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1
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Berg T, Aehling NF, Bruns T, Welker MW, Weismüller T, Trebicka J, Tacke F, Strnad P, Sterneck M, Settmacher U, Seehofer D, Schott E, Schnitzbauer AA, Schmidt HH, Schlitt HJ, Pratschke J, Pascher A, Neumann U, Manekeller S, Lammert F, Klein I, Kirchner G, Guba M, Glanemann M, Engelmann C, Canbay AE, Braun F, Berg CP, Bechstein WO, Becker T, Trautwein C. S2k-Leitlinie Lebertransplantation der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutschen Gesellschaft für Allgemein- und Viszeralchirurgie (DGAV). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1397-1573. [PMID: 39250961 DOI: 10.1055/a-2255-7246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Affiliation(s)
- Thomas Berg
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Niklas F Aehling
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Tony Bruns
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martin-Walter Welker
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin. Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Tobias Weismüller
- Klinik für Innere Medizin - Gastroenterologie und Hepatologie, Vivantes Humboldt-Klinikum, Berlin, Deutschland
| | - Jonel Trebicka
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Deutschland
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Pavel Strnad
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martina Sterneck
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - Utz Settmacher
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Jena, Deutschland
| | - Daniel Seehofer
- Klinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Eckart Schott
- Klinik für Innere Medizin II - Gastroenterologie, Hepatologie und Diabetolgie, Helios Klinikum Emil von Behring, Berlin, Deutschland
| | | | - Hartmut H Schmidt
- Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Essen, Essen, Deutschland
| | - Hans J Schlitt
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg, Regensburg, Deutschland
| | - Johann Pratschke
- Chirurgische Klinik, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - Andreas Pascher
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Münster, Münster, Deutschland
| | - Ulf Neumann
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Essen, Deutschland
| | - Steffen Manekeller
- Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Bonn, Bonn, Deutschland
| | - Frank Lammert
- Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - Ingo Klein
- Chirurgische Klinik I, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - Gabriele Kirchner
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg und Innere Medizin I, Caritaskrankenhaus St. Josef Regensburg, Regensburg, Deutschland
| | - Markus Guba
- Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Universitätsklinikum München, München, Deutschland
| | - Matthias Glanemann
- Klinik für Allgemeine, Viszeral-, Gefäß- und Kinderchirurgie, Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - Cornelius Engelmann
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Ali E Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - Felix Braun
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
| | - Christoph P Berg
- Innere Medizin I Gastroenterologie, Hepatologie, Infektiologie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Wolf O Bechstein
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Thomas Becker
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
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Cicalese L, Walton ZC, Du X, Kulkarni R, Qiu S, El Hag M, Stevenson HL. Antibody-Mediated Rejection in Liver Transplantation: Immuno-Pathological Characteristics and Long-Term Follow-Up. Transpl Int 2024; 37:13232. [PMID: 39267618 PMCID: PMC11391112 DOI: 10.3389/ti.2024.13232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 07/16/2024] [Indexed: 09/15/2024]
Abstract
The diagnosis of liver antibody-mediated rejection (AMR) is challenging and likely under-recognized. The association of AMR with donor-specific antibodies (DSA), and its clinical course in relation to pathologic findings and treatment are ill defined. We identified cases of liver AMR by following the criteria outlined by the 2016 Banff Working Group. Patient demographics, native liver disease, histopathologic findings, treatment type, clinical outcome, and transaminase levels during AMR diagnosis, treatment, and resolution were determined. Patients (n = 8) with AMR average age was 55.2 years (range: 19-68). Seven of eight cases met the Banff criteria for AMR. Personalized treatment regimens consisted of optimization of immunosuppression, intravenous pulse steroids, plasmapheresis, IVIG, rituximab, and bortezomib. Five patients experienced complete resolution of AMR, return of transaminases to baseline, and decreased DSA at long-term follow-up. One patient developed chronic AMR and two patients required re-transplantation. Follow-up after AMR diagnosis ranged from one to 11 years. Because AMR can present at any time, crossmatch, early biopsy, and routine monitoring of DSA levels should be implemented following transaminase elevation to recognize AMR. Furthermore, treatment should be immediately implemented to reverse AMR and prevent graft failure, chronic damage, re-transplantation, and possibly mortality.
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Affiliation(s)
- Luca Cicalese
- Division of Transplant Surgery, Department of Surgery, University of Texas Medical Branch, UTMB, Galveston, TX, United States
| | - Zachary C Walton
- John Sealy School of Medicine, University of Texas Medical Branch, UTMB, Galveston, TX, United States
| | - Xiaotang Du
- Department of Pathology, University of Texas Medical Branch, UTMB, Galveston, TX, United States
| | - Rupak Kulkarni
- Division of Transplant Surgery, Department of Surgery, University of Texas Medical Branch, UTMB, Galveston, TX, United States
| | - Suimin Qiu
- Department of Pathology, University of Texas Medical Branch, UTMB, Galveston, TX, United States
| | - Mohamed El Hag
- Department of Pathology, Cleveland Clinic, Cleveland, OH, United States
| | - Heather L Stevenson
- Department of Pathology, University of Texas Medical Branch, UTMB, Galveston, TX, United States
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Zhang IW, Lurje I, Lurje G, Knosalla C, Schoenrath F, Tacke F, Engelmann C. Combined Organ Transplantation in Patients with Advanced Liver Disease. Semin Liver Dis 2024; 44:369-382. [PMID: 39053507 PMCID: PMC11449526 DOI: 10.1055/s-0044-1788674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/27/2024]
Abstract
Transplantation of the liver in combination with other organs is an increasingly performed procedure. Over the years, continuous improvement in survival could be realized through careful patient selection and refined organ preservation techniques, in spite of the challenges posed by aging recipients and donors, as well as the increased use of steatotic liver grafts. Herein, we revisit the epidemiology, allocation policies in different transplant zones, indications, and outcomes with regard to simultaneous organ transplants involving the liver, that is combined heart-liver, liver-lung, liver-kidney, and multivisceral transplantation. We address challenges surrounding combined organ transplantation such as equity, utility, and logistics of dual organ implantation, but also advantages that come along with combined transplantation, thereby focusing on molecular mechanisms underlying immunoprotection provided by the liver to the other allografts. In addition, the current standing and knowledge of machine perfusion in combined organ transplantation, mostly based on center experience, will be reviewed. Notwithstanding all the technical advances, shortage of organs, and the lack of universal eligibility criteria for certain multi-organ combinations are hurdles that need to be tackled in the future.
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Affiliation(s)
- Ingrid Wei Zhang
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) at Charité - Universitätsmedizin, Berlin, Germany
- European Foundation for the Study of Chronic Liver Failure (EF CLIF) and Grifols Chair, Barcelona, Spain
| | - Isabella Lurje
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Georg Lurje
- Department of Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Christoph Knosalla
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Felix Schoenrath
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) at Charité - Universitätsmedizin, Berlin, Germany
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4
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Demir Z, Raynaud M, Aubert O, Debray D, Sebagh M, Duong Van Huyen JP, Del Bello A, Jolivet NC, Paradis V, Durand F, Muratot S, Lozach C, Chardot C, Francoz C, Kamar N, Sarnacki S, Coilly A, Samuel D, Vibert E, Féray C, Lefaucheur C, Loupy A. Identification of liver transplant biopsy phenotypes associated with distinct liver biological markers and allograft survival. Am J Transplant 2024; 24:954-966. [PMID: 38097016 DOI: 10.1016/j.ajt.2023.12.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 11/07/2023] [Accepted: 12/06/2023] [Indexed: 01/01/2024]
Abstract
The intricate association between histologic lesions and circulating antihuman leucocyte antigen donor-specific antibodies (DSA) in liver transplantation (LT) requires further clarification. We conducted a probabilistic, unsupervised approach in a comprehensively well-annotated LT cohort to identify clinically relevant archetypes. We evaluated 490 pairs of LT biopsies with DSA testing from 325 recipients transplanted between 2010 and 2020 across 3 French centers and an external cohort of 202 biopsies from 128 recipients. Unsupervised archetypal analysis integrated all clinico-immuno-histologic parameters of each biopsy to identify biopsy archetypes. The median time after LT was 1.17 (interquartile range, 0.38-2.38) years. We identified 7 archetypes distinguished by clinico-immuno-histologic parameters: archetype #1: severe T cell-mediated rejection (15.9%); #2: chronic rejection with ductopenia (1.8%); #3: architectural and microvascular damages (3.5%); #4: (sub)normal (55.9%); #5: mild T cell-mediated rejection (4.9%); #6: acute antibody-mediated rejection (6.5%); and #7: chronic rejection with DSA (11.4%). Cell infiltrates vary in the archetype. These archetypes were associated with distinct liver biological markers and allograft outcomes. These findings remained consistent when stratified using the patient's age or indications for LT, with good performance in the external cohort (mean highest probability assignment = 0.58, standard deviation ± 0.17). In conclusion, we have identified clinically meaningful archetypes, providing valuable insights into the intricate DSA-histology association, which may help standardize liver allograft pathology classification.
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Affiliation(s)
- Zeynep Demir
- Paris Translational Research Center for Organ Transplantation, Université de Paris Cité, INSERM, PARCC, Paris, France
| | - Marc Raynaud
- Paris Translational Research Center for Organ Transplantation, Université de Paris Cité, INSERM, PARCC, Paris, France
| | - Olivier Aubert
- Paris Translational Research Center for Organ Transplantation, Université de Paris Cité, INSERM, PARCC, Paris, France; Kidney Transplantation Department, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Dominique Debray
- Pediatric Hepatology and Liver Transplantation Unit, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Mylène Sebagh
- Pathology Department Paul-Brousse Hospital, Assistance Publique - Hôpitaux de Paris, Villejuif, France
| | - Jean-Paul Duong Van Huyen
- Pathology Department, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Arnaud Del Bello
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Nicolas Congy Jolivet
- Department of Immunology, Hôpital de Rangueil, CHU de Toulouse, Molecular Immunogenetics Laboratory, EA 3034, IFR150 (INSERM), Toulouse, France
| | - Valérie Paradis
- Pathology Department, Beaujon Hospital, Assistance Publique - Hôpitaux de Paris, Clichy, France
| | - François Durand
- Hepatology Department, Beaujon Hospital, Assistance Publique - Hôpitaux de Paris, Clichy, France
| | - Sophie Muratot
- Paris Translational Research Center for Organ Transplantation, Université de Paris Cité, INSERM, PARCC, Paris, France
| | - Cécile Lozach
- Department of Pediatric Radiology, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Christophe Chardot
- Department of Pediatric Surgery, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Claire Francoz
- Hepatology Department, Beaujon Hospital, Assistance Publique - Hôpitaux de Paris, Clichy, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Sabine Sarnacki
- Department of Pediatric Surgery, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Audrey Coilly
- Hepatobiliary Center, Paul-Brousse Hospital, Assistance Publique - Hôpitaux de Paris, Inserm Paris-Saclay Research Unit 1193, Paris-Saclay University, Villejuif, France
| | - Didier Samuel
- Hepatobiliary Center, Paul-Brousse Hospital, Assistance Publique - Hôpitaux de Paris, Inserm Paris-Saclay Research Unit 1193, Paris-Saclay University, Villejuif, France
| | - Eric Vibert
- Hepatobiliary Center, Paul-Brousse Hospital, Assistance Publique - Hôpitaux de Paris, Inserm Paris-Saclay Research Unit 1193, Paris-Saclay University, Villejuif, France
| | - Cyrille Féray
- Hepatobiliary Center, Paul-Brousse Hospital, Assistance Publique - Hôpitaux de Paris, Inserm Paris-Saclay Research Unit 1193, Paris-Saclay University, Villejuif, France
| | - Carmen Lefaucheur
- Paris Translational Research Center for Organ Transplantation, Université de Paris Cité, INSERM, PARCC, Paris, France; Department of Nephrology and Kidney Transplantation, Saint-Louis Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Alexandre Loupy
- Paris Translational Research Center for Organ Transplantation, Université de Paris Cité, INSERM, PARCC, Paris, France; Kidney Transplantation Department, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France.
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5
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Bellamy COC, O'Leary JG, Adeyi O, Baddour N, Batal I, Bucuvalas J, Del Bello A, El Hag M, El-Monayeri M, Farris AB, Feng S, Fiel MI, Fischer SE, Fung J, Grzyb K, Guimei M, Haga H, Hart J, Jackson AM, Jaeckel E, Khurram NA, Knechtle SJ, Lesniak D, Levitsky J, McCaughan G, McKenzie C, Mescoli C, Miquel R, Minervini MI, Nasser IA, Neil D, O'Neil MF, Pappo O, Randhawa P, Ruiz P, Fueyo AS, Schady D, Schiano T, Sebagh M, Smith M, Stevenson HL, Taner T, Taubert R, Thung S, Trunecka P, Wang HL, Wood-Trageser M, Yilmaz F, Zen Y, Zeevi A, Demetris AJ. Banff 2022 Liver Group Meeting report: Monitoring long-term allograft health. Am J Transplant 2024; 24:905-917. [PMID: 38461883 DOI: 10.1016/j.ajt.2024.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 02/27/2024] [Accepted: 03/06/2024] [Indexed: 03/12/2024]
Abstract
The Banff Working Group on Liver Allograft Pathology met in September 2022. Participants included hepatologists, surgeons, pathologists, immunologists, and histocompatibility specialists. Presentations and discussions focused on the evaluation of long-term allograft health, including noninvasive and tissue monitoring, immunosuppression optimization, and long-term structural changes. Potential revision of the rejection classification scheme to better accommodate and communicate late T cell-mediated rejection patterns and related structural changes, such as nodular regenerative hyperplasia, were discussed. Improved stratification of long-term maintenance immunosuppression to match the heterogeneity of patient settings will be central to improving long-term patient survival. Such personalized therapeutics are in turn contingent on a better understanding and monitoring of allograft status within a rational decision-making approach, likely to be facilitated in implementation with emerging decision-support tools. Proposed revisions to rejection classification emerging from the meeting include the incorporation of interface hepatitis and fibrosis staging. These will be opened to online testing, modified accordingly, and subject to consensus discussion leading up to the next Banff conference.
