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Stark H, Ho QY, Cross A, Alessandrini A, Bertaina A, Brennan D, Busque S, Demetris A, Devey L, Fruhwirth G, Fuchs E, Friend P, Geissler E, Guillonneau C, Hester J, Isaacs J, Jaeckel E, Kawai T, Lakkis F, Leventhal J, Levings M, Levitsky J, Lombardi G, Martinez-Llordella M, Mathew J, Moreau A, Reinke P, Riella LV, Sachs D, Fueyo AS, Schreeb K, Sykes M, Tang Q, Thomson A, Tree T, Trzonkowski P, Uchida K, Veale J, Weiner J, Wekerle T, Issa F. Meeting Report: The Sixth International Sam Strober Workshop on Clinical Immune Tolerance. Transplantation 2025; 109:569-579. [PMID: 39800883 DOI: 10.1097/tp.0000000000005311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2025]
Affiliation(s)
- Helen Stark
- Translational Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Quan Yao Ho
- Translational Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
- Department of Renal Medicine, Singapore General Hospital, Singapore
| | - Amy Cross
- Translational Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Alessandro Alessandrini
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Alice Bertaina
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Daniel Brennan
- Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Stephan Busque
- Department of Surgery, Division of Abdominal Transplantation, Stanford University School of Medicine, Palo Alto, CA
| | - Anthony Demetris
- Department of Pathology, Division of Transplantation, University of Pittsburgh, Pittsburgh, PA
| | - Luke Devey
- Quell Therapeutics, Translation and Innovation Hub, London, UK
| | - Gilbert Fruhwirth
- Imaging Therapies and Cancer Group, School of Cancer and Pharmaceutical Sciences, King's College London, London, UK
| | | | - Peter Friend
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Ed Geissler
- Division of Experimental Surgery, Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Carole Guillonneau
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Joanna Hester
- Translational Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - John Isaacs
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
- Musculoskeletal Unit and NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Elmar Jaeckel
- Ajmera Transplant Centre, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Tatsuo Kawai
- Department of Surgery, Transplant Center, Massachusetts General Hospital, Boston, MA
| | - Fadi Lakkis
- Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
| | - Joseph Leventhal
- Comprehensive Transplant Center at Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, IL
| | - Megan Levings
- Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Josh Levitsky
- Department of Medicine, Northwestern University, Chicago, IL
| | - Giovanna Lombardi
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Science, King's College London, London, UK
| | | | - James Mathew
- Departments of Surgery and Microbiology-Immunology, Comprehensive Transplant Center, Northwestern University, Chicago, IL
| | - Aurélie Moreau
- INSERM, Nantes Université, CHU Nantes, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Petra Reinke
- Charité - Universitätsmedizin Berlin, Berlin Center for Advanced Therapies (BeCAT), Berlin, Germany
| | - Leonardo V Riella
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - David Sachs
- Department of Surgery, Massachusetts General Hospital, Harvard University, Boston, MA
- Medical School, Harvard University, Boston, MA
- Columbia Center of Translational Immunology, Columbia University Medical Center, New York, NY
| | | | | | - Megan Sykes
- Columbia Center for Translational Immunology, Departments of Medicine, Surgery, and Microbiology and Immunology, Columbia University, New York, NY
| | - Qizhi Tang
- Department of Surgery, Diabetes Center, University of California, San Francisco, CA
| | - Angus Thomson
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Timothy Tree
- Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Piotr Trzonkowski
- Medical University of Gdansk, Department of Medical Immunology, Gdansk, Poland
| | - Koichiro Uchida
- Juntendo University Center for Immunotherapy and Diagnosis, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Jeffrey Veale
- Department of Urology, University of California, Los Angeles, CA
| | - Josh Weiner
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY
| | - Thomas Wekerle
- Division of Transplantation, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Fadi Issa
- Translational Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
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Iesari S, Nava FL, Zais IE, Coubeau L, Ferraresso M, Favi E, Lerut J. Advancing immunosuppression in liver transplantation: A narrative review. Hepatobiliary Pancreat Dis Int 2024; 23:441-448. [PMID: 38523030 DOI: 10.1016/j.hbpd.2024.03.001] [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: 03/14/2024] [Indexed: 03/26/2024]
Abstract
Immunosuppression is essential to ensure recipient and graft survivals after liver transplantation (LT). However, our understanding and management of the immune system remain suboptimal. Current immunosuppressive therapy cannot selectively inhibit the graft-specific immune response and entails a significant risk of serious side effects, i.e., among others, de novo cancers, infections, cardiovascular events, renal failure, metabolic syndrome, and late graft fibrosis, with progressive loss of graft function. Pharmacological research, aimed to develop alternative immunosuppressive agents in LT, is behind other solid-organ transplantation subspecialties, and, therefore, the development of new compounds and strategies should get priority in LT. The research trajectories cover mechanisms to induce T-cell exhaustion, to inhibit co-stimulation, to mitigate non-antigen-specific inflammatory response, and, lastly, to minimize the development and action of donor-specific antibodies. Moreover, while cellular modulation techniques are complex, active research is underway to foster the action of T-regulatory cells, to induce tolerogenic dendritic cells, and to promote the function of B-regulatory cells. We herein discuss current lines of research in clinical immunosuppression, particularly focusing on possible applications in the LT setting.
