13 August 2019 : Original article
Alloresponses of Mixed Lymphocyte Hepatocyte Culture to Immunosuppressive Drugs as an In-Vitro Model of Hepatocyte TransplantationFelix Oldhafer1ABCDEF*, Eva-Maria Wittauer1BCE, Christine S. Falk23BCDEG, Daphne E. DeTemple1BDE, Oliver Beetz1BCDE, Kai Timrott1ABE, Moritz Kleine1ADE, Florian W.R. Vondran12ABCDEG
Ann Transplant 2019; 24:472-480
BACKGROUND: Hepatocyte transplantation (HCTx) has the potential for the treatment of end-stage liver disease. However, failure of engraftment and the long-term acceptance of cellular allografts remain significant challenges for its clinical application. The aim of this study was to investigate the efficacy of the immunosuppressive agents, Cyclosporine, Everolimus, and Belatacept to suppress the alloresponse of primary human hepatocytes in a mixed lymphocyte-hepatocyte culture (MLHC) and their potential hepatotoxicity in vitro.
MATERIAL AND METHODS: Primary human hepatocytes were co-cultured with allogeneic peripheral blood mononuclear cells (PBMCs) in an MLHC. Proliferative alloresponses were determined by flow cytometry, and cytokine secretion was measured using Luminex-based multiplex technology. Using an MLHC, the alloresponses of primary human hepatocytes were compared in the presence and absence of Cyclosporine, Everolimus, and Belatacept. Cultured primary human hepatocytes were assessed for the production of albumin, urea, aspartate transaminase (AST) and DNA content. Metabolic activity was determined with the MTT assay.
RESULTS: Immune responses induced by primary human hepatocytes were effectively suppressed by Cyclosporine, Everolimus, and Belatacept. Everolimus significantly reduced the metabolic activity of primary human hepatocytes in vitro, suggesting impairment of cell viability. However, further functional analysis showed no significant differences between treated and untreated controls.
CONCLUSIONS: Cyclosporine, Everolimus, and Belatacept suppressed the alloresponse of primary human hepatocytes in an MLHC without significant cytotoxicity or functional cell impairment.
Keywords: Cell Transplantation, Hepatocytes, Immunosuppression, Abatacept, Coculture Techniques, Cyclosporine, End stage liver disease, Everolimus, Immunosuppressive Agents, Lymphocytes
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