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Affiliation(s)
- Christopher O C Bellamy
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland and Department of Pathology, Edinburgh Royal Infirmary, Edinburgh, Scotland.
| | - Jacqueline G O'Leary
- Dallas VA Medical Center & University of Texas, Southwestern, Department of Medicine, Dallas Texas, USA
| | - Oyedele Adeyi
- University of Minnesota Medical School, Department of Pathology, Minneapolis, Minnesota, USA
| | - Nahed Baddour
- Faculty of Medicine, University of Alexandria, Egypt
| | - Ibrahim Batal
- Pathology, Columbia University Irving Medical Center, New York, New York, USA
| | | | | | | | | | - Alton B Farris
- Pathology, Emory University Hospital, Atlanta, Georgia, USA
| | - Sandy Feng
- UCSF Health, Department of Surgery, San Francisco, California, USA
| | - Maria Isabel Fiel
- Pathology, Icahn School of Medicine, Mount Sinai, New York, New York, USA
| | | | - John Fung
- Uchicago Medicine, Department of Surgery, Chicago, Illinois, USA
| | | | - Maha Guimei
- Armed Forces College of Medicine, Cairo, Egypt
| | | | - John Hart
- Uchicago Medicine, Department of Pathology, Chicago, Illinois, USA
| | | | | | - Nigar A Khurram
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | | | - Drew Lesniak
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | | | | | | | | | - Rosa Miquel
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Marta I Minervini
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | - Imad Ahmad Nasser
- Beth Israel Deaconess Medical Center, Harvard, Boston, Massachusetts, USA
| | - Desley Neil
- University Hospitals Birmingham NHS Foundation Trust, United Kingdom
| | - Maura F O'Neil
- University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Orit Pappo
- Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Parmjeet Randhawa
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | - Phillip Ruiz
- University of Miami Hospital, Miami, Florida, USA
| | | | | | - Thomas Schiano
- Recanati/Miller Transplantation Institute, Mount Sinai Medical Center, New York, New York, USA
| | | | - Maxwell Smith
- Pathology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | | | - Timucin Taner
- Division of Transplantation Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Richard Taubert
- Dept. of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Swan Thung
- Pathology, Icahn School of Medicine, Mount Sinai, New York, New York, USA
| | - Pavel Trunecka
- Institute for Clinical and Experimental Medicine (IKEM), Prague, Czechia
| | - Hanlin L Wang
- Pathology, UCLA Health, Los Angeles, California, USA
| | - Michelle Wood-Trageser
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | - Funda Yilmaz
- Pathology, University of Ege, Imir, Bornova, Turkey
| | - Yoh Zen
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Adriana Zeevi
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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6
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Kosuta I, Kelava T, Ostojic A, Sesa V, Mrzljak A, Lalic H. Immunology demystified: A guide for transplant hepatologists. World J Transplant 2024; 14:89772. [PMID: 38576757 PMCID: PMC10989464 DOI: 10.5500/wjt.v14.i1.89772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 01/24/2024] [Accepted: 02/29/2024] [Indexed: 03/15/2024] Open
Abstract
Liver transplantation has become standard practice for treating end-stage liver disease. The success of the procedure relies on effective immunosuppressive medications to control the host's immune response. Despite the liver's inherent capacity to foster tolerance, the early post-transplant period is marked by significant immune reactivity. To ensure favorable outcomes, it is imperative to identify and manage various rejection types, encompassing T-cell-mediated, antibody-mediated, and chronic rejection. However, the approach to prescribing immunosuppressants relies heavily on clinical judgment rather than evidence-based criteria. Given that the majority of patients will require lifelong immuno suppression as the mechanisms underlying operational tolerance are still being investigated, healthcare providers must possess an understanding of immune responses, rejection mechanisms, and the pathways targeted by immunosuppressive drugs. This knowledge enables customization of treatments and improved patient care, even though a consensus on an optimal immunosuppressive regimen remains elusive.
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Affiliation(s)
- Iva Kosuta
- Department of Intensive Care Medicine, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Tomislav Kelava
- Department of Physiology, School of Medicine, Univeristy of Zagreb, Zagreb 10000, Croatia
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, Zagreb 10000, Croatia
| | - Ana Ostojic
- Department of Gastroenterology and Hepatology, Liver Transplant Center, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Vibor Sesa
- Department of Gastroenterology and Hepatology, Liver Transplant Center, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Anna Mrzljak
- Department of Gastroenterology and Hepatology, University Hospital Centre Zagreb, Zagreb 10000, Croatia
- Department of Medicine, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Hrvoje Lalic
- Department of Physiology, University of Zagreb School of Medicine, Zagreb 10000, Croatia
- Laboratory for Cell Biology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb 10000, Croatia
- Department of Laboratory Immunology, Clinical Department of Laboratory Diagnostics, University Hospital Center Zagreb, Zagreb 10000, Croatia
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7
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Shafqat F, Ur Rehman S, Khan MS, Niaz K. Liver. ENCYCLOPEDIA OF TOXICOLOGY 2024:897-913. [DOI: 10.1016/b978-0-12-824315-2.00138-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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8
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Appenzeller-Herzog C, Rosat A, Mathes T, Baroja-Mazo A, Chruscinski A, Feng S, Herrero I, Londono MC, Mazariegos G, Ohe H, Pons JA, Sanchez-Fueyo A, Waki K, Vionnet J. Time since liver transplant and immunosuppression withdrawal outcomes: Systematic review and individual patient data meta-analysis. Liver Int 2024; 44:250-262. [PMID: 37905605 DOI: 10.1111/liv.15764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 09/22/2023] [Accepted: 10/08/2023] [Indexed: 11/02/2023]
Abstract
BACKGROUND & AIMS Successful immunosuppression withdrawal (ISW) is possible for a subfraction of liver transplant (LT) recipients but the factors that define the risk of ISW failure are largely unknown. One candidate prognostic factor for ISW success or operational tolerance (OT) is longer time between LT and ISW which we term "pre-withdrawal time". To clarify the impact of pre-withdrawal time span on subsequent ISW success or failure, we conducted a systematic review with meta-analysis. METHODS We systematically interrogated the literature for LT recipient ISW studies reporting pre-withdrawal time. Eligible articles from Embase, Medline, and the Cochrane Central Register of Controlled Trials were used for backward and forward citation searching. Pre-withdrawal time individual patient data (IPD) was requested from authors. Pooled mean differences and time-response curves were calculated using random-effects meta-analyses. RESULTS We included 17 studies with 691 patients, 15 of which (620 patients) with IPD. Study-level risk of bias was heterogeneous. Mean pre-withdrawal time was greater by 427 days [95% confidence interval (CI) 67-788] in OT compared to non-OT patients. This increase was potentiated to 799 days (95% CI 369-1229) or 1074 days (95% CI 685-1463) when restricting analysis to adult or European study participants. In time-response meta-analysis for adult or European ISW candidates, likelihood of OT increased by 7% (95% CI 4-10%) per year after LT (GRADE low- and moderate-certainty of evidence, respectively). CONCLUSIONS Our data support the impact of pre-withdrawal time in ISW decision-making for adult and European LT recipients. PROSPERO REGISTRATION CRD42021272995.
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Affiliation(s)
| | - Aurélie Rosat
- Service of Gastroenterology and Hepatology, University of Lausanne, Lausanne, Switzerland
| | - Tim Mathes
- Department for Medical Statistics, University Medical Centre Goettingen, Goettingen, Germany
| | - Alberto Baroja-Mazo
- Digestive and Endocrine Surgery and Transplantation of Abdominal Organs, Biomedical Research Institute of Murcia (Instituto Murciano de Investigación Biosanitaria-Arrixaca), Murcia, Spain
| | | | - Sandy Feng
- School of Medicine, University of California, San Francisco, California, USA
| | - Ignacio Herrero
- Liver Unit, Clinica Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra, Centro de investigación Biomédica en Red, Navarra, Spain
- Enfermedades Hepáticas y Digestivas, Pamplona, Spain
| | - Maria-Carlota Londono
- Liver Unit, Hospital Clinic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de investigación Biomédica en Red, Barcelona, Spain
- Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain
| | - George Mazariegos
- UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Hidenori Ohe
- Department of Surgery, Kyoto University, Kyoto, Japan
| | - José A Pons
- Hepatology and Liver Transplant Unit, University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, King's College London University and King's College Hospital, London, UK
| | - Kayo Waki
- Department of Biomedical Informatics, The University of Tokyo, Tokyo, Japan
- Department of Diabetes and Metabolic Diseases, The University of Tokyo, Tokyo, Japan
| | - Julien Vionnet
- Service of Gastroenterology and Hepatology, University of Lausanne, Lausanne, Switzerland
- Institute of Liver Studies, King's College London University and King's College Hospital, London, UK
- Transplantation Centre, University Hospital of Lausanne and University of Lausanne, Lausanne, Switzerland
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9
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Chen G, Hu X, Huang Y, Xiang X, Pan S, Chen R, Xu X. Role of the immune system in liver transplantation and its implications for therapeutic interventions. MedComm (Beijing) 2023; 4:e444. [PMID: 38098611 PMCID: PMC10719430 DOI: 10.1002/mco2.444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 11/23/2023] [Accepted: 11/24/2023] [Indexed: 12/17/2023] Open
Abstract
Liver transplantation (LT) stands as the gold standard for treating end-stage liver disease and hepatocellular carcinoma, yet postoperative complications continue to impact survival rates. The liver's unique immune system, governed by a microenvironment of diverse immune cells, is disrupted during processes like ischemia-reperfusion injury posttransplantation, leading to immune imbalance, inflammation, and subsequent complications. In the posttransplantation period, immune cells within the liver collaboratively foster a tolerant environment, crucial for immune tolerance and liver regeneration. While clinical trials exploring cell therapy for LT complications exist, a comprehensive summary is lacking. This review provides an insight into the intricacies of the liver's immune microenvironment, with a specific focus on macrophages and T cells as primary immune players. Delving into the immunological dynamics at different stages of LT, we explore the disruptions after LT and subsequent immune responses. Focusing on immune cell targeting for treating liver transplant complications, we provide a comprehensive summary of ongoing clinical trials in this domain, especially cell therapies. Furthermore, we offer innovative treatment strategies that leverage the opportunities and prospects identified in the therapeutic landscape. This review seeks to advance our understanding of LT immunology and steer the development of precise therapies for postoperative complications.
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Affiliation(s)
- Guanrong Chen
- The Fourth School of Clinical MedicineZhejiang Chinese Medical UniversityHangzhouChina
| | - Xin Hu
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Yingchen Huang
- The Fourth School of Clinical MedicineZhejiang Chinese Medical UniversityHangzhouChina
| | - Xiaonan Xiang
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Sheng Pan
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Ronggao Chen
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiao Xu
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
- Zhejiang Chinese Medical UniversityHangzhouChina
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10
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Antala S, DiNorcia J, Bucuvalas J. Balancing immunosuppression in pediatric liver transplantation: Playing the long game. Pediatr Transplant 2023; 27:e14575. [PMID: 37439035 DOI: 10.1111/petr.14575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 07/03/2023] [Indexed: 07/14/2023]
Abstract
The overarching goal in the care of pediatric liver transplant recipients is to optimize allograft and patient health. Balancing immunosuppression to maintain allograft health while avoiding medication side effects is essential for long-term survival and optimal quality of life in pediatric liver transplant recipients. Utilizing precision medicine to personalize immunosuppression, which includes minimization and withdrawal, is core to this effort. The unique anatomy and physiology of the liver make it more tolerant to immune-mediated injury and a more favorable organ for immunosuppression minimization and withdrawal. However, several challenges exist. Standard biochemical values and histologic features may not reliably predict allograft health after a reduction in immunosuppression. Additionally, biochemical values alone do not reliably identify which patients can successfully develop operational tolerance, as there may be occult allograft injury despite normal liver enzymes. Finally, the durability of tolerance after successful reduction in immunosuppression remains uncertain over time. Innovative tools show promise in circumventing these challenges, but more research is needed to determine actual clinical utility. While immunosuppression-free transplant may not be a current reality for most pediatric liver transplant recipients, strategies to safely minimize immunosuppression without compromising allograft health are within reach. Each liver allograft and recipient pair requires a different degree of immune modulation, and through a structured process of minimization and withdrawal, immunosuppression can indeed be tailored in a precise, personalized way to optimize outcomes. This review focuses on the progress that has been made to individualize immunosuppression in pediatric liver transplantation to ensure optimal allograft and recipient health.
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Affiliation(s)
- Swati Antala
- Department of Pediatrics, Icahn School of Medicine, Kravis Children's Hospital at Mount Sinai, New York City, New York, USA
| | - Joseph DiNorcia
- Recanati-Miller Transplantation Institute, Mount Sinai Hospital, New York City, New York, USA
| | - John Bucuvalas
- Department of Pediatrics, Icahn School of Medicine, Kravis Children's Hospital at Mount Sinai, New York City, New York, USA
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11
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Dumortier J, Conti F, Hiriart JB, Dharancy S, Duvoux C, Besch C, Houssel-Debry P, Latournerie M, Chermak F, Meszaros M, Pageaux GP, Radenne S, Boillot O, Hardwigsen J, Kounis I, Kamar N, Saliba F, Erard D, Del Bello A. Treatment of donor-specific anti-HLA antibodies-mediated rejection after liver transplantation: A French nationwide retrospective study. Liver Transpl 2023; 29:1313-1322. [PMID: 37367954 DOI: 10.1097/lvt.0000000000000200] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 05/25/2023] [Indexed: 06/28/2023]
Abstract
The deleterious effect of donor-specific anti-HLA antibodies (DSA) after liver transplantation (LT) has been increasingly recognized during the past decade. Antibody-mediated rejection (AMR) represents a rare but severe complication in the presence of DSA. However, little is known concerning the treatment of AMR after LT. The nationwide French study aimed to describe LT recipients who received specific treatment of AMR. We performed a multicenter retrospective study on 44 patients who were treated with B-cell targeting agents from January 2008 to December 2020. Median patient age at the time of AMR treatment was 51.6 years (range: 17.9-68.0). AMR was classified as acute (n = 19) or chronic (n = 25). The diagnosis of AMR was made after a median time of 16.8 months (range: 0.4-274.2) after LT. The main therapeutic combination was plasma exchange/rituximab/IVIG (n = 25, 56.8%). The median follow-up after the treatment of AMR was 32 months (range: 1-115). After the treatment, 1-, 5- and 10-year patient and graft survivals were 77%, 55.9%, and 55.9%, and 69.5%, 47.0%, and 47.0%, respectively. Initial total bilirubin (Q1-Q3 vs. Q4) was significantly associated with patient survival (log-rank test, p = 0.005) and graft survival (log-rank test, p = 0.002). After a median follow-up of 21 months (range: 12-107), DSA became undetectable in 15/38 patients (39.5%) with available DSA monitoring. In conclusion, specific treatment of AMR in LT recipients has slowly emerged in France during the past decade and has probably been considered in the most severe patients; this explains the global poor outcome, even if the outcome was favorable in some cases.
