title: Splenectomy prolongs the effects of corticosteroids in mouse models of autoimmune hepatitis.
abstract: OBJECTIVE
  Most patients with autoimmune hepatitis (AIH) initially respond to treatment with corticosteroids but often experience a relapse after treatment is withdrawn. BALB/c mice with disruption of programmed cell death 1 (PD-1(-/-) mice) that undergo thymectomy 3 days after birth develop a deregulated immune system, have reduced numbers of Foxp3(+) regulatory T cells, and develop fulminant hepatic failure that resembles acute-onset AIH in humans. We examined whether splenectomy overcomes corticosteroid insufficiency and reduces the severity of AIH in these mice. We also developed a mouse model of chronic AIH to investigate the effects of splenectomy.
  
  
  METHODS
  After thymectomy, BALB/c PD-1(-/-) mice were treated with dexamethasone before or after induction of AIH; splenectomy was performed in mice that had and had not been treated with dexamethasone. Neonatal C57BL/6 PD-1(-/-) mice underwent thymectomy to create a model of chronic AIH.
  
  
  RESULTS
  Injection of dexamethasone before or after induction of AIH prevented development of fatal AIH in BALB/c PD-1(-/-) mice. However, injection of dexamethasone after induction of AIH did not suppress splenic production of follicular helper T cells, and discontinuation of dexamethasone led to a relapse of AIH. Splenectomy (even without administration of dexamethasone) prevented AIH. Neonatal C57BL/6 PD-1(-/-) mice that underwent thymectomy developed chronic hepatitis with fibrosis and hypergammaglobulinemia and produced antinuclear antibodies; AIH was found to be induced in the spleen. Splenectomy reduced liver inflammation in these mice and in BALB/c PD-1(-/-) mice with AIH.
  
  
  CONCLUSIONS
  AIH can be induced in mice via disruption of PD-1 and thymectomy; these cause the same disruptions in immune regulation in BALB/c and C57BL/6 mice but produce different phenotypes. Splenectomy overcomes corticosteroid insufficiency in mice and prolongs the effects of dexamethasone.
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Maruoka
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Aoki
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kido
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Iwamoto
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hisayo
authors.initials: H
authors.lastname: Nishiura
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Ikeda
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: norihiko@kuhp.kyoto-u.ac.jp.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004268:DNA-Binding Proteins / Q000502:physiology; D003907:Dexamethasone / Q000627:therapeutic use*; D004195:Disease Models, Animal; D019693:Hepatitis, Autoimmune / Q000188:drug therapy* / Q000601:surgery*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000502:physiology; D013156:Splenectomy; D013934:Thymectomy
chemical_list: D004268:DNA-Binding Proteins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; C499308:Rag2 protein, mouse; D003907:Dexamethasone