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Affiliation(s)
- Samuele Iesari
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy
| | - Francesca Laura Nava
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy
| | - Ilaria Elena Zais
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy
| | - Laurent Coubeau
- Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, 10 Avenue Hippocrate, 1200 Brussels, Belgium; Service de Chirurgie et Transplantation Abdominale, Cliniques Universitaires Saint-Luc, 55 Avenue Hippocrate, 1200 Brussels, Belgium
| | - Mariano Ferraresso
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 19 Via della Commenda, 20122 Milan, Italy
| | - Evaldo Favi
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 19 Via della Commenda, 20122 Milan, Italy.
| | - Jan Lerut
- Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, 10 Avenue Hippocrate, 1200 Brussels, Belgium
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Wang B, Zhou A, Wu Y, Pan Q, Wei X, Gao Y, Xiao W, Jin J, Zhou T, Luo Y, Zhan Z, Liu Y, Gao W, Liu Y, Xia Q. Establishment and validation of a predictive model of immune tolerance after pediatric liver transplantation: a multicenter cohort study. Int J Surg 2024; 110:5615-5626. [PMID: 38833360 PMCID: PMC11392161 DOI: 10.1097/js9.0000000000001671] [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: 01/25/2024] [Accepted: 05/09/2024] [Indexed: 06/06/2024]
Abstract
Background: Side-effect of life-long immunosuppressants (IS) administration is a major obstacle for the long-term survival of pediatric liver transplantation (LT) recipients. Immunotolerance is the status that recipients discontinued IS with normal liver function and intrahepatic histology. So far, only a few clinical parameters were identified related with tolerance but failed to accurately discriminate tolerant recipients in clinical practice. Here, the authors aimed to provide a comprehensive view of pre-LT and post-LT risk factors associated with the achievement of tolerance after pediatric LT and established a tolerance predictive nomogram (ITPLT) with high accuracy and specificity. Methods: The authors enrolled 2228 pediatric recipients who received LT in Renji Hospital between October 2006 and December 2020. All participants survived over 3 years after transplantation with comprehensive and intact medical history and follow-up data. They were randomly assigned to training and validation cohorts in accordance with a ratio of 1:1. Univariate and multivariable Logistic regression were used to identify clinical factors associated with post-LT immune tolerance and establish a predictive model. The model was further validated in an independent external validation cohort from Tianjin First Central Hospital. Results: Among all participants, 6% recipients successfully tapered IS with intact allograft function. The most common reason for IS discontinuity was pneumonia. Univariate analysis identified 15 clinical factors associated with tolerance achievement, including age at LT, follow-up time, preoperative total bilirubin, creatinine, INR, CYP polymorphism, types of transplantation, massive postoperative ascites, episodes of acute rejection, and the severity of EBV and CMV infection. Using multivariable Logistic regression, the authors established the predictive ITPLT model for post-LT tolerance, which included seven easily accessible clinical factors (age at LT, CYP3A5 genotype, types of transplantation, post-LT massive ascites, preoperative INR, creatinine, and total bilirubin levels). Then, the authors visualized the model using nomogram. The c -statistics for predicting tolerance achievement in the training, internal validation, and external validation cohorts were 0.854, 0.787, and 0.746, respectively. Conclusion: Multiple pre-LT and post-LT clinical factors affected the process of immune remodeling after pediatric LT. The predictive ITPLT model, composed of seven easily accessible clinical factors, could comprehensively reveal the effect of these clinical parameters on immune remodeling and accurately identify tolerant recipients after pediatric LT. The application of ITPLT could facilitate the individualized IS strategy in the future.