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Affiliation(s)
- Jérôme Dumortier
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités digestives, et Université Claude Bernard Lyon 1, Lyon, France
| | - Filomena Conti
- APHP, Hôpital de la Pitié Salpêtrière, Service d'hépatologie et transplantation hépatique, Paris, France
| | - Jean-Baptiste Hiriart
- CHU de Bordeaux, Hôpital Haut-Lévêque, Service de Chirurgie hépatobiliaire et de transplantation hépatique, Bordeaux, France
| | - Sébastien Dharancy
- CHU Lille, Hôpital Claude Huriez, Service des maladies de l'appareil digestif, Lille, France
| | | | - Camille Besch
- CHRU Hautepierre, Service de chirurgie hépato-bilio-pancréatique et transplantation hépatique, Strasbourg, France
| | - Pauline Houssel-Debry
- Hôpital Universitaire de Pontchaillou, Service d'Hépatologie et Transplantation hépatique, Rennes, France
| | - Marianne Latournerie
- CHU Dijon, Service d'Hépato-gastroentérologie et oncologie digestive, Inserm EPICAD LNC-UMR1231, Université de Bourgogne-Franche Comté, Dijon, France
| | - Faiza Chermak
- CHU de Bordeaux, Hôpital Haut-Lévêque, Service de Chirurgie hépatobiliaire et de transplantation hépatique, Bordeaux, France
| | - Magdalena Meszaros
- CHU Saint Eloi, Département d'hépato-gatroentérologie et transplantation hépatique, et Université de Montpellier, Montpellier, France
| | - Georges-Philippe Pageaux
- CHU Saint Eloi, Département d'hépato-gatroentérologie et transplantation hépatique, et Université de Montpellier, Montpellier, France
| | - Sylvie Radenne
- Hospices civils de Lyon, Hôpital de la Croix Rousse, Service d'Hépato-Gastroentérologie, Lyon, France
| | - Olivier Boillot
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités digestives, et Université Claude Bernard Lyon 1, Lyon, France
| | - Jean Hardwigsen
- APHM, Hôpital La Timone, Service chirurgie générale et transplantation hépatique Marseille, France
| | - Ilias Kounis
- AP-HP, Hôpital Paul Brousse, Centre Hépato-Biliaire, INSERM, Unité 1193, Hepatinov, et Université Paris Saclay, Villejuif, France
| | - Nassim Kamar
- CHU Rangueil, Département de Néphrologie et Transplantation d'Organes, Toulouse, France
| | - Faouzi Saliba
- AP-HP, Hôpital Paul Brousse, Centre Hépato-Biliaire, INSERM, Unité 1193, Hepatinov, et Université Paris Saclay, Villejuif, France
| | - Domitille Erard
- Hospices civils de Lyon, Hôpital de la Croix Rousse, Service d'Hépato-Gastroentérologie, Lyon, France
| | - Arnaud Del Bello
- CHU Rangueil, Département de Néphrologie et Transplantation d'Organes, Toulouse, France
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12
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Du X, Li M, Huan C, Lv G. Dendritic cells in liver transplantation immune response. Front Cell Dev Biol 2023; 11:1277743. [PMID: 37900282 PMCID: PMC10606587 DOI: 10.3389/fcell.2023.1277743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 09/27/2023] [Indexed: 10/31/2023] Open
Abstract
Dendritic cells (DCs) are the most powerful antigen presenting cells (APCs), they are considered one of the key regulatory factors in the liver immune system. There is currently much interest in modulating DC function to improve transplant immune response. In liver transplantation, DCs participate in both the promotion and inhibition of the alloreponse by adopting different phenotypes and function. Thus, in this review, we discussed the origin, maturation, migration and pathological effects of several DC subsets, including the conventional DC (cDC), plasmacytoid DC (pDC) and monocyte-derived DC (Mo-DC) in liver transplantation, and we summarized the roles of these DC subsets in liver transplant rejection and tolerance. In addition, we also outlined the latest progress in DC-based related treatment regimens. Overall, our discussion provides a beneficial resource for better understanding the biology of DCs and their manipulation to improve the immune adaptability of patients in transplant status.
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Affiliation(s)
- Xiaodong Du
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Mingqian Li
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Chen Huan
- Center of Infectious Diseases and Pathogen Biology, Institute of Virology and AIDS Research, Key Laboratory of Organ Regeneration and Transplantation of The Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Guoyue Lv
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
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13
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Park HJ, Choi J, Kim H, Yang DY, An TH, Lee EW, Han BS, Lee SC, Kim WK, Bae KH, Oh KJ. Cellular heterogeneity and plasticity during NAFLD progression. Front Mol Biosci 2023; 10:1221669. [PMID: 37635938 PMCID: PMC10450943 DOI: 10.3389/fmolb.2023.1221669] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 07/18/2023] [Indexed: 08/29/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a progressive liver disease that can progress to nonalcoholic steatohepatitis (NASH), NASH-related cirrhosis, and hepatocellular carcinoma (HCC). NAFLD ranges from simple steatosis (or nonalcoholic fatty liver [NAFL]) to NASH as a progressive form of NAFL, which is characterized by steatosis, lobular inflammation, and hepatocellular ballooning with or without fibrosis. Because of the complex pathophysiological mechanism and the heterogeneity of NAFLD, including its wide spectrum of clinical and histological characteristics, no specific therapeutic drugs have been approved for NAFLD. The heterogeneity of NAFLD is closely associated with cellular plasticity, which describes the ability of cells to acquire new identities or change their phenotypes in response to environmental stimuli. The liver consists of parenchymal cells including hepatocytes and cholangiocytes and nonparenchymal cells including Kupffer cells, hepatic stellate cells, and endothelial cells, all of which have specialized functions. This heterogeneous cell population has cellular plasticity to adapt to environmental changes. During NAFLD progression, these cells can exert diverse and complex responses at multiple levels following exposure to a variety of stimuli, including fatty acids, inflammation, and oxidative stress. Therefore, this review provides insights into NAFLD heterogeneity by addressing the cellular plasticity and metabolic adaptation of hepatocytes, cholangiocytes, hepatic stellate cells, and Kupffer cells during NAFLD progression.
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Affiliation(s)
- Hyun-Ju Park
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Juyong Choi
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Hyunmi Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Da-Yeon Yang
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Tae Hyeon An
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Eun-Woo Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Baek-Soo Han
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
- Biodefense Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Sang Chul Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Won Kon Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Kwang-Hee Bae
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Kyoung-Jin Oh
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
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14
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O’Leary JG, Farris AB, Gebel HM, Asrani SK, Askar M, Garcia V, Snipes GJ, Lo DJ, Knechtle SJ, Klintmalm GB, Demetris AJ. Detailed Analysis of Simultaneous Renal and Liver Allografts in the Presence of DSA. Transplant Direct 2023; 9:e1500. [PMID: 37456590 PMCID: PMC10348731 DOI: 10.1097/txd.0000000000001500] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/12/2023] [Accepted: 04/25/2023] [Indexed: 07/18/2023] Open
Abstract
Liver allografts protect renal allografts from the same donor from some, but not all, preformed donor specific alloantibodies (DSA). However, the precise mechanisms of protection and the potential for more subtle alterations/injuries within the grafts resulting from DSA interactions require further study. Methods We reevaluated allograft biopsies from simultaneous liver-kidney transplant recipients who had both allografts biopsied within 60 d of one another and within 30 d of DSA being positive in serum (positive: mean florescence intensity ≥5000). Routine histology, C4d staining, and specialized immunohistochemistry for Kupffer cells (KCs; CD163) and a C4d receptor immunoglobulin-like transcript-4 were carried out in 4 patients with 6 paired biopsies. Results Overt antibody-mediated rejection was found in 3 of 4 renal and liver allografts. One patient had biopsy-confirmed renal and liver allograft antibody-mediated rejection despite serum clearance of DSA. All biopsies showed KC hypertrophy (minimal: 1; mild: 2; moderate: 1; severe: 2) and cytoplasmic C4d KC staining was easily detected in 2 biopsies from 2 patients; minimal and negative in 2 biopsies each. Implications of which are discussed. Control 1-y protocol liver allograft biopsies from DSA- recipients showed neither KC hypertrophy nor KC C4d staining (n = 6). Conclusions Partial renal allograft protection by a liver allograft from the same donor may be partially mediated by phagocytosis/elimination of antibody and complement split products by KCs, as shown decades ago in controlled sensitized experimental animal experiments.
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Affiliation(s)
| | - Alton B. Farris
- Department of Pathology, Emory University Hospital, Atlanta, GA
| | - Howard M. Gebel
- Department of Pathology, Emory University Hospital, Atlanta, GA
| | - Sumeet K. Asrani
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas TX
| | - Medhat Askar
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas TX
| | - Vanessa Garcia
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas TX
| | - George J. Snipes
- Department of Pathology, Baylor University Medical Center, Dallas TX
| | - Denise J. Lo
- Department of Surgery, Duke University, Durham, NC
| | | | - Goran B. Klintmalm
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas TX
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15
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El Hag MI, Kaneku H, Jorgensen D, Zeevi A, Stevenson HL, Yadak N, Hassan M, Du X, Demetris AJ. Morphologic and immunophenotypic evaluation of liver allograft biopsies with contemporaneous serum DSA measurements. Clin Transplant 2023; 37:e14997. [PMID: 37096730 DOI: 10.1111/ctr.14997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 02/27/2023] [Accepted: 04/09/2023] [Indexed: 04/26/2023]
Abstract
BACKGROUND Acute antibody mediated rejection is increasingly identified in liver allografts as a unique form of alloimmune injury associated with donor specific antibodies (DSA). This manifests pathologically as microvascular injury and C4d uptake. Despite the liver allograft's relative resistance to alloimmune injury, liver allografts are not impervious to cellular and antibody-mediated rejection. METHODS In this blinded control study, we evaluated CD163 immunohistochemistry and applied the Banff 2016 criteria for diagnosis of acute AMR on a group of indication allograft liver biopsies from DSA positive patients and compared them to indication biopsies from DSA negative controls. RESULTS Most DSA positive patients were females (75%, p = .027), and underwent transplantation for HCV infection. Significant histopathological predictors of serum DSA positivity were Banff H-score (p = .01), moderate to severe cholestasis (p = .03), and CD163 score > 2 (p = .029). Other morphologic features that showed a trend with DSA positivity include Banff portal C4d-score (p = .06), bile ductular reaction (p = .07), and central perivenulitis (p = .07). The odds of DSA sMFI ≥5000 was 12.5 times higher in those with a C4d score >1 than those with a C4d score ≤ 1 (p = .04). Incidence of definite for aAMR in the DSA positive cohort was 25% (n = 5), and 0% in the DSA negative cohort. A group of 5 DSA positive cases were not classifiable by the current scheme. CONCLUSION Sinusoidal CD163, Banff H-score, and diffuse C4d are predictors of serum DSA, and facilitate recognition of histopathological features associated with serum DSA and tissue-antibody interaction.
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Affiliation(s)
- Mohamed I El Hag
- Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Hugo Kaneku
- Department of Surgery - Immunology and Histocompatibility Laboratory, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Dana Jorgensen
- Thomas E Starzl Transplantation Institute (STI), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Adriana Zeevi
- Thomas E Starzl Transplantation Institute (STI), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Division of Hepatic and Transplantation Pathology, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Heather L Stevenson
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Nour Yadak
- Department of Pathology, Methodist University Hospital, University of Tennessee, Memphis, Tennessee, USA
| | - Mohamed Hassan
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Xiaotang Du
- Department of Pathology, University of Chicago, Chicago, IL, USA
| | - Anthony J Demetris
- Thomas E Starzl Transplantation Institute (STI), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Division of Hepatic and Transplantation Pathology, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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16
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Wang H, Li C, Xiong Z, Li T. Luteolin attenuates acute liver allograft rejection in rats by inhibiting T cell proliferation and regulating T cell subsets. Int Immunopharmacol 2023; 121:110407. [PMID: 37290328 DOI: 10.1016/j.intimp.2023.110407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 05/28/2023] [Accepted: 05/28/2023] [Indexed: 06/10/2023]
Abstract
Allograft rejection continues to be a significant cause of morbidity and graft failure for liver transplant recipients. Existing immunosuppressive regimens have many drawbacks, thus safe and effective long-term immunosuppressive regimens are still required. Luteolin (LUT), a natural component found in many plants, has a variety of biological and pharmacological effects and shows good anti-inflammatory activity in inflammatory and autoimmune diseases. Nevertheless, it remains unclear how it affects acute organ rejection after allogeneic transplantation. In this study, a rat liver transplantation model was constructed to investigate the effect of LUT on acute rejection of organ allografts. We found that LUT significantly protected the structure and function of liver grafts, prolonged recipient rat survival, ameliorated T cell infiltration, and downregulated proinflammatory cytokines. Moreover, LUT inhibited the proliferation of CD4+ T cells and Th cell differentiation but increased the proportion of Tregs, which is the key to its immunosuppressive effect. In vitro, LUT also significantly inhibited CD4+ T cell proliferation and Th1 differentiation. There may be important implications for improving immunosuppressive regimens for organ transplantation as a result of this discovery.
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Affiliation(s)
- Hao Wang
- Department of Liver Transplantation, The Second Xiang-ya Hospital, Central South University, Changsha, Hunan 410011, China; The First Central Clinical School, Tianjin Medical University, Tianjin 300190, China
| | - Chenxuan Li
- Department of Liver Transplantation, The Second Xiang-ya Hospital, Central South University, Changsha, Hunan 410011, China; Transplant Medical Research Center, The Second Xiang-ya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Zhiwei Xiong
- Department of Liver Transplantation, The Second Xiang-ya Hospital, Central South University, Changsha, Hunan 410011, China; Transplant Medical Research Center, The Second Xiang-ya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Ting Li
- Department of Liver Transplantation, The Second Xiang-ya Hospital, Central South University, Changsha, Hunan 410011, China; Transplant Medical Research Center, The Second Xiang-ya Hospital, Central South University, Changsha, Hunan 410011, China.
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17
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Sebagh M, Yilmaz F, Kounis I, Saliba F, Feray C, Taupin JL, Cherqui D, Azoulay D, Samuel D, Coilly A, Demetris AJ, Neil D. Evidence for Alloimmune Sinusoidal Injury in De Novo Nodular Regenerative Hyperplasia After Liver Transplantation. Transpl Int 2023; 36:11306. [PMID: 37565050 PMCID: PMC10409867 DOI: 10.3389/ti.2023.11306] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 06/29/2023] [Indexed: 08/12/2023]
Abstract
Posttransplant nodular regenerative hyperplasia (NRH) mostly remains unexplained. Microvascular injury due to antibody-mediated rejection (AMR) is suspected, but lack of donor specific antibody (DSA) testing makes it difficult to prove. Centered around a 1-year period of routine DSA testing, concomitant protocol, and indicated posttransplant liver biopsies (LB), recipients with NRH (n = 18) were compared with a matched control group (n = 36). All index, previous, and subsequent LB were reviewed. Both groups were similar in terms of demographics, timing of index LB, and DSA. In the index LB, the NRH group had higher sinusoidal C4d positivity (p = 0.029) and perisinusoidal fibrosis (p = 0.034), both independently associated with NRH (p = 0.038 and 0.050, respectively). Features of "possible" chronic AMR were detected in 28.5% of the NRH group without a known cause and 0% of the control group (p = 0.009). The NRH group had more preceding indicated LB with increased incidence of rejection and biliary obstruction pattern. In the follow-up histology, overall, sinusoidal and portal C4d positivity, sinusoidal microvasculitis, and perisinusoidal fibrosis were also higher (all p < 0.050). In conclusion, we provide evidence towards the hypothesis that some cases of posttransplant NRH are related to preceding active and persistent AMR. Large multicenter studies with protocol DSA testing are required to confirm.
