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We sought to determine the effects of exogenous administration of human coagulation factors following pig-to-baboon liver xenotransplantation (LXT) using GalT-KO donors. Post-LXT, baboons received either: no coagulation factors (historical control, n=1), bolus administration of a human prothrombin concentrate complex (hPCC) (2.5 mL/kg, n = 2), continuous infusion of hPCC (1.0 ml/hr, n=1) or a continuous infusion of human recombinant Factor VIIa (1 mcg/kg/hr, n=3). The historical control recipient demonstrated persistent thrombocytopenia despite platelet administration post-transplant along with widespread thrombotic microangiopathy (TMA). In contrast, platelet levels were maintained in bolus hPCC recipients, however these animals quickly developed large vessel thrombosis and TMA leading to graft failure with shortened survival. Recipients of continuous coagulation factor administration experienced either stabilization or an increase in their circulating platelets with escalating doses. Furthermore, transfusion requirements were decreased and hepatic TMA was noticeably absent in recipients of continuous coagulation factor infusions when compared to the historical control and bolus hPCC recipients. This effect was most profound with a continuous, escalating dose of Factor VIIa. Further studies are warranted as this regimen may allow for prolonged survival following LXT.

Primary biliary cholangitis (PBC) is an immune-mediated cholestatic disease. Vitamin D receptor (VDR)-dependent signaling constrains an inflammatory response by targeting the miRNA155-SOCS1 (suppressor of cytokine signaling 1) axis. The VDR-miRNA155-SOCS1 pathway was investigated in the context of the autoimmune response associated with PBC. Human liver tissues from non-cirrhotic PBC (n = 22), cirrhotic PBC (n = 22), cirrhotic primary sclerosing cholangitis (PSC, n = 13), controls (n = 23), and peripheral blood mononuclear cells (PBMC) obtained from PBC (n = 16) and PSC (n = 10) patients and healthy subjects (n = 11) were used for molecular analyses. VDR mRNA and protein expressions were substantially reduced in PBC livers (51% and 59%, respectively). Correspondingly, the decrease of SOCS1 protein expression in PBC livers, after normalization to a marker of lymphocytes and forkhead family transcriptional regulator box P3 (FOXP3, marker of Treg), was observed, and this phenomenon was accompanied by enhanced miRNA155 expression. In PSC livers, protein expressions of VDR and SOCS1 were comparable to the controls. However, in PBM cells, protein expressions of VDR and SOCS1 were considerably decreased in both PBC and PSC. We demonstrated that VDR/miRNA155-modulated SOCS1 expression is decreased in PBC which may lead to insufficient negative regulation of cytokine signaling. These findings suggest that the decreased VDR signaling in PBC could be of importance in the pathogenesis of PBC.

Development of liver transplantation program provided more than 1000 transplantations and excellent long-term results. Liver failure caused by hepatitis C and B infections remains the most common cause of liver transplantation and structure of other indications is consistent with European data.

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