Ryutaro Maruoka1, Nobuhiro Aoki1, Masahiro Kido1, Satoru Iwamoto1, Hisayo Nishiura1, Aki Ikeda1, Tsutomu Chiba2, Norihiko Watanabe3. 1. 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. 2. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 3. 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.
Abstract
BACKGROUND & AIMS: 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hepatitis (AIH) initially respond to treatment with corticosteroids but often experience a relapse after treatment is withdrawn.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.
BACKGROUND & AIMS: 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: Muhammed Yüksel; Debby Laukens; Femke Heindryckx; Hans Van Vlierberghe; Anja Geerts; F Susan Wong; Li Wen; Isabelle Colle Journal: Int J Exp Pathol Date: 2014-08-12 Impact factor: 1.925
Authors: Yongjuan Wang; Xiaopei Guo; Guohui Jiao; Lili Luo; Lu Zhou; Jie Zhang; Bangmao Wang Journal: Biomed Res Int Date: 2019-01-06 Impact factor: 3.411