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Affiliation(s)
- Mylène Sebagh
- Laboratoire d’Anatomopathologie, AP-HP Hôpital Paul-Brousse, Villejuif, France
- Inserm, Unité 1193, Université Paris-Saclay, Villejuif, France
- Université Paris-Saclay, Villejuif, France
| | - Funda Yilmaz
- Ege University Organ Transplantation Center, Department of Pathology, School of Medicine, Ege University, Bornova, Izmir, Türkiye
| | - Ilias Kounis
- Inserm, Unité 1193, Université Paris-Saclay, Villejuif, France
- Université Paris-Saclay, Villejuif, France
- Centre Hépato-Biliaire, AP-HP Hôpital Paul-Brousse, Villejuif, France
| | - Faouzi Saliba
- Inserm, Unité 1193, Université Paris-Saclay, Villejuif, France
- Université Paris-Saclay, Villejuif, France
- Centre Hépato-Biliaire, AP-HP Hôpital Paul-Brousse, Villejuif, France
| | - Cyrille Feray
- Inserm, Unité 1193, Université Paris-Saclay, Villejuif, France
- Université Paris-Saclay, Villejuif, France
- Centre Hépato-Biliaire, AP-HP Hôpital Paul-Brousse, Villejuif, France
| | - Jean-Luc Taupin
- Département d’Immunologie and d’Histocompatibilité, AP-HP Hôpital Saint-Louis, Paris, France
| | - Daniel Cherqui
- Inserm, Unité 1193, Université Paris-Saclay, Villejuif, France
- Université Paris-Saclay, Villejuif, France
- Centre Hépato-Biliaire, AP-HP Hôpital Paul-Brousse, Villejuif, France
| | - Daniel Azoulay
- Inserm, Unité 1193, Université Paris-Saclay, Villejuif, France
- Université Paris-Saclay, Villejuif, France
- Centre Hépato-Biliaire, AP-HP Hôpital Paul-Brousse, Villejuif, France
| | - Didier Samuel
- Inserm, Unité 1193, Université Paris-Saclay, Villejuif, France
- Université Paris-Saclay, Villejuif, France
- Centre Hépato-Biliaire, AP-HP Hôpital Paul-Brousse, Villejuif, France
| | - Audrey Coilly
- Inserm, Unité 1193, Université Paris-Saclay, Villejuif, France
- Université Paris-Saclay, Villejuif, France
- Centre Hépato-Biliaire, AP-HP Hôpital Paul-Brousse, Villejuif, France
| | - Antony-Jake Demetris
- Division of Transplantation, Medical Center, University of Pittsburgh, Pittsburgh, PA, United States
| | - Desley Neil
- Cellular Pathology, Queen Elizabeth Hospital, Birmingham, United Kingdom
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18
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Tajima T, Hata K, Haga H, Kusakabe J, Kageyama S, Yurugi K, Hishida R, Zhao X, Nishikori M, Nagao M, Takaori-Kondo A, Uemoto S, Hatano E. Risk factors for antibody-mediated rejection in ABO blood-type incompatible and donor-specific antibody-positive liver transplantation. Liver Transpl 2023; 29:711-723. [PMID: 36749821 DOI: 10.1097/lvt.0000000000000084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 01/07/2023] [Indexed: 02/09/2023]
Abstract
Antibody-mediated rejection (AMR) is a refractory rejection after ABO blood-type incompatible (ABOi) or donor-specific antibody (DSA)-positive liver transplantation (LT). Pretransplant rituximab desensitization dramatically reduced posttransplant AMR development; however, risk factors for AMR in the rituximab era remain unclear in both ABOi living-donor LT (ABOi-LDLT) and preformed DSA-positive LT (pDSA-LT). Of our 596 adult LDLTs (≥18 y) after rituximab introduction (2004-2019), 136 were ABOi-LDLT (22.8%). After excluding retransplants (9), acute liver failure (7), and protocol deviations (16), 104 ABOi-LDLTs were finally enrolled. Of these, 19 recipients developed AMR, 18 of which occurred within 2 weeks after transplantation (95%). ABOi-AMR significantly worsened graft and recipient survival than those without ( p =0.02 and 0.04, respectively). Model for End-stage Liver Disease (MELD) ≤13 (OR: 5.15 [1.63-16.3], p =0.005) and pre-rituximab anti-ABO IgM-titer ≥128 (OR: 3.25 [1.05-10.0], p =0.03) were identified as independent risk factors for ABOi-AMR development. Recipients fulfilling both factors showed significantly worse survival rates than those who did not ( p =0.003). Of 352 adult LTs, after introducing the LABScreen Single Ag method (2009-2019), pDSA with mean fluorescence intensity (MFI) ≥500 was detected in 50 cases (14.2%). After excluding 10 ABOi-LDLTs, 40 pDSA-LTs were finally analyzed, of which 5 developed AMR. The combination of high-titer (sum-MFI ≥10,000) and multi-loci pDSAs was a significant risk factor for pDSA-AMR development ( p <0.001); however, it did not affect the 5-year recipient survival compared with those without ( p =0.56). In conclusion, preoperative MELD ≤13 and pre-rituximab anti-ABO IgM-titer ≥128 for ABOi-LDLT, and the combination of sum-MFI ≥10,000 and multi-loci pDSAs for pDSA-LT, are risk factors for AMR in the era of rituximab desensitization. Characteristically, ABOi-AMR significantly deteriorated graft and recipient survival, whereas pDSA-AMR did not.
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Affiliation(s)
- Tetsuya Tajima
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Koichiro Hata
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hironori Haga
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Jiro Kusakabe
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shoichi Kageyama
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kimiko Yurugi
- Department of Clinical Laboratory Medicine, Kyoto University Hospital, Kyoto, Japan
| | - Rie Hishida
- Department of Clinical Laboratory Medicine, Kyoto University Hospital, Kyoto, Japan
| | - Xiangdong Zhao
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Momoko Nishikori
- Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Miki Nagao
- Department of Clinical Laboratory Medicine, Kyoto University Hospital, Kyoto, Japan
| | - Akifumi Takaori-Kondo
- Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Shiga University of Medical Science, Otsu, Japan
| | - Etsuro Hatano
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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19
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Taner T, Hilscher MB, Broda CR, Drenth JPH. Issues in multi-organ transplantation of the liver with kidney or heart in polycystic liver-kidney disease or congenital heart disease: Current practices and immunological aspects. J Hepatol 2023; 78:1157-1168. [PMID: 37208103 DOI: 10.1016/j.jhep.2023.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 02/08/2023] [Accepted: 02/09/2023] [Indexed: 05/21/2023]
Abstract
Solid organ transplantation has become an integral part of the management of patients with end-stage diseases of the kidney, liver, heart and lungs. Most procedures occur in isolation, but multi-organ transplantation of the liver with either the kidney or heart has become an option. As more patients with congenital heart disease and cardiac cirrhosis survive into adulthood, particularly after the Fontan procedure, liver transplant teams are expected to face questions regarding multi-organ (heart-liver) transplantation. Similarly, patients with polycystic kidneys and livers may be managed by multi-organ transplantation. Herein, we review the indications and outcomes of simultaneous liver-kidney transplantation for polycystic liver-kidney disease, and discuss the indications, timing and procedural aspects of combined heart-liver transplantation. We also summarise the evidence for, and potential mechanisms underlying, the immunoprotective impact of liver allografts on the simultaneously transplanted organs.
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Affiliation(s)
- Timucin Taner
- Departments of Surgery & Immunology, Mayo Clinic, Rochester, MN, USA.
| | - Moira B Hilscher
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Christopher R Broda
- Department of Pediatrics, Baylor College of Medicine/Texas Children's Hospital, Houston, TX, USA
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University, Nijmegen, the Netherlands
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20
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Montano-Loza AJ, Rodríguez-Perálvarez ML, Pageaux GP, Sanchez-Fueyo A, Feng S. Liver transplantation immunology: Immunosuppression, rejection, and immunomodulation. J Hepatol 2023; 78:1199-1215. [PMID: 37208106 DOI: 10.1016/j.jhep.2023.01.030] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/30/2022] [Accepted: 01/30/2023] [Indexed: 05/21/2023]
Abstract
Outcomes after liver transplantation have continuously improved over the past decades, but long-term survival rates are still lower than in the general population. The liver has distinct immunological functions linked to its unique anatomical configuration and to its harbouring of a large number of cells with fundamental immunological roles. The transplanted liver can modulate the immunological system of the recipient to promote tolerance, thus offering the potential for less aggressive immunosuppression. The selection and adjustment of immunosuppressive drugs should be individualised to optimally control alloreactivity while mitigating toxicities. Routine laboratory tests are not accurate enough to make a confident diagnosis of allograft rejection. Although several promising biomarkers are being investigated, none of them is sufficiently validated for routine use; hence, liver biopsy remains necessary to guide clinical decisions. Recently, there has been an exponential increase in the use of immune checkpoint inhibitors due to the unquestionable oncological benefits they provide for many patients with advanced-stage tumours. It is expected that their use will also increase in liver transplant recipients and that this might affect the incidence of allograft rejection. Currently, the evidence regarding the efficacy and safety of immune checkpoint inhibitors in liver transplant recipients is limited and cases of severe allograft rejection have been reported. In this review, we discuss the clinical relevance of alloimmune disease, the role of minimisation/withdrawal of immunosuppression, and provide practical guidance for using checkpoint inhibitors in liver transplant recipients.
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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, AB, Canada.
| | - Manuel L Rodríguez-Perálvarez
- Department of Hepatology and Liver Transplantation, Hospital Universitario Reina Sofía, Universidad de Córdoba, IMIBIC, Córdoba, Spain; CIBER de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - George-Philippe Pageaux
- Liver Transplantation Unit, Digestive Department, Saint Eloi University Hospital, University of Montpellier, 34295, Montpellier Cedex 5, France
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, King's College London University and King's College Hospital, London, United Kingdom
| | - Sandy Feng
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
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21
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Wu G, Liu C, Ma N, Zhou X, Zhao L, Zhang Y, Zhang W, Liang T. Successful combined auxiliary partial liver and intestinal transplantation in two highly sensitized, cross-match positive patients. Clin Transplant 2023; 37:e14865. [PMID: 36416299 DOI: 10.1111/ctr.14865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 09/09/2022] [Accepted: 10/29/2022] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Sensitization to human leukocyte antigen (HLA) creates an immunological barrier to intestinal transplantation (ITx). Current desensitization therapies are limited and ineffective in the most highly sensitized patients. A co-transplanted whole liver transplant can protect a kidney, heart, or intestinal allograft from antibody-mediated injury. Whether an auxiliary partial liver allograft provides effective protection for highly sensitized intestinal transplant recipients is unknown. METHODS Two patients with strong HLA donor-specific antibody at high titer against their deceased donors underwent combined auxiliary partial liver and ITx across a positive cross-match. The left lateral lobes from the combined-graft recipients and the right liver lobes from the deceased donors were transplanted as a domino procedure to other four patients. RESULTS Two combined-graft recipients have had an uneventful postoperative course without major complications at a 12- and 24-month follow-up, respectively. Intestinal graft function has been excellent with no evidence of humoral or cellular rejection. While a positive cross-match turned negative, titers of donor-specific HLA antibodies gradually declined over time after transplant. The left liver lobes procured from the combined-graft recipients were successfully transplanted into two pediatric patients (age 1.9, 2.4 years) and the right lobes from two deceased donors were successfully transplanted into two adult patients. All transplant procedures went well, without post-operative complications related to the splitting technique. CONCLUSION Our results indicate that an auxiliary liver transplant can effectively protect a co-transplanted intestinal allograft against rejection and suggest that this combined procedure may serve as a useful therapeutic adjunct for a highly sensitized intestinal transplant candidate.
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Affiliation(s)
- Guosheng Wu
- Intestinal Transplant Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chaoxu Liu
- Intestinal Transplant Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Nan Ma
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xile Zhou
- Intestinal Transplant Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Long Zhao
- Intestinal Transplant Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuntao Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wentong Zhang
- Intestinal Transplant Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang University Cancer Center, Zhejiang University, Hangzhou, China
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22
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Sosa RA, Mone T, Naini BV, Kohn DB, Reed EF, Wheeler K, Campo-Fernandez B, Davila A, Chaffin DJ, DiNorcia J, Kaldas FM, Cohen A, Lum EL, Veale JL, Kogut NM. Apheresis of Deceased Donors as a New Source of Mobilized Peripheral Blood Hematopoietic Stem Cells for Transplant Tolerance. Transplantation 2023; 107:504-510. [PMID: 35974436 PMCID: PMC9877104 DOI: 10.1097/tp.0000000000004288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND Solid organ transplantation is the therapy of choice for many patients with end-stage organ failure; however, recipients must remain on lifelong immunosuppression, leaving them susceptible to infections and cancer. The study of transplant tolerance to prolong graft survival in the absence of immunosuppression has been restricted to recipients of living donor allografts; however, deceased donors significantly outnumber living donors. Mobilization of hematopoietic stem cells (HSCs) from the bone marrow to peripheral blood (PB) could allow PB-HSCs to be used to induce tolerance in deceased donor kidney recipients; however, a major concern is the well-known concomitant mobilization of immune cells into the liver. METHODS We mobilized HSCs to the PD using a protocol of 2 doses of granulocyte colony-stimulating factor and 1 dose of plerixafor, followed by the collection of mobilized cells via apheresis in 3 deceased donors. The physiological, laboratory, and radiographic parameters were monitored throughout the procedure. Longitudinal biopsies were performed to assess the potential for ectopic liver mobilization. RESULTS The use of both agents led to the successful mobilization of peripheral blood CD34+ cells, demonstrating the potential for use in transplant tolerance protocols. Increased immune cell trafficking into the liver was not observed, and apheresis of mobilized cells resulted in a uniform decrease in all liver leukocyte subsets. CONCLUSIONS HSCs can be mobilized and collected from the PB of brain-dead donors. This new approach may facilitate the dissemination of immune tolerance trials beyond living-donor kidney transplantation to deceased-donor transplantation, without sacrificing the transplantability of the liver.
