Host and immunosuppression-related factors influencing fibrosis occurrence post liver transplantation
Post liver transplantation (LT) fibrosis has a negative impact on graft function. Cytokine production in the host immune response after LT may contribute to the variable CYP3A-dependent immunosuppressive drug disposition, with subsequent impact on liver fibrogenesis, together with host-related facto...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1042664/full |
| _version_ | 1811344174812758016 |
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| author | Speranta Iacob Speranta Iacob Speranta Iacob Razvan Iacob Razvan Iacob Razvan Iacob Ioana Manea Ioana Manea Mihaela Uta Mihaela Uta Andrei Chiosa Andrei Chiosa Mona Dumbrava Mona Dumbrava Gabriel Becheanu Gabriel Becheanu Gabriel Becheanu Luminita Stoica Luminita Stoica Codruta Popa Codruta Popa Codruta Popa Vlad Brasoveanu Vlad Brasoveanu Doina Hrehoret Doina Hrehoret Cristian Gheorghe Cristian Gheorghe Cristian Gheorghe Liana Gheorghe Liana Gheorghe Liana Gheorghe Simona Dima Simona Dima Irinel Popescu Irinel Popescu |
| author_facet | Speranta Iacob Speranta Iacob Speranta Iacob Razvan Iacob Razvan Iacob Razvan Iacob Ioana Manea Ioana Manea Mihaela Uta Mihaela Uta Andrei Chiosa Andrei Chiosa Mona Dumbrava Mona Dumbrava Gabriel Becheanu Gabriel Becheanu Gabriel Becheanu Luminita Stoica Luminita Stoica Codruta Popa Codruta Popa Codruta Popa Vlad Brasoveanu Vlad Brasoveanu Doina Hrehoret Doina Hrehoret Cristian Gheorghe Cristian Gheorghe Cristian Gheorghe Liana Gheorghe Liana Gheorghe Liana Gheorghe Simona Dima Simona Dima Irinel Popescu Irinel Popescu |
| author_sort | Speranta Iacob |
| collection | DOAJ |
| description | Post liver transplantation (LT) fibrosis has a negative impact on graft function. Cytokine production in the host immune response after LT may contribute to the variable CYP3A-dependent immunosuppressive drug disposition, with subsequent impact on liver fibrogenesis, together with host-related factors. We aimed to investigate whether the cytochrome P4503A5*3 (CYP3A5*3) or TBX21 genotypes impact post-LT liver fibrogenesis. Furthermore, the impact of immunosuppressants on cellular apoptosis has been evaluated using human hepatocytes harvested from cirrhotic explanted livers. We have enrolled 98 LT recipients that were followed for occurrence of liver fibrosis for at least 12 months. There was a statistically significant higher trough level of TAC in patients with homozygous CC-TBX21 genotype (7.83 ± 2.84 ng/ml) vs. 5.66 ± 2.16 ng/ml in patients without this genotype (p = 0.009). The following variables were identified as risk factors for fibrosis ≥2: donor age (p = 0.02), neutrophil to lymphocyte ratio (p = 0.04) and TBX21 genotype CC (p = 0.009). In the cell culture model cytometry analysis has indicated the lowest apoptotic cells percentage in human cirrhotic hepatocytes cultures treated with mycophenolate mofetil (MMF) (5%) and TAC + MMF (2%) whereas the highest apoptosis percentage was registered for the TAC alone (11%). The gene expression results are concordant to cytometry study results, indicating the lowest apoptotic effect for MMF and MMF + TAC immunosuppressive regimens. The allele 1993C of the SNP rs4794067 may predispose to the development of late significant fibrosis of the liver graft. MMF-based regimens have a favourable anti-apoptotic profile in vitro, supporting its use in case of LT recipients at high risk for liver graft fibrosis. |
| first_indexed | 2024-04-13T19:43:05Z |
| format | Article |
| id | doaj.art-4c3fd051f70248d6b5c7da992d305466 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T19:43:05Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-4c3fd051f70248d6b5c7da992d3054662022-12-22T02:32:49ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-10-011310.3389/fphar.2022.10426641042664Host and immunosuppression-related factors influencing fibrosis occurrence post liver transplantationSperanta Iacob0Speranta Iacob1Speranta Iacob2Razvan Iacob3Razvan Iacob4Razvan Iacob5Ioana Manea6Ioana Manea7Mihaela Uta8Mihaela Uta9Andrei Chiosa10Andrei Chiosa11Mona Dumbrava12Mona Dumbrava13Gabriel Becheanu14Gabriel Becheanu15Gabriel Becheanu16Luminita Stoica17Luminita Stoica18Codruta Popa19Codruta Popa20Codruta Popa21Vlad Brasoveanu22Vlad Brasoveanu23Doina Hrehoret24Doina Hrehoret25Cristian Gheorghe26Cristian Gheorghe27Cristian Gheorghe28Liana Gheorghe29Liana Gheorghe30Liana Gheorghe31Simona Dima32Simona Dima33Irinel Popescu34Irinel Popescu35Gastroenterology Department, University of Medicine and Pharmacy “Carol Davila”, Bucharest, RomaniaCenter for Excellence in Translational Medicine, Bucharest, RomaniaFundeni Clinical Institute, Bucharest, RomaniaGastroenterology Department, University of Medicine and Pharmacy “Carol Davila”, Bucharest, RomaniaCenter for Excellence in Translational Medicine, Bucharest, RomaniaFundeni Clinical Institute, Bucharest, RomaniaGastroenterology Department, University of Medicine and Pharmacy “Carol Davila”, Bucharest, RomaniaCenter for Excellence in Translational Medicine, Bucharest, RomaniaCenter for Excellence in Translational Medicine, Bucharest, RomaniaFundeni Clinical Institute, Bucharest, RomaniaCenter for Excellence in Translational