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Affiliation(s)
- Bingran Wang
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Aiwei Zhou
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Yichi Wu
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Qi Pan
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Xinzhe Wei
- Department of Pediatric Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin
| | - Yunmu Gao
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Wanglong Xiao
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Jing Jin
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Tao Zhou
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Yi Luo
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | | | - Yongbo Liu
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
- Shanghai Institute of Transplantation
| | - Wei Gao
- Department of Pediatric Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin
| | - Yuan Liu
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
- Shanghai Immune Therapy Institute
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
- Shanghai Institute of Transplantation
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, People’s Republic of China
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Chapin CA, Whitehead B, Shakhin V, Taylor SA, Kriegermeier A, Mohammad S, Alonso EM. Immunosuppression minimization is safe and associated with good long-term success in pediatric recipients of liver transplant. Liver Transpl 2024; 30:707-716. [PMID: 37934051 DOI: 10.1097/lvt.0000000000000300] [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: 08/18/2023] [Accepted: 11/02/2023] [Indexed: 11/08/2023]
Abstract
Immunosuppression reduction after liver transplant is an important strategy to mitigate long-term medication side effects. We describe our center's experience with immunosuppression minimization to once-daily calcineurin inhibitor dosing. Success was defined as continuing daily calcineurin inhibitor monotherapy with normal transaminases and no rejection. We performed a retrospective review of eligible children who received a liver transplant between 2009 and 2016, had a surveillance biopsy, and were on twice-daily calcineurin inhibitor monotherapy. Twenty-eight of 51 eligible patients were minimized to daily calcineurin inhibitor with goal 12-hour trough detectable. Nineteen patients (68%) had 1-year success, and 17 (61%) had long-term success at a median follow-up of 5.0 years (interquartile range (IQR): 2.9-6.6). Minimization failure occurred at a median of 0.6 years (IQR: 0.3-1.0) after dose reduction. Patients with long-term success had lower aspartate aminotransferase levels prior to minimization compared to those who failed with a median of 28.0 IU/L (IQR: 20.5-32.0) versus 32.0 IU/L (IQR: 30.0-37.0), p = 0.047. The long-term success group demonstrated a trend toward greater recipients of liver transplant from living donors (53% vs. 18%, p = 0.07). At the time of the last follow-up at a median of 5.0 years (IQR: 2.9-6.1) after surveillance biopsy, most (73%) patients who failed had returned to twice-daily calcineurin inhibitor monotherapy, all had liver enzymes <2 times the upper limit of normal, and there were no patient deaths or graft losses. In conclusion, immunosuppression minimization is safe in pediatric recipients of liver transplant and should be considered to reduce long-term medication side effects and improve patient quality of life. Future studies are necessary to follow long-term outcomes and develop biomarkers to predict minimization success.