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Affiliation(s)
- Rebecca A. Sosa
- Dept of Pathology and Lab Medicine, UCLA, Los Angeles, CA
- UCLA Immunogenetics Center, Los Angeles, CA
| | | | - Bita V. Naini
- Dept of Pathology and Lab Medicine, UCLA, Los Angeles, CA
| | - Donald B. Kohn
- Department of Microbiology, Immunology & Molecular Genetics, UCLA, Los Angeles, CA
- Dept of Pediatrics, Los Angeles, CA
- Dept of Molecular & Medical Pharmacology, Los Angeles, CA
| | - Elaine F. Reed
- Dept of Pathology and Lab Medicine, UCLA, Los Angeles, CA
- UCLA Immunogenetics Center, Los Angeles, CA
| | | | | | - Alejandra Davila
- Department of Microbiology, Immunology & Molecular Genetics, UCLA, Los Angeles, CA
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23
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Mugaanyi J, Tong J, Lu C, Mao S, Huang J, Lu C. Risk factors for acute rejection in liver transplantation and its impact on the outcomes of recipients. Transpl Immunol 2023; 76:101767. [PMID: 36470573 DOI: 10.1016/j.trim.2022.101767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 10/10/2022] [Accepted: 11/28/2022] [Indexed: 12/03/2022]
Abstract
OBJECTIVE To determine the risk factors for acute rejection in liver transplantation and its impact on the outcomes of the recipients. METHODS Clinicopathological data of 290 patients who underwent liver transplantation from January 2012 to December 2021 at our center were retrospectively evaluated. Patients were grouped into an acute rejection (AR) group and a normal (NM) group based on the confirmed histopathological diagnosis of acute rejection. Univariate and multivariate logistic regression were used to determine the risk factors for acute rejection. RESULTS 244 patients were included in the study. Acute rejection occurred in 27 (11.1%) of the patients. Warm ischemia time (P = 0.137), cold ischemia time (P = 0.064) and chronic liver failure (P = 0.001) were potential risk factors for acute rejection. Chronic liver failure (P < 0.001, OR = 8.22, 95% CI = 2.47-27.32) was the independent risk factor. There was no significant difference in overall survival between recipients with acute rejection and those without it (P = 0.985). The 1-, 3- and 5-year overall survival in the NM group was 98.1%, 85.7% and 78.6% respectively vs 88.9%, 82.5% and 82.5% respectively in the AR group. CONCLUSION Acute rejection does not appear to affect the long-term survival of the recipients. Only chronic liver failure was an independent risk factor for acute rejection. Our findings further illustrate that contradictions still exist on which factors influence acute rejection in liver transplant recipients. SUMMARY Clinicopathological data of 290 liver transplant recipients at our center between January 2012 and December 2021 were retrospectively evaluated to determine the risk factors for acute rejection and its impact on the outcomes of the recipients. 244 patients were included in the analysis. 27 of the 244 experienced acute rejection. Propensity score matching was performed to reduce the confounding effect. Patients were assigned to an acute rejection group (n = 27) and a normal group (n = 54). Chronic liver failure (P < 0.001, OR = 8.22, 95% CI = 2.47-27.32) was the determined to be independent risk factor for acute rejection. Acute rejection did not appear to affect the long-term survival of the recipients and there was no significant difference in overall survival between the patients with acute rejection and those without it.
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Affiliation(s)
- Joseph Mugaanyi
- Medical School of Ningbo University, Ningbo, Zhejiang, China; Department of Hepato-Pancreato-Biliary Surgery, Ningbo Medical Center Lihuili Hospital, The affiliated hospital of Ningbo University, Ningbo, Zhejiang, China.
| | - Jinshu Tong
- Department of Hepato-Pancreato-Biliary Surgery, Ningbo Medical Center Lihuili Hospital, The affiliated hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Changjiang Lu
- Department of Hepato-Pancreato-Biliary Surgery, Ningbo Medical Center Lihuili Hospital, The affiliated hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Shuqi Mao
- Department of Hepato-Pancreato-Biliary Surgery, Ningbo Medical Center Lihuili Hospital, The affiliated hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Jing Huang
- Department of Hepato-Pancreato-Biliary Surgery, Ningbo Medical Center Lihuili Hospital, The affiliated hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Caide Lu
- Department of Hepato-Pancreato-Biliary Surgery, Ningbo Medical Center Lihuili Hospital, The affiliated hospital of Ningbo University, Ningbo, Zhejiang, China.
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24
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El Sabagh A, Mohamed IB, Aloor FZ, Abdelwahab A, Hassan MM, Jalal PK. Current Status of Biomarkers and Molecular Diagnostic Tools for Rejection in Liver Transplantation: Light at the End of the Tunnel? J Clin Exp Hepatol 2023; 13:139-148. [PMID: 36647415 PMCID: PMC9840072 DOI: 10.1016/j.jceh.2022.06.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/24/2022] [Indexed: 01/19/2023] Open
Abstract
Strategies to minimize immune-suppressive medications after liver transplantation are limited by allograft rejection. Biopsy of liver is the current standard of care in diagnosing rejection. However, it adds to physical and economic burden to the patient and has diagnostic limitations. In this review, we aim to highlight the different biomarkers to predict and diagnose acute rejection. We also aim to explore recent advances in molecular diagnostics to improve the diagnostic yield of liver biopsies.
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Key Words
- 3BMBs, third bifurcation mucosal endo-bronchial biopsies
- AMR, antibody mediated rejection
- APC, antigen presenting cells
- AR, Acute rejection
- ATCMR, acute T-cell mediated rejection
- ATG, Anti-thymoglobulin
- AUC, area under curve
- AUROC, area under receiver operating characteristic curve
- B-HOT, Banff Human Organ Transplant
- CNI, Calcineurin inhibitors
- DSA, Donor specific antibodies
- FDA, Food and drug administration
- FFPE, formalin fixed paraffin embedded preparation
- GLUT-4, glucose transport-4
- HLA, human leukocyte antigens
- HNMR, high nuclear magnetic resonance
- ILTS, International liver transplantation society
- LT, Liver transplantation
- Liver transplantation
- MDWG, molecular diagnostic work group
- MFI, mean fluorescence intensity
- MHC, major histo–compatibility complex
- MMDX
- MMDX, Molecular microscopic diagnostic system
- MMF, Mycophenolate Mofetil
- MToR, Mechanistic target of Rapamycin
- NPV, Negative predictive value
- PPV, Positive predictive value
- RATs, rejection associated transcripts
- TBB, trans-bronchial biopsies
- UNOS, United network for organ sharing and procurement
- biomarker
- dd cfDNA, donor-derived cell-free DNA
- donor-derived cell-free DNA
- immune-suppression
- mRNA, messenger RNA
- miRNA, micro-RNA
- micro-RNA
- molecular diagnosis
- nano-string
- rejection
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Affiliation(s)
- Ahmed El Sabagh
- Division of Gastroenterology, Baylor College of Medicine, Houston, TX, USA
- Department of Internal Medicine, Gastroenterology & Hepatology, Ain Shams University, Cairo, Egypt
| | - Islam B. Mohamed
- Division of Gastroenterology, Baylor College of Medicine, Houston, TX, USA
- Department of Internal Medicine, Gastroenterology & Hepatology, Ain Shams University, Cairo, Egypt
| | - Fuad Z. Aloor
- Division of Gastroenterology, Baylor College of Medicine, Houston, TX, USA
| | - Ahmed Abdelwahab
- Division of Gastroenterology, Baylor College of Medicine, Houston, TX, USA
| | - Manal M. Hassan
- Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Prasun K. Jalal
- Division of Gastroenterology, Baylor College of Medicine, Houston, TX, USA
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25
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Cao W, Lu J, Li S, Song F, Xu J. Transcriptomic analysis of graft liver provides insight into the immune response of rat liver transplantation. Front Immunol 2022; 13:947437. [DOI: 10.3389/fimmu.2022.947437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 10/07/2022] [Indexed: 11/05/2022] Open
Abstract
BackgroundAs an “immune-privileged organ”, the liver has higher rates of both spontaneous tolerance and operational tolerance after being transplanted compared with other solid organs. Also, a large number of patients still need to take long-term immunosuppression regimens. Liver transplantation (LT) rejection involves varieties of pathophysiological processes and cell types, and a deeper understanding of LT immune response is urgently needed.MethodsHomogenic and allogeneic rat LT models were established, and recipient tissue was collected on postoperative day 7. The degree of LT rejection was evaluated by liver pathological changes and liver function. Differentially expressed genes (DEGs) were detected by transcriptome sequencing and confirmed by reverse transcription-polymerase chain reaction. The functional properties of DEGs were characterized by the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway analyses. The cells infiltrating the graft and recipient spleen and peripheral blood were evaluated by immunofluorescence and flow cytometry.ResultA total of 1,465 DEGs were screened, including 1,177 up-regulated genes and 288 down-regulated genes. GO enrichment and KEGG pathway analysis indicated that DEGs were involved in several immunobiological processes, including T cell activation, Th1, Th2 and Th17 cell differentiation, cytokine-cytokine receptor interaction and other immune processes. Reactome results showed that PD-1 signaling was enriched. Further research confirmed that mRNA expression of multiple immune cell markers increased and markers of T cell exhaustion significantly changed. Flow cytometry showed that the proportion of Treg decreased, and that of PD-1+CD4+ T cells and PD-1+CD8+ T cells increased in the allogeneic group.ConclusionUsing an omic approach, we revealed that the development of LT rejection involved multiple immune cells, activation of various immune pathways, and specific alterations of immune checkpoints, which would benefit risk assessment in the clinic and understanding of pathogenesis regarding LT tolerance. Further clinical validations are warranted for our findings.
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Parajuli S, Hidalgo LG, Foley D. Immunology of simultaneous liver and kidney transplants with identification and prevention of rejection. FRONTIERS IN TRANSPLANTATION 2022; 1:991546. [PMID: 38994375 PMCID: PMC11235231 DOI: 10.3389/frtra.2022.991546] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 10/12/2022] [Indexed: 07/13/2024]
Abstract
Simultaneous liver and kidney (SLK) transplantation is considered the best treatment modality among selected patients with both chronic kidney disease (CKD) and end-stage liver disease (ESLD). Since the first SLK transplant in 1983, the number of SLK transplants has increased worldwide, and particularly in the United States since the implementation of the MELD system in 2002. SLK transplants are considered a relatively low immunological risk procedure evidenced by multiple studies displaying the immunomodulatory properties of the liver on the immune system of SLK recipients. SLK recipients demonstrate lower rates of both cellular and antibody-mediated rejection on the kidney allograft when compared to kidney transplant-alone recipients. Therefore, SLK transplants in the setting of preformed donor-specific HLA antibodies (DSA) are a common practice, at many centers. Acceptance and transplantation of SLKs are based solely on ABO compatibility without much consideration of crossmatch results or DSA levels. However, some studies suggest an increased risk for rejection for SLK recipients transplanted across high levels of pre-formed HLA DSA. Despite this, there is no consensus regarding acceptable levels of pre-formed DSA, the role of pre-transplant desensitization, splenectomy, or immunosuppressive management in this unique population. Also, the impact of post-transplant DSA monitoring on long-term outcomes is not well-studied in SLK recipients. In this article, we review recent and relevant past articles in this field with a focus on the immunological risk factors among SLK recipients, and strategies to mitigate the negative outcomes among them.
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Affiliation(s)
- Sandesh Parajuli
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Luis G Hidalgo
- Division of Transplantation, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - David Foley
- Division of Transplantation, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
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Motomura T, Faccioli LA, Diaz-Aragon R, Kocas-Kilicarslan ZN, Haep N, Florentino RM, Amirneni S, Cetin Z, Peri BS, Morita K, Ostrowska A, Takeishi K, Soto-Gutierrez A, Tafaleng EN. From a Single Cell to a Whole Human Liver: Disease Modeling and Transplantation. Semin Liver Dis 2022; 42:413-422. [PMID: 36044927 PMCID: PMC9718640 DOI: 10.1055/a-1934-5404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Although the underlying cause may vary across countries and demographic groups, liver disease is a major cause of morbidity and mortality globally. Orthotopic liver transplantation is the only definitive treatment for liver failure but is limited by the lack of donor livers. The development of drugs that prevent the progression of liver disease and the generation of alternative liver constructs for transplantation could help alleviate the burden of liver disease. Bioengineered livers containing human induced pluripotent stem cell (iPSC)-derived liver cells are being utilized to study liver disease and to identify and test potential therapeutics. Moreover, bioengineered livers containing pig hepatocytes and endothelial cells have been shown to function and survive after transplantation into pig models of liver failure, providing preclinical evidence toward future clinical applications. Finally, bioengineered livers containing human iPSC-derived liver cells have been shown to function and survive after transplantation in rodents but require considerable optimization and testing prior to clinical use. In conclusion, bioengineered livers have emerged as a suitable tool for modeling liver diseases and as a promising alternative graft for clinical transplantation. The integration of novel technologies and techniques for the assembly and analysis of bioengineered livers will undoubtedly expand future applications in basic research and clinical transplantation.
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Affiliation(s)
- Takashi Motomura
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Lanuza A.P. Faccioli
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Ricardo Diaz-Aragon
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | | | - Nils Haep
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Rodrigo M. Florentino
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Sriram Amirneni
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Zeliha Cetin
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Bhaavna S. Peri
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Kazutoyo Morita
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Alina Ostrowska
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Kazuki Takeishi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Alejandro Soto-Gutierrez
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania
| | - Edgar N. Tafaleng
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Yigitbilek F, Ozdogan E, Abrol N, Park W, Hansen M, Dasari S, Stegall M, Taner T. Liver mesenchymal stem cells are superior inhibitors of NK cell functions through differences in their secretome compared to other mesenchymal stem cells. Front Immunol 2022; 13:952262. [PMID: 36211345 PMCID: PMC9534521 DOI: 10.3389/fimmu.2022.952262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 09/07/2022] [Indexed: 11/25/2022] Open
Abstract
Liver-resident mesenchymal stem cells (L-MSCs) are superior inhibitors of alloreactive T cell responses compared to their counterparts from bone marrow (BM-MSCs) or adipose tissue (A-MSCs), suggesting a role in liver’s overall tolerogenic microenvironment. Whether L-MSCs also impact NK cell functions differently than other MSCs is not known. We generated and characterized L-MSCs, A-MSCs and BM-MSCs from human tissues. The mass spectrometry analysis demonstrated that L-MSC secretome is uniquely different than that of A-MSC/BM-MSC, with enriched protein sets involved in IFNγ responses and signaling. When co-cultured with primary human NK cells, L-MSCs but not other MSCs, decreased surface expression of activating receptors NKp44 and NKG2D. L-MSCs also decreased IFNγ secretion by IL-2-stimulated NK cells more effectively than other MSCs. Cytolytic function of NK cells were reduced significantly when co-cultured with L-MSCs, whereas A-MSCs or BM-MSCs did not have a major impact. Mechanistic studies showed that the L-MSC-mediated reduction in NK cell cytotoxicity is not through changes in secretion of the cytotoxic proteins Perforin, Granzyme A or B, but through increased production of HLA-C1 found in L-MSC secretome that inhibits NK cells by stimulating their inhibitory receptor KIRDL2/3. L-MSCs are more potent inhibitors of NK cell functions than A-MSC or BM-MSC. Combined with their T cell inhibitory features, these results suggest L-MSCs contribute to the tolerogenic liver microenvironment and liver-induced systemic tolerance often observed after liver transplantation.