Medicine, Bucharest, RomaniaFundeni Clinical Institute, Bucharest, RomaniaCenter for Excellence in Translational Medicine, Bucharest, RomaniaFundeni Clinical Institute, Bucharest, RomaniaGastroenterology Department, University of Medicine and Pharmacy “Carol Davila”, Bucharest, RomaniaCenter for Excellence in Translational Medicine, Bucharest, RomaniaFundeni Clinical Institute, Bucharest, RomaniaCenter for Excellence in Translational Medicine, Bucharest, RomaniaFundeni Clinical Institute, Bucharest, RomaniaGastroenterology Department, University of Medicine and Pharmacy “Carol Davila”, Bucharest, RomaniaCenter for Excellence in Translational Medicine, Bucharest, RomaniaFundeni Clinical Institute, Bucharest, RomaniaCenter for Excellence in Translational Medicine, Bucharest, RomaniaFundeni Clinical Institute, Bucharest, RomaniaCenter for Excellence in Translational Medicine, Bucharest, RomaniaFundeni Clinical Institute, Bucharest, RomaniaGastroenterology Department, University of Medicine and Pharmacy “Carol Davila”, Bucharest, RomaniaCenter for Excellence in Translational Medicine, Bucharest, RomaniaFundeni Clinical Institute, Bucharest, RomaniaGastroenterology Department, University of Medicine and Pharmacy “Carol Davila”, Bucharest, RomaniaCenter for Excellence in Translational Medicine, Bucharest, RomaniaFundeni Clinical Institute, Bucharest, RomaniaCenter for Excellence in Translational Medicine, Bucharest, RomaniaFundeni Clinical Institute, Bucharest, RomaniaCenter for Excellence in Translational Medicine, Bucharest, RomaniaFundeni Clinical Institute, Bucharest, RomaniaPost liver transplantation (LT) fibrosis has a negative impact on graft function. Cytokine production in the host immune response after LT may contribute to the variable CYP3A-dependent immunosuppressive drug disposition, with subsequent impact on liver fibrogenesis, together with host-related factors. We aimed to investigate whether the cytochrome P4503A5*3 (CYP3A5*3) or TBX21 genotypes impact post-LT liver fibrogenesis. Furthermore, the impact of immunosuppressants on cellular apoptosis has been evaluated using human hepatocytes harvested from cirrhotic explanted livers. We have enrolled 98 LT recipients that were followed for occurrence of liver fibrosis for at least 12 months. There was a statistically significant higher trough level of TAC in patients with homozygous CC-TBX21 genotype (7.83 ± 2.84 ng/ml) vs. 5.66 ± 2.16 ng/ml in patients without this genotype (p = 0.009). The following variables were identified as risk factors for fibrosis ≥2: donor age (p = 0.02), neutrophil to lymphocyte ratio (p = 0.04) and TBX21 genotype CC (p = 0.009). In the cell culture model cytometry analysis has indicated the lowest apoptotic cells percentage in human cirrhotic hepatocytes cultures treated with mycophenolate mofetil (MMF) (5%) and TAC + MMF (2%) whereas the highest apoptosis percentage was registered for the TAC alone (11%). The gene expression results are concordant to cytometry study results, indicating the lowest apoptotic effect for MMF and MMF + TAC immunosuppressive regimens. The allele 1993C of the SNP rs4794067 may predispose to the development of late significant fibrosis of the liver graft. MMF-based regimens have a favourable anti-apoptotic profile in vitro, supporting its use in case of LT recipients at high risk for liver graft fibrosis.https://www.frontiersin.org/articles/10.3389/fphar.2022.1042664/fullgraft fibrosistacrolimusmycophenolate mofetilCYP3A5 genotypeapoptosishepatocytes culture |
| spellingShingle | Speranta Iacob Speranta Iacob Speranta Iacob Razvan Iacob Razvan Iacob Razvan Iacob Ioana Manea Ioana Manea Mihaela Uta Mihaela Uta Andrei Chiosa Andrei Chiosa Mona Dumbrava Mona Dumbrava Gabriel Becheanu Gabriel Becheanu Gabriel Becheanu Luminita Stoica Luminita Stoica Codruta Popa Codruta Popa Codruta Popa Vlad Brasoveanu Vlad Brasoveanu Doina Hrehoret Doina Hrehoret Cristian Gheorghe Cristian Gheorghe Cristian Gheorghe Liana Gheorghe Liana Gheorghe Liana Gheorghe Simona Dima Simona Dima Irinel Popescu Irinel Popescu Host and immunosuppression-related factors influencing fibrosis occurrence post liver transplantation Frontiers in Pharmacology graft fibrosis tacrolimus mycophenolate mofetil CYP3A5 genotype apoptosis hepatocytes culture |
| title | Host and immunosuppression-related factors influencing fibrosis occurrence post liver transplantation |
| title_full | Host and immunosuppression-related factors influencing fibrosis occurrence post liver transplantation |
| title_fullStr | Host and immunosuppression-related factors influencing fibrosis occurrence post liver transplantation |
| title_full_unstemmed | Host and immunosuppression-related factors influencing fibrosis occurrence post liver transplantation |
| title_short | Host and immunosuppression-related factors influencing fibrosis occurrence post liver transplantation |
| title_sort | host and immunosuppression related factors influencing fibrosis occurrence post liver transplantation |
| topic | graft fibrosis tacrolimus mycophenolate mofetil CYP3A5 genotype apoptosis hepatocytes culture |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1042664/full |
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