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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hepatitis (AIH) initially respond to treatment with corticosteroids but often experience a relapse after treatment is withdrawn.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. [ABSTRACT FROM AUTHOR]

Background & Aims: To clarify mechanisms involved in the development of autoimmune hepatitis (AIH), we recently developed a mouse model of spontaneous AIH by inducing a concurrent loss of Foxp3+ regulatory T cells and programmed cell death 1 (PD-1)–mediated signaling. Fatal AIH in these mice was characterized by severe T-cell infiltration and huge production of antinuclear antibodies (Abs). This study aims to identify induction sites, responsible T-cell subsets, and key molecules for induction of AIH. Methods: To develop the mouse model of AIH, neonatal thymectomy (NTx) was performed on PD-1–deficient (PD-1−/−) mice. We then conducted neonatal splenectomy or in vivo administration of Abs to cytokines, chemokines, or cell-surface molecules. Results: In NTx-PD-1−/− mice, either neonatal splenectomy or in vivo CD4+ T-cell depletion suppressed CD4+ and CD8+ T-cell infiltration in the liver. In the induction phase of AIH, splenic CD4+ T cells were localized in B-cell follicles with huge germinal centers and showed the Bcl6+ inducible costimulator (ICOS)+ interleukin (IL)-21+ IL-21 receptor (IL-21R)+ follicular helper T (TFH) cell phenotype. Blocking Abs to ICOS or IL-21 suppressed TFH-cell generation and induction of AIH. In addition, IL-21 produced by TFH cells drove CD8+ T-cell activation. Splenic TFH cells and CD8+ T cells expressed CCR6, and CCL20 expression was elevated in the liver. Administration of anti-CCL20 suppressed migration of these T cells to the liver and induction of AIH. Conclusions: Dysregulated TFH cells in the spleen are responsible for the induction of fatal AIH, and CCR6-CCL20 axis-dependent migration of splenic T cells is crucial to induce AIH in NTx-PD-1 −/− mice. [ABSTRACT FROM AUTHOR]