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Affiliation(s)
| | - Elif Ozdogan
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
| | - Nitin Abrol
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
| | - Walter D. Park
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
| | | | - Surendra Dasari
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States
| | - Mark D. Stegall
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
- Department of Immunology, Mayo Clinic, Rochester, MN, United States
| | - Timucin Taner
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
- Department of Immunology, Mayo Clinic, Rochester, MN, United States
- *Correspondence: Timucin Taner,
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The New Challenge in Pediatric Liver Transplantation: Chronic Antibody-Mediated Rejection. J Clin Med 2022; 11:jcm11164834. [PMID: 36013073 PMCID: PMC9409831 DOI: 10.3390/jcm11164834] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 08/07/2022] [Accepted: 08/16/2022] [Indexed: 12/21/2022] Open
Abstract
Antibody-mediated rejection (AMR) of liver allograft transplantation was considered as anecdotal for many decades. However recently, AMR has gained clinical awareness as a potential cause of chronic liver injury, leading to liver allograft fibrosis and eventual graft failure. (1) Methods: Literature on chronic AMR (cAMR) in pediatric post-liver transplant patients was reviewed for epidemiologic data, physiopathology, diagnosis, and treatment approaches. (2) Results: Accurate incidence of cAMR in pediatric liver transplantation remains unknown. Diagnostic criteria of cAMR were suggested by the Banff Working Group in 2016 and are based on standardized histopathological findings, C4d staining pattern, associated with the presence of donor-specific antibodies (DSA). Physio-pathological mechanisms are not clear for the technically difficult-to-obtain animal models reproducing cAMR. Treatment protocols are not established, being limited to case reports and case series, based on experience in ABO incompatible transplantation and kidney transplantation. Immunosuppression compliance with adequate dose adjustment may prevent cAMR. Conversion of Cyclosporine to Tacrolimus may improve pathological findings if treated in early phase. The association of steroids, Mycophenolate Mofetil (MMF) and mTOR inhibitors have shown some synergistic effects. Second-line treatments such as intravenous immunoglobulin (IVIG) and plasma exchange may decrease antibody titers based on ABO incompatible transplant protocols. The use of anti-CD20 (Rituximab) and proteasome inhibitors (Bortezomib) is controversial due to the lack of qualified studies. Therefore, multicenter randomized trials are needed to establish the best therapeutic strategy. In refractory cases, re-transplantation is the only treatment for allograft failure. (3) Conclusions: This literature review collects recent clinical, histopathological, and therapeutical advances of cAMR in liver allograft transplantation of pediatric patients. There are many physio-pathological aspects of cAMR to be clarified. Further efforts with multicenter prospective protocols to manage patients with cAMR are needed to improve its outcome.
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Acute Antibody-Mediated Rejection in Liver Transplantation: Impact and Applicability of the Banff Working Group on Liver Allograft Pathology 2016 Criteria. Hum Pathol 2022; 127:67-77. [PMID: 35728694 DOI: 10.1016/j.humpath.2022.06.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/14/2022] [Accepted: 06/14/2022] [Indexed: 11/22/2022]
Abstract
This study was aimed to examine the clinical utility and impact of the 2016 Banff criteria for acute antibody-mediated rejection (acute AMR) in patients with liver transplantation. Among adult patients with donor-specific antibody (DSA) assays performed between 2015 and 2020, cases with proved DSA (mean fluorescent index >2000) and matched liver biopsy available were reviewed. Among 55 patients identified, 28 (51%) had class I DSA, 45 (82%) had class II DSA and 18 (33%) had both. Mild, moderate and severe microvasculitis were observed in 11 (20%), 2 (4%) and 1 (2%) case, respectively. Diffuse immunoreactivity to C4d on portal microvascular endothelia was confirmed in 5 cases (9%), which met the criteria of definite (n=2) or suspicious for acute AMR (n=3). Cases of acute AMR more commonly had class I DSA (100% vs. 46%; p=0.027) or both class I and II DSA (80% vs. 28%; p=0.018) than cases of non-acute AMR. One case of pure acute AMR with veno-occlusion was successfully treated with plasma exchange. The remaining 4 cases had features of combined acute AMR/T cell-mediated rejection (TCMR), and two progressed to ductopenic rejection within 3 weeks. In conclusion, only 9% of DSA-positive patients met the Banff criteria for acute AMR, necessitating careful morphological and immunohistochemical assessments of the allograft biopsies according to the proposed standards. Combined acute AMR/TCMR was more common than isolated acute AMR, and additional AMR in TCMR cases may be associated with rapid progression to ductopenic rejection.
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31
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Bone marrow mesenchymal stem cells modified with heme oxygenase-1 alleviate rejection of donation after circulatory death liver transplantation by inhibiting dendritic cell maturation in rats. Int Immunopharmacol 2022; 107:108643. [PMID: 35240383 DOI: 10.1016/j.intimp.2022.108643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/10/2022] [Accepted: 02/18/2022] [Indexed: 12/21/2022]
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32
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Jiang Z, Zhu H, Wang P, Que W, Zhong L, Li X, Du F. Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity. MedComm (Beijing) 2022; 3:e137. [PMID: 35474948 PMCID: PMC9023873 DOI: 10.1002/mco2.137] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 04/06/2022] [Accepted: 04/07/2022] [Indexed: 12/11/2022] Open
Abstract
CD4+CD25+ regulatory T cells (Tregs), a subpopulation of naturally CD4+ T cells that characteristically express transcription factor Forkhead box P3 (FOXP3), play a pivotal role in the maintenance of immune homeostasis and the prevention of autoimmunity. With the development of biological technology, the understanding of plasticity and stability of Tregs has been further developed. Recent studies have suggested that human Tregs are functionally and phenotypically diverse. The functions and mechanisms of different phenotypes of Tregs in different disease settings, such as tumor microenvironment, autoimmune diseases, and transplantation, have gradually become hot spots of immunology research that arouse extensive attention. Among the complex functions, CD4+CD25+FOXP3+ Tregs possess a potent immunosuppressive capacity and can produce various cytokines, such as IL‐2, IL‐10, and TGF‐β, to regulate immune homeostasis. They can alleviate the progression of diseases by resisting inflammatory immune responses, whereas promoting the poor prognosis of diseases by helping cells evade immune surveillance or suppressing effector T cells activity. Therefore, methods for targeting Tregs to regulate their functions in the immune microenvironment, such as depleting them to strengthen tumor immunity or expanding them to treat immunological diseases, need to be developed. Here, we discuss that different subpopulations of Tregs are essential for the development of immunotherapeutic strategies involving Tregs in human diseases.
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Affiliation(s)
- Zhongyi Jiang
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Haitao Zhu
- Department of Hepatobiliary Surgery The Affiliated Hospital of Guizhou Medical University Guizhou P. R. China
| | - Pusen Wang
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Weitao Que
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Lin Zhong
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Xiao‐Kang Li
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
- Division of Transplantation Immunology National Research Institute for Child Health and Development Tokyo Japan
| | - Futian Du
- Department of Hepatobiliary Surgery Weifang People's Hospital Shandong P. R. China
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33
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Goto R, Ito M, Kawamura N, Watanabe M, Ganchiku Y, Kamiyama T, Shimamura T, Taketomi A. The impact of preformed donor‐specific antibodies in living donor liver transplantation according to graft volume. Immun Inflamm Dis 2022; 10:e586. [PMID: 35064772 PMCID: PMC8926496 DOI: 10.1002/iid3.586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 12/09/2021] [Accepted: 12/31/2021] [Indexed: 11/06/2022] Open
Affiliation(s)
- Ryoichi Goto
- Department of Gastroenterological Surgery I Hokkaido University Graduate School of Medicine Sapporo Japan
| | - Makoto Ito
- Division of Laboratory and Transfusion Medicine Hokkaido University Hospital Sapporo Japan
| | - Norio Kawamura
- Department of Transplant Surgery Hokkaido University Graduate School of Medicine Sapporo Japan
| | - Masaaki Watanabe
- Department of Transplant Surgery Hokkaido University Graduate School of Medicine Sapporo Japan
| | - Yoshikazu Ganchiku
- Department of Gastroenterological Surgery I Hokkaido University Graduate School of Medicine Sapporo Japan
| | - Toshiya Kamiyama
- Department of Gastroenterological Surgery I Hokkaido University Graduate School of Medicine Sapporo Japan
| | - Tsuyoshi Shimamura
- Division of Organ Transplantation Hokkaido University Hospital Sapporo Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I Hokkaido University Graduate School of Medicine Sapporo Japan
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Gambella A, Mastracci L, Caporalini C, Francalanci P, Mescoli C, Ferro J, Alaggio R, Grillo F. Not only a small liver - The pathologist's perspective in the pediatric liver transplant setting. Pathologica 2022; 114:89-103. [PMID: 35212319 PMCID: PMC9040542 DOI: 10.32074/1591-951x-753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 01/26/2022] [Indexed: 11/30/2022] Open
Abstract
Pediatric liver transplantation represents a safe and long-lasting treatment option for various disease types, requiring the pathologist’s input. Indeed, an accurate and timely diagnosis is crucial in reporting and grading native liver diseases, evaluating donor liver eligibility and identifying signs of organ injury in the post-transplant follow-up. However, as the procedure is more frequently and widely performed, deceptive and unexplored histopathologic features have emerged with relevant consequences on patient management, particularly when dealing with long-term treatment and weaning of immunosuppression. In this complex and challenging scenario, this review aims to depict the most relevant histopathologic conditions which could be encountered in pediatric liver transplantation. We will tackle the conditions representing the main indications for transplantation in childhood as well as the complications burdening the post-transplant phases, either immunologically (i.e., rejection) or non-immunologically mediated. Lastly, we hope to provide concise, yet significant, suggestions related to innovative pathology techniques in pediatric liver transplantation.
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Affiliation(s)
| | - Luca Mastracci
- Department of Surgical and Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy.,Pathology Unit, Ospedale Policlinico San Martino IRCCS, Genoa, Italy
| | - Chiara Caporalini
- Pathology Unit, Anna Meyer Children's University Hospital, Florence, Italy
| | - Paola Francalanci
- Unit of Pathology, Children's Hospital Bambino Gesù, IRCCS, Rome, Italy
| | - Claudia Mescoli
- Department of Pathology, Azienda Ospedale, Università Padova, Padova, Italy
| | - Jacopo Ferro
- Department of Surgical and Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy
| | - Rita Alaggio
- Unit of Pathology, Children's Hospital Bambino Gesù, IRCCS, Rome, Italy
| | - Federica Grillo
- Department of Surgical and Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy.,Pathology Unit, Ospedale Policlinico San Martino IRCCS, Genoa, Italy
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Komagome M, Maki A, Nagata R, Masuda W, Kogure R, Mitsui T, Ninomiya R, Akamatsu N, Hasegawa K, Beck Y. Refractory Acute Antibody Mediated Rejection in Liver Transplant After Desensitization of Preformed Donor Specific Antibody-Validity of Bortezomib and Everolimus: A Case Report. Transplant Proc 2022; 54:147-152. [PMID: 34974892 DOI: 10.1016/j.transproceed.2021.11.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 10/27/2021] [Accepted: 11/01/2021] [Indexed: 10/19/2022]
Abstract
Here, we report a case of living donor liver transplantation (LDLT) complicated with severe acute antibody-mediated rejection (aAMR), although desensitization was performed for preformed donor-specific anti-human leukocyte antigen antibody (DSA). LDLT was performed in a 59-year-old woman with alcoholic cirrhosis with a graft from her 60-year-old husband as a living donor. She had reproductive history of 4 gravidity and parity with her husband. Preoperative serologic studies showed positive complement-dependent cytotoxic crossmatch and anti-human leukocyte antigen-A26 antibody was identified as DSA. Desensitization for preformed DSA with rituximab and plasma exchange was performed before LDLT. We decided to perform LDLT using her husband right liver as living donor graft since the DSA mean fluoro-intensity was down to negative range. The immunosuppressive regimen was comprised with steroid and tacrolimus. However, the recipient developed acute cellular rejection on day 5 after LDLT, followed by severe aAMR. Re-administration of rituximab followed by 4 courses of plasma exchange failed to treat aAMR. The DSA mean fluoro-intensity was successfully suppressed after bortezomib was administered however impaired serologic liver function test and cholestasis were remained. The liver function test and cholestasis in the graft were improved after Everolimus was administered. The recipient was discharged on postoperative day 196. In conclusion, we report a case of LDLT who developed aAMR after desensitization of preformed DSA and was successfully treated with intensive therapy with bortezomib and everolimus.
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Affiliation(s)
- Masahiko Komagome
- Hepato-Pancreato-Biliary Surgery, Saitama Medical University Saitama Medical Center, Kawagoe, Saitama, Japan
| | - Akira Maki
- Hepato-Pancreato-Biliary Surgery, Saitama Medical University Saitama Medical Center, Kawagoe, Saitama, Japan.
| | - Rihito Nagata
- Department of Pathology, Saitama Medical University Saitama Medical Center, Kawagoe, Saitama, Japan
| | - Wataru Masuda
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Ryota Kogure
- Hepato-Pancreato-Biliary Surgery, Saitama Medical University Saitama Medical Center, Kawagoe, Saitama, Japan
| | - Tetsuya Mitsui
- Hepato-Pancreato-Biliary Surgery, Saitama Medical University Saitama Medical Center, Kawagoe, Saitama, Japan
| | - Riki Ninomiya
- Hepato-Pancreato-Biliary Surgery, Saitama Medical University Saitama Medical Center, Kawagoe, Saitama, Japan
| | - Nobuhisa Akamatsu
- Department of Pathology, Saitama Medical University Saitama Medical Center, Kawagoe, Saitama, Japan
| | - Kiyoshi Hasegawa
- Department of Pathology, Saitama Medical University Saitama Medical Center, Kawagoe, Saitama, Japan
| | - Yoshifumi Beck
- Hepato-Pancreato-Biliary Surgery, Saitama Medical University Saitama Medical Center, Kawagoe, Saitama, Japan
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Dumortier J, Besch C, Moga L, Coilly A, Conti F, Corpechot C, Del Bello A, Faitot F, Francoz C, Hilleret MN, Houssel-Debry P, Jezequel C, Lavayssière L, Neau-Cransac M, Erard-Poinsot D, de Lédinghen V, Bourlière M, Bureau C, Ganne-Carrié N. Non-invasive diagnosis and follow-up in liver transplantation. Clin Res Hepatol Gastroenterol 2022; 46:101774. [PMID: 34332131 DOI: 10.1016/j.clinre.2021.101774] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 07/23/2021] [Indexed: 02/04/2023]
Abstract
The field of liver transplantation directly or indirectly embodies all liver diseases, in addition to specific ones related to organ rejection (cellular and humoral). The recommended non-invasive methods for determining the indication for liver transplantation are the Model for End-stage Liver Disease score, and the alpha-foetoprotein score in case of hepatocellular carcinoma. Radiological methods are the cornerstones for the diagnosis of vascular and biliary complications after liver transplantation. The possible diseases of the liver graft after transplantation are multiple and often intertwined. Non-invasive diagnostic methods have been poorly evaluated in this context, apart from the recurrence of hepatitis C. Liver biopsy remains the gold standard for evaluating graft lesions in the majority of cases, especially graft rejection.
