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The long-term course and outcome of DAIH is unknown. A retrospective multicenter study assessing associations and long-term consequences of DAIH developing in a transplanted allograft is presented. Children with DAIH were followed from diagnosis until death, re-LT, or transfer of care and for a minimum of 1 year. A total of 31 patients of 1833 (1.7%) LT were identified; 29 followed for a median of 7.1 years (range, 1.6-15); 52% had no rejection preceding diagnosis of DAIH. Transaminases fell following treatment with steroids and antimetabolites (ALT 108 vs 39 U/L (P=.002); AST 112 vs 52 U/L (P=.003); GGT 72 vs 36 U/L (P=.03), but this was not universally sustained. Transaminases >2X ULN observed in 38% of patients at last follow-up; commonly GGT, attributed to bile duct injury and ductopenia. Portal hypertension (PHT) was seen in four patients and associated with severe fibrosis and cirrhosis. Re-LT occurred in two patients for chronic rejection (CR) and uncontrolled PHT with gastrointestinal bleeding, respectively. No deaths from DAIH were reported. DAIH is an uncommon complication following pediatric LT requiring prolonged and augmented immunosuppression. It is associated with continued allograft dysfunction and may lead to bile duct injury, CR, and PHT necessitating re-LT., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A subset of human regulatory T cells (Tregs) can secrete IFN-γ or IL-17, and thus share features of TH1 or TH17 effector cells and lose suppressive function. The main factors driving this differentiation of Tregs toward a proinflammatory phenotype include IL-12 for TH1-like and IL-6 for TH17-type Tregs. In this study we show that Tregs of patients with de novo autoimmune hepatitis (dAIH) display increased frequencies of proinflammatory IFN-γ and IL-17 cytokines. Irrespective of a fully demethylated FOXP3 locus, Tregs of subjects with dAIH are functionally impaired. In line with the observed Treg phenotype, we detected the presence of two dominant cytokines (IL-12 and IL-6) clustering with CD68(+) monocyte/macrophage cells in livers of subjects with dAIH, and isolated monocytes of subjects with dAIH secrete high levels of proinflammatory IL-12 and IL-6, suggesting that this inflammatory milieu is key for functional impairment of Tregs. Importantly, the blockade of IFN-γ partially restores suppressive function of Tregs of subjects with dAIH, indicating that monocyte/macrophage-derived triggers might play a central role in Treg dysfunction and pathogenesis of dAIH., (Copyright © 2016 by The American Association of Immunologists, Inc.)

This retrospective case series reviews our center's experience with sirolimus and a CNI as alternative therapy for the treatment of PTAH. It also characterizes regulatory T cells (Tregs) in PTAH. LT recipients with PTAH who had received or were receiving treatment with sirolimus were retrospectively identified (n = 12). Liver enzymes, immunohistochemistry, and histology were compared in all 12 patients. Immunophenotyping for Tregs in peripheral blood mononuclear cells was performed on LT recipients with PTAH on conventional therapy with CNI, azathioprine ± prednisone (CT) (n = 11), recipients with PTAH on sirolimus, CNI ± prednisone (n = 8), recipients without PTAH (n = 25), and pre-transplant patients (n = 5). Severity of necro-inflammatory changes markedly improved with sirolimus. Treg frequency and number were significantly lower in recipients with PTAH on CT compared to (i) those on sirolimus (p = 0.002 and p = 0.01, respectively), and (ii) recipients without PTAH (p = 0.07 and p = 0.009, respectively). Treg frequency was significantly higher in recipients with PTAH on sirolimus compared to recipients without PTAH under CNI therapy (p = 0.027). Sirolimus in addition to a CNI is successful in reversing inflammation in LT recipients with PTAH. This is associated with significantly higher circulating Tregs., (© 2012 John Wiley & Sons A/S.)