Splenectomy Prolongs the Effects of Corticosteroids in Mouse Models of Autoimmune Hepatitis

Abstract

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hepatitis (AIH) initially respond to treatment with corticosteroids but often experience a relapse after treatment is withdrawn.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. Wealso developed a mouse model of chronic AIH to investigate the effects of splenectomy. 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. 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 inthe spleen. Splenectomy reduced liver inflammation inthese mice and in BALB/c PD-1(-/-) mice with AIH. 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.