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Affiliation(s)
- Catherine A Chapin
- Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
| | - Bridget Whitehead
- Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
| | - Victoria Shakhin
- Department of Pediatrics, University of Michigan Health System, University of Michigan, C.S. Mott Children's Hospital, Ann Arbor, Michigan, USA
| | - Sarah A Taylor
- Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Alyssa Kriegermeier
- Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
| | - Saeed Mohammad
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Estella M Alonso
- Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
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Norman DJ, Enestvedt CK, Naugler WE, Erhan R, Shaut CA. The fate of anti-HLA antibodies following liver transplantation. FRONTIERS IN NEPHROLOGY 2024; 4:1403096. [PMID: 38933742 PMCID: PMC11199851 DOI: 10.3389/fneph.2024.1403096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 05/13/2024] [Indexed: 06/28/2024]
Abstract
Introduction Liver transplant recipients may have pre-formed anti-HLA antibodies directed to mismatched HLA of the liver donor (donor specific antibodies, DSA) or not directed to the liver donor (non-donor specific, non-DSA). We observed the fate of these antibodies (DSA and non-DSA) at 12 months after transplant. Methods Patients transplanted between 4/2015 and 12/2018 (N = 216) who had anti-HLA antibody measurements at both transplant and 12 months posttransplant (N = 124) and with DSAs at transplant (N = 31) were considered informative for a paired analysis of the natural history of DSA and non-DSA following liver transplantation. Results Class I DSAs and non-DSAs decreased between transplant and 12 months; however, Class I DSAs essentially disappeared by 12 months while Class I non-DSAs did not. Anti-HLA Class II DSAs performed differently. While there was a significant drop in values between transplant and 12 months, these antibodies mostly persisted at a low level. Discussion Our study demonstrated a significant difference in the kinetics of DSA compared to non-DSA following liver transplantation, most profoundly for anti-HLA Class I antibodies. Class I DSAs were mostly absent at 12 months while Class II DSAs persisted, although at lower levels. The mechanisms of reduction in anti-HLA antibodies following liver transplantation are not completely understood and were not pursued as a part of this study. This detailed analysis of Class I and Class II DSAs and non-DSAs represents and important study to explore the change in antibodies at one year from liver transplantation.
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Affiliation(s)
- Douglas J. Norman
- Laboratory of Immunogenetics and Transplantation, Oregon Health & Science University, Portland, OR, United States
- Section of Transplantation Medicine, Division of Nephrology, Department of Medicine, Oregon Health & Science University, Portland, OR, United States
| | - C. Kristian Enestvedt
- Division of Abdominal Organ Transplantation, Department of Surgery, Oregon Health & Science University, Portland, OR, United States
| | - Willscott E. Naugler
- Division of Gastroenterology and Hepatology, Department of Medicine, Oregon Health & Science University, Portland, OR, United States
| | - Rouella Erhan
- Laboratory of Immunogenetics and Transplantation, Oregon Health & Science University, Portland, OR, United States
| | - Carley A. Shaut
- Laboratory of Immunogenetics and Transplantation, Oregon Health & Science University, Portland, OR, United States
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von Scheidt W, Reichart B, Meiser B, von Scheidt M, Sen P, Schwarz F, Harmel E, Bengel FM, Dick A, Ueberfuhr P, Reichenspurner H, Jaeckel E, Schwinzer R, Hagl C. Unique 40-year survival after heart transplantation with normal graft function and spontaneous operational tolerance. Clin Res Cardiol 2024; 113:661-671. [PMID: 37982861 PMCID: PMC11026283 DOI: 10.1007/s00392-023-02341-x] [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: 10/03/2023] [Accepted: 11/07/2023] [Indexed: 11/21/2023]
Abstract
Unique 40-year survival after heart transplantation with normal graft function and spontaneous operational tolerance.
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Affiliation(s)
- Wolfgang von Scheidt
- I.Medizinische Klinik, University Hospital Augsburg, University of Augsburg, Stenglinstr. 2, 86156, Augsburg, Germany.
- Ludwig-Maximilians-University Munich, Munich, Germany.
