
authors: J
authors: Prieto
authors: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra, 31008 Pamplona, Spain; ggasegui@unav.es.
authors: Gloria
authors: 0000-0002-1600-4562
authors: G
authors: Gonzalez-Aseguinolaza
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D005260:Female; D019693:Hepatitis, Autoimmune / Q000188:drug therapy / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D006942:Hypergammaglobulinemia / Q000209:etiology; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000235:genetics*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D018664:Interleukin-12; D007371:Interferon-gamma