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Affiliation(s)
- Jérôme Dumortier
- Service d'hépato-gastroentérologie, Unité de transplantation hépatique, Hôpital Edouard Herriot - HCL, CHU Lyon, Lyon.
| | - Camille Besch
- Service de chirurgie hépato-bilio-pancréatique et transplantation hépatique, Hôpital Hautepierre, CHRU Strasbourg, Strasbourg
| | - Lucile Moga
- Service d'Hépatologie et Transplantation Hépatique, Hôpital Beaujon, APHP, Clichy
| | - Audrey Coilly
- Centre Hépato-Biliaire, Hôpital Paul Brousse, APHP, Villejuif
| | - Filomena Conti
- Service d'Hépatologie et Transplantation Hépatique, Hôpital de la Pitié Salpétrière, APHP, Paris
| | | | - Arnaud Del Bello
- Département de néphrologie et transplantation d'organes, Hôpital Rangueil, CHU Toulouse, Toulouse
| | - François Faitot
- Service de chirurgie hépato-bilio-pancréatique et transplantation hépatique, Hôpital Hautepierre, CHRU Strasbourg, Strasbourg
| | - Claire Francoz
- Service d'Hépatologie et Transplantation Hépatique, Hôpital Beaujon, APHP, Clichy
| | | | | | | | - Laurence Lavayssière
- Département de néphrologie et transplantation d'organes, Hôpital Rangueil, CHU Toulouse, Toulouse
| | | | - Domitille Erard-Poinsot
- Service d'hépato-gastroentérologie, Unité de transplantation hépatique, Hôpital Edouard Herriot - HCL, CHU Lyon, Lyon
| | - Victor de Lédinghen
- Unité Transplantation Hépatique, Hôpital Haut-Lévêque, CHU Bordeaux, Bordeaux
| | - Marc Bourlière
- Service d'hépato-gastroentérologie, Hôpital Saint Joseph & INSERM UMR 1252 IRD SESSTIM Aix Marseille Université, Marseille
| | | | - Nathalie Ganne-Carrié
- Service d'hépatologie, Hôpital Avicenne, APHP, Université Sorbonne Paris Nord, Bobigny & INSERM UMR 1138, Centre de Recherche des Cordeliers, Université de Paris
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Jiang Z, Xing C, Wang P, Liu X, Zhong L. Identification of Therapeutic Targets and Prognostic Biomarkers Among Chemokine (C-C Motif) Ligands in the Liver Hepatocellular Carcinoma Microenvironment. Front Cell Dev Biol 2021; 9:748269. [PMID: 34938730 PMCID: PMC8685337 DOI: 10.3389/fcell.2021.748269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 11/17/2021] [Indexed: 12/23/2022] Open
Abstract
Background: Liver hepatocellular carcinoma (LIHC) is the third leading cause of cancer-related death and the sixth most common solid tumor worldwide. In the tumor microenvironment, the cross-talk between cancer cells, immune cells, and stromal cells exerts significant effects on neoplasia and tumor development and is modulated in part by chemokines. Chemokine (C-C motif) ligands (CCL) can directly target tumor cells and stromal cells, and they have been shown to regulate tumor cell proliferation, cancer stem-like cell properties, cancer invasiveness and metastasis, which directly and indirectly affect tumor immunity and influence cancer progression, therapy and patient outcomes. However, the prognostic values of chemokines CCL in LIHC have not been clarified. Methods: In this study, we comprehensively analyzed the relationship between transcriptional chemokines CCL and disease progression of LIHC using the ONCOMINE dataset, GEPIA, UALCAN, STRING, WebGestalt, GeneMANIA, TRRUST, DAVID 6.8, LinkedOmics, TIMER, GSCALite, and Open Targets. We validated the protein levels of chemokines CCL through western blot and immunohistochemistry. Results: The transcriptional levels of CCL5/8/11/13/15/18/20/21/25/26/27/28 in LIHC tissues were significantly elevated while CCL2/3/4/14/23/24 were significantly reduced. A significant correlation was found between the expression of CCL14/25 and the pathological stage of LIHC patients. LIHC patients with low transcriptional levels of CCL14/21 were associated with a significantly poor prognosis. The functions of differentially expressed chemokines CCL were primarily related to the chemokine signaling pathway, cytokine–cytokine receptor interactions, and TNF-α signaling pathway. Our data suggested that RELA/REL, NFKB1, STAT1/3/6, IRF3, SPI1, and JUN were key transcription factors for chemokines CCL. We found significant correlations among the expression of chemokines CCL and the infiltration of six types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells) and immune checkpoints (PD-1. PD-L1, and CTLA-4). The western blot and immunohistochemistry results showed that protein expression levels of CCL5 and CCL20 were upregulated in LIHC. CCL5 and CCL20 were significantly correlated with the clinical outcome of patients with LIHC, and could be negatively regulated by some drugs or small molecules. Conclusions: Our results may provide novel insights for the potential suitable targets of immunological therapy and prognostic biomarkers for LIHC.
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Affiliation(s)
- Zhongyi Jiang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Changchang Xing
- Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Pusen Wang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xueni Liu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lin Zhong
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Lee BT, Fiel MI, Schiano TD. Antibody-mediated rejection of the liver allograft: An update and a clinico-pathological perspective. J Hepatol 2021; 75:1203-1216. [PMID: 34343613 DOI: 10.1016/j.jhep.2021.07.027] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 07/06/2021] [Accepted: 07/14/2021] [Indexed: 12/16/2022]
Abstract
Antibody-mediated rejection after liver transplantation is an under-recognised cause of allograft injury. While definitions of acute and chronic antibody-mediated rejection have increased clinical awareness, timely identification and management of antibody-mediated rejection remain difficult because of complexities in diagnosis and histopathology, lack of treatment protocols, and unclear long-term outcomes. While recent cohort studies assessing the importance of donor-specific antibodies have aided in its diagnosis, literature on the treatment of antibody-mediated rejection in liver transplantation remain limited to case reports and small series. Further increasing the awareness and timely recognition of antibody-mediated rejection post-liver transplantation is crucial in order to stimulate future research and the development of protocols for its diagnosis and treatment. This review will summarise recent advances in the clinical diagnosis and treatment of antibody-mediated rejection in liver transplantation, as well as some of the histopathologic features (on liver biopsy tissue) of acute and chronic antibody-mediated rejection.
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Affiliation(s)
- Brian T Lee
- Division of Gastroenterology and Transplant Institute, Loma Linda University Health, Loma Linda, CA, USA.
| | - M Isabel Fiel
- Department of Pathology, Molecular and Cell-Based Medicine, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Thomas D Schiano
- Division of Liver Diseases, Department of Medicine, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
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Appenzeller-Herzog C, Hartleif S, Vionnet J. Clinical parameters and biomarkers predicting spontaneous operational tolerance after liver transplantation: A scoping review. Am J Transplant 2021; 21:3312-3323. [PMID: 33783969 DOI: 10.1111/ajt.16585] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 03/19/2021] [Accepted: 03/21/2021] [Indexed: 01/25/2023]
Abstract
Indefinite allograft acceptance after immunosuppression withdrawal (ISW), also known as operational tolerance (OT), can occur spontaneously after liver transplantation (LT), but reliable and reproducible prognosis of OT versus non-OT outcomes remains elusive. To prime this, systematic extraction of OT-predictive factors from the literature is crucial. We provide the first comprehensive identification and synthesis of clinical parameters and biomarkers predicting spontaneous OT in non-autoimmune/non-replicative viral LT recipients selected for ISW. We searched Embase, Medline, the Cochrane Central Register of Controlled Trials, clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform for articles, conference abstracts, and ongoing trials. We contacted principal investigators of stand-alone abstracts and ongoing trials for unpublished data and screened citations and references of eligible articles. Twenty-three articles reporting on 11 completed ISW studies, 13 abstracts, and five trial registry entries were included. Longer time between LT and ISW was the only clinical parameter that may increase the incidence of OT. Prognostic biomarkers conspicuously differed between pediatric and adult ISW candidates. These included allograft gene expression patterns and peripheral blood immune exhaustion markers for adults, and histological allograft scores for children. Our results will foster cross-validation efforts to facilitate safe and harmonized candidate selection for successful ISW.
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Affiliation(s)
| | - Steffen Hartleif
- University Hospital Tübingen, Pediatric Gastroenterology and Hepatology, Stuttgart, Germany
| | - Julien Vionnet
- Institute of Liver Studies, King's College Hospital, London, UK
- Transplantation Centre, University Hospital of Lausanne and University of Lausanne, Lausanne, Switzerland
- Service of Gastroenterology and Hepatology, University Hospital of Lausanne and University of Lausanne, Lausanne, Switzerland
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Gül-Klein S, Hegermann H, Röhle R, Schmelzle M, Tacke F, Schöning W, Öllinger R, Dziodzio T, Maier P, Plewe JM, Horst D, Sauer IM, Pratschke J, Lachmann N, Eurich D. Donor-Specific Antibodies Against Donor Human Leukocyte Antigen are Associated with Graft Inflammation but Not with Fibrosis Long-Term After Liver Transplantation: An Analysis of Protocol Biopsies. J Inflamm Res 2021; 14:2697-2712. [PMID: 34188517 PMCID: PMC8236257 DOI: 10.2147/jir.s307778] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 05/04/2021] [Indexed: 02/06/2023] Open
Abstract
Background Donor-specific antibodies (DSA) against donor human leukocyte antigen after liver transplantation, which are associated with histological changes, have been widely studied with respect to their sustained impact on transplant function. However, their long-term impact after liver transplantation remains unclear. Methods We performed a cross-sectional analysis from June 2016 to July 2017 that included all patients who presented themselves for scheduled follow-up after receiving a liver transplantation between September 1989 and December 2016. In addition to a liver protocol biopsy, patients were screened for human leukocyte antigen antibodies (HLAab) and donor-specific antibodies. Subsequently, the association between human leukocyte antigen antibodies, donor-specific antibodies, histologic and clinical features, and immunosuppression was analyzed. Results Analysis for human leukocyte antigen antibodies and donor-specific antibodies against donor human leukocyte antigen was performed for 291 and 271 patients. A significant association between higher inflammation grades and the presence of human leukocyte antigen antibodies and donor-specific antibodies was detected, while fibrosis stages remained unaffected. These results were confirmed by multivariate logistic regression for inflammation showing a significant increase for presence of human leukocyte antigen antibodies and donor-specific antibodies (OR: 4.43; 95% CI: 1.67–12.6; p=0.0035). Furthermore, the use of everolimus in combination with tacrolimus was significantly associated with the status of negative human leukocyte antigen antibodies and donor-specific antibodies. Viral etiology for liver disease, hepatocellular carcinoma (HCC) and higher steatosis grades of the graft were significantly associated with a lower rate of human leukocyte antigen antibodies. The impact of human leukocyte antigen antibodies and donor-specific antibodies against donor human leukocyte antigen was associated with higher levels of laboratory parameters, such as transaminases and bilirubin. Conclusion Donor-specific antibodies against donor human leukocyte antigen are associated with histological and biochemical graft inflammation after liver transplantation, while fibrosis seems to be unaffected. Future studies should validate these findings for longer observation periods and specific subgroups.
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Affiliation(s)
- Safak Gül-Klein
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Henriette Hegermann
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Robert Röhle
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Biometry and Clinical Epidemiology, Berlin, Germany.,Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Coordinating Center for Clinical Studies, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany
| | - Moritz Schmelzle
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hepatology & Gastroenterology, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Wenzel Schöning
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Robert Öllinger
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Tomasz Dziodzio
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Patrick Maier
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Julius M Plewe
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - David Horst
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Igor Maximilian Sauer
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Biometry and Clinical Epidemiology, Berlin, Germany
| | - Johann Pratschke
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Nils Lachmann
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, HLA Laboratory, Institute of Transfusion Medicine, Histocompatibility and Immunogenetics, Charité - Universitätsmedizin, Berlin, Germany
| | - Dennis Eurich
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
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Götz JK, Kiene H, Goldschmidt I, Junge N, Pfister ED, Leiskau C, Brown RM, Immenschuh S, Baumann U. Current Evidence on the Clinical Relevance of Donor-specific Antibodies in Paediatric Liver Transplantation. J Pediatr Gastroenterol Nutr 2021; 72:788-793. [PMID: 33908737 DOI: 10.1097/mpg.0000000000003127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
ABSTRACT The clinical impact of donor-specific antibodies (DSA) occurring before or after liver transplantation (LT) against donor-human leucocyte antigen (HLA) on graft outcome is still unclear. We aim to present the current consensus based on recent paediatric LT case series. Compared to kidney transplantation, the liver seems to be less susceptible to antibody-mediated graft damage, which is likely due to protective Kupffer cell activity. The incidence of DSA after liver transplantation is higher in children than in adults. DSA directed against HLA class II molecules, mainly DQ, occur more often. The presence of such anti-class II DSA (DQ/DR), especially of the complement-binding IgG3 subclass, may be associated with endothelial injury, T-cell-mediated rejection (TCMR), inflammation, and fibrosis. Regular DSA-posttransplant monitoring cannot as yet be recommended in routine practice but may be useful in selected cases.
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Affiliation(s)
- Juliane K Götz
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases
| | - Hella Kiene
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases
| | - Imeke Goldschmidt
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases
| | - Norman Junge
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases
| | - Eva-Doreen Pfister
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases
| | - Christoph Leiskau
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases
| | - Rachel M Brown
- Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham
- Department of Histopathology, Birmingham Children's Hospital
| | - Stephan Immenschuh
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Ulrich Baumann
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases
- Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
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Considerations and experience driving expansion of combined heart-liver transplantation. Curr Opin Organ Transplant 2021; 25:496-500. [PMID: 32796180 DOI: 10.1097/mot.0000000000000804] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
PURPOSE OF REVIEW Heart transplantation concomitant with a liver transplant may be warranted when end-stage heart failure results in irreversible liver failure. Previously reported outcomes have been excellent yet the specific immunoprotective role of the liver allograft is not known. We review the current literature about the immunologic benefit for combined heart and liver transplantation (CHLT). RECENT FINDINGS The total number of combined heart and liver transplants continues to increase and accounts for approximately 25 cases per year. Familial amyloid polyneuropathy with cardiac cirrhosis is the most common indication for CHLT while adult congenital heart disease (CHD) with associated cirrhosis is increasing in frequency. The majority of recent registry data suggest a statistically equivalent to modestly improved survival advantage for CHLT compared with isolated heart transplantation. Direct mechanisms accounting for this survival advantage are not proven, but combined heart and liver transplants experience lower rates of acute cardiac rejection and cardiac allograft vasculopathy (CAV). SUMMARY Combined heart and liver transplants remain a small percentage of the total heart transplants worldwide, but the majority of recent literature confirms the safety and viability of this option for patients with end-stage heart and liver disease. Equivalent to modestly improved survival outcomes, lower rates of acute cardiac rejection and CAV warrant further investigation into the liver allograft's immunoprotective effect on the transplanted heart. The key mechanisms of tolerogenicity have important implications for surgical technique and immunosuppression requirements. Future directions include development of criteria for heart-liver transplant candidacy and identification of equitable allocation protocols.