| | - Bruno Reichart
- Department of Cardiac Surgery, University Hospital Großhadern, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Bruno Meiser
- Transplant Center, University Hospital Großhadern, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Moritz von Scheidt
- Department of Cardiovascular Diseases, German Heart Center Munich, Technical University Munich, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Partho Sen
- Department of Cardiovascular Diseases, German Heart Center Munich, Technical University Munich, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Florian Schwarz
- Ludwig-Maximilians-University Munich, Munich, Germany
- Department of Diagnostic and Interventional Radiology, University Hospital Augsburg, University of Augsburg, Augsburg, Germany
| | - Eva Harmel
- I.Medizinische Klinik, University Hospital Augsburg, University of Augsburg, Stenglinstr. 2, 86156, Augsburg, Germany
| | - Frank M Bengel
- Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany
| | - Andrea Dick
- Laboratory for Immunogenetics and Molecular Diagnostics, University Hospital Großhadern, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Peter Ueberfuhr
- Department of Cardiac Surgery, University Hospital Großhadern, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Hermann Reichenspurner
- Department of Cardiovascular Surgery, University Heart and Vascular Center Hamburg, Hamburg, Germany
| | - Elmar Jaeckel
- Ajmera Transplant Center, UHN, University of Toronto, Toronto, Canada
| | - Reinhard Schwinzer
- Department of General-, Visceral- and Transplantation-Surgery, Hannover Medical School, Hannover, Germany
| | - Christian Hagl
- Department of Cardiac Surgery, University Hospital Großhadern, Ludwig-Maximilians-University Munich, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
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Kortbeek S, Anderson SG, Alonso EM, Rand EB, Bucuvalas J, Mazariegos GV, Campbell KM, Lobritto SJ, Feldman AG, Mysore KR, Anand R, Selzner N, Ng VL. Immunosuppression-Free Life after Pediatric Liver Transplant: A Case-Control Study from the Society of Pediatric Liver Transplant (SPLIT) Registry. J Pediatr 2024; 264:113744. [PMID: 37726087 DOI: 10.1016/j.jpeds.2023.113744] [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: 05/12/2023] [Revised: 08/29/2023] [Accepted: 09/13/2023] [Indexed: 09/21/2023]
Abstract
OBJECTIVE To compare long-term outcomes of pediatric liver transplant (LT) recipients off immunosuppression (IS) with matched controls on IS using data from the Society of Pediatric Liver Transplant (SPLIT) registry. STUDY DESIGN This was a retrospective case-control study. SPLIT participants <18 years of age, ≥4 years after isolated LT, and off IS for ≥1 year (cases) were age- and sex-matched 1:2 to patients with the same primary diagnosis and post-LT follow-up duration (controls). Primary outcomes included retransplantation, allograft rejection, IS comorbidities, and prevalence of SPLIT-derived composite ideal outcome (c-IO) achieved at the end of the follow-up period. Differences were compared using multiple linear regression for continuous outcomes and logistic regression for dichotomous data. RESULTS The study cohort was composed of 33 cases (42.4% male, 60.6% biliary atresia, median age at LT of 0.7 [P25, P75, 0.5, 1.6] years, median IS withdrawal time of 9 [P25, P75, 6, 12] years after LT) and 66 age- and sex-matched controls. No cases required retransplantation. Cases and controls had similar growth parameters, laboratory values, calculated glomerular filtration rates, rates of post-transplant lymphoproliferative disease, graft rejection, and attainment of c-IO. CONCLUSIONS No differences in allograft rejection rates, IS complications, or c-IO prevalence were seen between SPLIT patients off IS and age- and sex-matched controls remaining on IS. Discontinuation of IS most commonly occurred in the context of rigorously designed IS withdrawal trials. The available sample size was small, affecting generalizability to the broader pediatric LT population.