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Zhang W, Cao D, Wang M, Wu Y, Gong J, Li J, Liu Y. XBP1s repression regulates Kupffer cell polarization leading to immune suppressive effects protecting liver allograft in rats. Int Immunopharmacol 2021; 91:107294. [PMID: 33395585 DOI: 10.1016/j.intimp.2020.107294] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 11/30/2020] [Accepted: 12/08/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND Polarized kupffer cells (KCs) influence the immune response after liver transplantation. We report an undiscovered immune regulatory role of X-box binding protein 1 (XBP1) on immune function of kupffer cells (KCs). METHODS Acute rejection model using rats. RESULTS We found that suppression of XBP1s in lipopolysaccharide (LPS) -activated KCs could increase the expression of arginase-1 (Arg-1) and CD204 but also decrease the expression levels of MHC-II and CD40 and shift the phenotype markers of KCs toward M2 via the janus kinase (JAK) 3- Signal Transducer And Activator Of Transcription (STAT) 6 pathway, presenting an immunosuppressive function by enhancing anti-inflammatory cytokine secretion and accelerating apoptosis of activated T cells. XBP1s over-expression in KCs shift the phenotype markers on KCs towards M1 via the JAK1-STAT1 pathway and have shown a strong pro-inflammatory property. Down-regulation of XBP1s in KCs changed the phenotype and cytokine secretion profile towards M2 and markedly protected the function and structure of allograft liver, prolonging the recipient's survival compared with control and normal saline groups in rats. CONCLUSIONS Our findings reveal a novel regulatory mechanism of XBP1 in an induced immuno-suppressive state to protect rat's liver allograft via JAK-STAT mediated KCs polarization.
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Affiliation(s)
- Weikang Zhang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430022, China
| | - Ding Cao
- Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.
| | - Menghao Wang
- Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
| | - Yakun Wu
- Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
| | - Jianping Gong
- Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
| | - Jingzheng Li
- Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
| | - Yiming Liu
- Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.
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Kovandova B, Slavcev A, Honsova E, Erhartova D, Skibova J, Viklicky O, Trunecka P. De novo HLA Class II antibodies are associated with the development of chronic but not acute antibody-mediated rejection after liver transplantation - a retrospective study. Transpl Int 2020; 33:1799-1806. [PMID: 33020979 DOI: 10.1111/tri.13763] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/04/2020] [Accepted: 09/28/2020] [Indexed: 02/02/2023]
Abstract
Donor-specific antibodies (DSA) cause antibody-mediated rejection (AMR); however, their pathogenic role has not yet been adequately investigated after liver transplantation. The aim of our study was to analyse the clinical significance of DSA and complement-binding DSA for the prediction of AMR after liver transplantation. Our cohort included 120 liver recipients with assessed protocol biopsies one year post-transplant. All patients had defined HLA-specific and complement-binding (C1q + and C3d+) antibodies before and in regular intervals after transplantation. The incidence of DSA was evaluated in relation with clinical and histopathological data in the liver allografts. A higher occurrence of acute AMR was observed in recipients with preformed complement-binding DSA to HLA Class I antigens. Patients who developed chronic AMR had more frequently de novo-produced antibodies against HLA Class II antigens (P = 0.0002). A correlation was also found between de novo-formed C1q + and C3d+-binding antibodies to HLA Class II antigens and the development of chronic AMR (P = 0.043). Our study implies that preformed complement-binding DSA to HLA Class I antigens are related to increased risk of acute antibody-mediated rejection, while chronic AMR is more frequent in patients with de novo-produced antibodies to HLA Class II antigens after liver transplantation.
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Affiliation(s)
| | | | - Eva Honsova
- Department of Clinical & Transplantation Pathology, IKEM, Prague, Czech Republic
| | - Denisa Erhartova
- Department of Hepatogastroenterology, IKEM, Prague, Czech Republic
| | - Jelena Skibova
- Department of Medical Statistics, IKEM, Prague, Czech Republic
| | | | - Pavel Trunecka
- Department of Hepatogastroenterology, IKEM, Prague, Czech Republic
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Wang P, Jiang Z, Wang C, Liu X, Li H, Xu D, Zhong L. Immune Tolerance Induction Using Cell-Based Strategies in Liver Transplantation: Clinical Perspectives. Front Immunol 2020; 11:1723. [PMID: 33013824 PMCID: PMC7461870 DOI: 10.3389/fimmu.2020.01723] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 06/29/2020] [Indexed: 12/14/2022] Open
Abstract
Liver transplantation (LT) has become the best chance and a routine practice for patients with end-stage liver disease and small hepatocellular carcinoma. However, life-long immunosuppressive regimens could lead to many post-LT complications, including cancer recurrence, infections, dysmetabolic syndrome, and renal injury. Impeccable management of immunosuppressive regimens is indispensable to ensure the best long-term prognosis for LT recipients. This is challenging for these patients, who probably have a post-LT graft survival of more than 10 or even 20 years. Approximately 20% of patients after LT could develop spontaneous operational tolerance. They could maintain normal graft function and histology without any immunosuppressive regimens. Operational tolerance after transplantation has been an attractive and ultimate goal in transplant immunology. The liver, as an immunoregulatory organ, generates an immune hyporesponsive microenvironment under physiological conditions. In this regard, LT recipients may be ideal candidates for studies focusing on operative tolerance. Cell-based strategies are one of the most promising methods for immune tolerance induction, including chimerism induced by hematopoietic stem cells and adoptive transfer of regulatory T cells, regulatory dendritic cells, regulatory macrophages, regulatory B cells, and mesenchymal stromal cells. The safety and the efficacy of many cell products have been evaluated by prospective clinical trials. In this review, we will summarize the latest perspectives on the clinical application of cell-based strategies in LT and will address a number of concerns and future directions regarding these cell products.
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Affiliation(s)
- Pusen Wang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhongyi Jiang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chunguang Wang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xueni Liu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hao Li
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dingyin Xu
- Department of Hepatobiliary Surgery, Ruian People's Hospital, Ruian, China
| | - Lin Zhong
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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DSA Are Associated With More Graft Injury, More Fibrosis, and Upregulation of Rejection-associated Transcripts in Subclinical Rejection. Transplantation 2020; 104:551-561. [PMID: 31651790 DOI: 10.1097/tp.0000000000003034] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND Subclinical T cell-mediated rejection (subTCMR) is commonly found after liver transplantation and has a good short-term prognosis, even when it is left untreated. Donor-specific antibodies (DSA) are putatively associated with a worse prognosis for recipient and graft after liver transplantation. METHODS To assess the immune regulation in subTCMR grafts, gene expression of 93 transcripts for graft injury, tolerance, and immune regulation was analyzed in 77 biopsies with "no histologic rejection" (NHR; n = 25), "clinical TCMR" (cTMCR; n = 16), and subTCMR (n = 36). In addition, all available subTCMR biopsies (n = 71) were tested for DSA with bead assays. RESULTS SubTCMR showed heterogeneous and intermediate expression profiles of transcripts that were upregulated in cTCMR. Graft gene expression suggested a lower activation of effector lymphocytes and a higher activation of regulatory T cells in grafts with subTCMR compared to cTCMR. DSA positivity in subTCMR was associated with histological evidence of more severe graft inflammation and fibrosis. This more severe DSA+ associated graft injury in subTCMR was converged with an upregulation of cTCMR-associated transcripts. In nonsupervised analysis, DSA positive subTCMR mostly clustered together with cTCMR, while DSA negative subTCMR clustered together with NHR. CONCLUSIONS T cell-mediated rejection seems to form a continuum of alloimmune activation. Although subTCMR exhibited less expression of TCMR-associated transcript, DSA positivity in subTCMR was associated with an upregulation of rejection-associated transcripts. The identification of DSA positive subclinical rejection might help to define patients with more inflammation in the graft and development of fibrosis.
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Ronca V, Wootton G, Milani C, Cain O. The Immunological Basis of Liver Allograft Rejection. Front Immunol 2020; 11:2155. [PMID: 32983177 PMCID: PMC7492390 DOI: 10.3389/fimmu.2020.02155] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 08/07/2020] [Indexed: 12/15/2022] Open
Abstract
Liver allograft rejection remains a significant cause of morbidity and graft failure in liver transplant recipients. Rejection is caused by the recognition of non-self donor alloantigens by recipient T-cells. Antigen recognition results in proliferation and activation of T-cells in lymphoid tissue before migration to the allograft. Activated T-cells have a variety of effector mechanisms including direct T-cell mediated damage to bile ducts, endothelium and hepatocytes and indirect effects through cytokine production and recruitment of tissue-destructive inflammatory cells. These effects explain the histological appearances of typical acute T-cell mediated rejection. In addition, donor specific antibodies, most typically against HLA antigens, may give rise to antibody-mediated rejection causing damage to the allograft primarily through endothelial injury. However, as an immune-privileged site there are several mechanisms in the liver capable of overcoming rejection and promoting tolerance to the graft, particularly in the context of recruitment of regulatory T-cells and promotors of an immunosuppressive environment. Indeed, around 20% of transplant recipients can be successfully weaned from immunosuppression. Hence, the host immunological response to the liver allograft is best regarded as a balance between rejection-promoting and tolerance-promoting factors. Understanding this balance provides insight into potential mechanisms for novel anti-rejection therapies.
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Affiliation(s)
- Vincenzo Ronca
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy.,National Institute of Health Research Liver Biomedical Research Unit Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Grace Wootton
- National Institute of Health Research Liver Biomedical Research Unit Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Chiara Milani
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
| | - Owen Cain
- Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
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Simpson MA. Liver Transplant Graft Histology, Cellular Infiltrates, and Peripheral Donor Specific Antibodies: Independent Observations or Interrelated Effectors? Transplantation 2020; 104:1533-1534. [PMID: 32732826 DOI: 10.1097/tp.0000000000003100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Affiliation(s)
- Mary Ann Simpson
- Department of Transplantation and Hepatobiliary Diseases, Lahey Hospital and Medical Center
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Cousin VL, Rougemont AL, Rubbia-Brandt L, Wildhaber BE, Villard J, Ferrari-Lacraz S, McLin VA. Peripheral Donor-specific Antibodies Are Associated With Histology and Cellular Subtypes in Protocol Liver Biopsies of Pediatric Recipients. Transplantation 2020; 104:1633-1643. [PMID: 32732841 DOI: 10.1097/tp.0000000000003099] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The cellular infiltrate in protocol liver biopsies (PB) following pediatric liver transplantation remains mostly uncharacterized, yet there is increasing concern about the role of inflammation and fibrosis in long-term liver allografts. We aimed to define cell types in PB and to analyze their relationship with donor-specific antibodies (DSA) and histological phenotype. METHODS PB were performed at least 1 year after transplantation. We identified 4 phenotypes: normal, fibrosis, inflammation, inflammation with fibrosis. Cell types were counted after immunostaining for CD3, CD4, CD8, CD68, CD20, MUM1, and FoxP3. RESULTS Forty-four patients underwent 1 PB between 2000 and 2015. Eleven percent (5/44) of PB displayed normal histology, 13.6% (6/44) fibrosis, 34.1% (15/44) inflammation, and 40.9% (18/44) inflammation and fibrosis. The main cell types in the portal tracts and lobules were CD3+ and CD68+ cells. Frequency of de novo DSA was 63% (27/44). The presence of CD8+ cells in the lobules was associated with fibrosis. Inflammation and fibrosis in PB were associated with the presence of circulating de novo DSA, number of de novo DSA, and C1q binding activity when compared to other phenotypes. CONCLUSIONS T cells (CD3+) and macrophages (CD68+) were the most prevalent cell-types in PB. In the presence of inflammation, portal tracts were enriched in CD3+, CD20+ but displayed fewer CD68+. This coincided with the presence and number of de novo DSA. How these cellular and humoral actors interact is unclear, but peripheral DSA may be a marker of immune cellular activity in the seemingly quiescent allograft.
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Affiliation(s)
- Vladimir L Cousin
- Swiss Pediatric Liver Center, Geneva University Hospitals, Department of Pediatrics, Gynecology, and Obstetrics, University of Geneva, Geneva, Switzerland
| | - Anne-Laure Rougemont
- Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Laura Rubbia-Brandt
- Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Barbara E Wildhaber
- Swiss Pediatric Liver Center, Geneva University Hospitals, Department of Pediatrics, Gynecology, and Obstetrics, University of Geneva, Geneva, Switzerland
- Department of Pediatrics, Gynecology, and Obstetrics, University of Geneva, Geneva, Switzerland
| | - Jean Villard
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
- Transplantation Immunology Unit and National Reference Laboratory for Histocompatibility, Geneva University Hospital and Medical School, Geneva, Switzerland
| | - Sylvie Ferrari-Lacraz
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
- Transplantation Immunology Unit and National Reference Laboratory for Histocompatibility, Geneva University Hospital and Medical School, Geneva, Switzerland
| | - Valérie A McLin
- Swiss Pediatric Liver Center, Geneva University Hospitals, Department of Pediatrics, Gynecology, and Obstetrics, University of Geneva, Geneva, Switzerland
- Department of Pediatrics, Gynecology, and Obstetrics, University of Geneva, Geneva, Switzerland
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Hann A, Osei-Bordom DC, Neil DAH, Ronca V, Warner S, Perera MTPR. The Human Immune Response to Cadaveric and Living Donor Liver Allografts. Front Immunol 2020; 11:1227. [PMID: 32655558 PMCID: PMC7323572 DOI: 10.3389/fimmu.2020.01227] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 05/15/2020] [Indexed: 12/13/2022] Open
Abstract
The liver is an important contributor to the human immune system and it plays a pivotal role in the creation of both immunoreactive and tolerogenic conditions. Liver transplantation provides the best chance of survival for both children and adults with liver failure or cancer. With current demand exceeding the number of transplantable livers from donors following brain death, improved knowledge, technical advances and the desire to prevent avoidable deaths has led to the transplantation of organs from living, ABO incompatible (ABOi), cardiac death donors and machine based organ preservation with acceptable results. The liver graft is the most well-tolerated, from an immunological perspective, of all solid organ transplants. Evidence suggests successful cessation of immunosuppression is possible in ~20–40% of liver transplant recipients without immune mediated graft injury, a state known as “operational tolerance.” An immunosuppression free future following liver transplantation is an ambitious but perhaps not unachievable goal. The initial immune response following transplantation is a sterile inflammatory process mediated by the innate system and the mechanisms relate to the preservation-reperfusion process. The severity of this injury is influenced by graft factors and can have significant consequences. There are minimal experimental studies that delineate the differences in the adaptive immune response to the various forms of liver allograft. Apart from ABOi transplants, antibody mediated hyperacute rejection is rare following liver transplant. T-cell mediated rejection is common following liver transplantation and its incidence does not differ between living or deceased donor grafts. Transplantation in the first year of life results in a higher rate of operational tolerance, possibly due to a bias toward Th2 cytokines (IL4, IL10) during this period. This review further describes the current understanding of the immunological response toward liver allografts and highlight the areas of this topic yet to be fully understood.
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Affiliation(s)
- Angus Hann
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | | | - Desley A H Neil
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Vincenzo Ronca
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Suz Warner
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,The Liver Unit, Birmingham Children's Hospital, Birmingham, United Kingdom
| | - M Thamara P R Perera
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.,The Liver Unit, Birmingham Children's Hospital, Birmingham, United Kingdom
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