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Affiliation(s)
- Simone Kortbeek
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Alberta Children's Hospital, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | | | - Estella M Alonso
- Division of Gastroenterology, Hepatology, and Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Elizabeth B Rand
- Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA
| | - John Bucuvalas
- Division of Pediatric Hepatology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - George V Mazariegos
- Division of Transplantation Surgery, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Kathleen M Campbell
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Steven J Lobritto
- Division of Gastroenterology, Hepatology, and Nutrition, Columbia University Irving Medical Center, New York, NY
| | - Amy G Feldman
- Division of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO
| | - Krupa R Mysore
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX
| | | | - Nazia Selzner
- Ajmera Transplant Center, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Vicky L Ng
- Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Transplant and Regenerative Medicine Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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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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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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10
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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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11
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Zhang Z, Zhao S, Si Z, Wang Z, Dong C, Sun C, Zheng W, Kai W, Zhang W, Song Z, Gao W, Shen Z. Incidence and risk factors of subclinical rejection after pediatric liver transplantation, and impact on allograft fibrosis. Clin Transplant 2023; 37:e14894. [PMID: 36581321 DOI: 10.1111/ctr.14894] [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: 09/29/2022] [Revised: 12/12/2022] [Accepted: 12/24/2022] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Subclinical rejection (SCR) is a common injury in protocol biopsy after pediatric liver transplantation (pLT), but its effect on the recipient is not clearly understood. We herein investigated the incidence and risk factors involved in SCR and analyzed the relationship between SCR and allograft fibrosis (AF). METHODS We retrospectively reviewed the biopsy results from 507 children between May 2013 and May 2019, and 352 patients underwent protocol biopsy 2 years after pLT, 203 underwent protocol biopsy 5 years after pLT, and 48 underwent protocol biopsy both 2 and 5 years after pLT. RESULTS The incidence of SCR in the 5-year group was higher than that in the 2-year group (20.2% vs.13.4%, respectively, p = .033). The number of patients with mild and moderate SCR in the 5-year group was also higher than that in the 2-year group (p = .039). Logistic regression analysis showed that acute rejection before liver biopsy and deceased donor liver transplantation (DDLT) were independent risk factors for SCR in the two groups, and that the incidence and severity of AF in protocol biopsies at both periods in the SCR group were higher than those in the non-SCR group (p < .05). CONCLUSIONS The incidence and severity of SCR increased with the prolongation of protocol biopsy time. We postulate that acute rejection and DDLT are independent risk factors for SCR after transplantation. As the occurrence of SCR also augmented the incidence and severity of AF.
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Affiliation(s)
- Zhixin Zhang
- First Central Clinic Institute, Tianjin Medical University, Tianjin, China
| | - Shengqiao Zhao
- First Central Clinic Institute, Tianjin Medical University, Tianjin, China
| | - Zhuyuan Si
- First Central Clinic Institute, Tianjin Medical University, Tianjin, China
| | - Zhenglu Wang
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Chong Dong
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Chao Sun
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Weiping Zheng
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Wang Kai
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Wei Zhang
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Zhuolun Song
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Wei Gao
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Zhongyang Shen
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
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12
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Clinical recommendations for posttransplant assessment of anti-HLA (Human Leukocyte Antigen) donor-specific antibodies: A Sensitization in Transplantation: Assessment of Risk consensus document. Am J Transplant 2023; 23:115-132. [PMID: 36695614 DOI: 10.1016/j.ajt.2022.11.013] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 10/29/2022] [Accepted: 11/04/2022] [Indexed: 01/13/2023]
Abstract
Although anti-HLA (Human Leukocyte Antigen) donor-specific antibodies (DSAs) are commonly measured in clinical practice and their relationship with transplant outcome is well established, clinical recommendations for anti-HLA antibody assessment are sparse. Supported by a careful and critical review of the current literature performed by the Sensitization in Transplantation: Assessment of Risk 2022 working group, this consensus report provides clinical practice recommendations in kidney, heart, lung, and liver transplantation based on expert assessment of quality and strength of evidence. The recommendations address 3 major clinical problems in transplantation and include guidance regarding posttransplant DSA assessment and application to diagnostics, prognostics, and therapeutics: (1) the clinical implications of positive posttransplant DSA detection according to DSA status (ie, preformed or de novo), (2) the relevance of posttransplant DSA assessment for precision diagnosis of antibody-mediated rejection and for treatment management, and (3) the relevance of posttransplant DSA for allograft prognosis and risk stratification. This consensus report also highlights gaps in current knowledge and provides directions for clinical investigations and trials in the future that will further refine the clinical utility of posttransplant DSA assessment, leading to improved transplant management and patient care.
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13
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Sood V, Lal BB, Ashwini N, Khanna R, Pamecha V, Trehanpati N, Alam S. Operational Tolerance after Liver Transplantation: First Report from India. J Clin Exp Hepatol 2023; 13:178-181. [PMID: 36647413 PMCID: PMC9840074 DOI: 10.1016/j.jceh.2022.09.002] [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: 07/25/2022] [Accepted: 09/08/2022] [Indexed: 01/19/2023] Open
Abstract
Operational tolerance after liver transplantation is an ideal goal to avoid long-term morbidities associated with chronic immunosuppressive medication use. It is achievable in a highly selected group of post-transplant recipients but requires long-term follow-up and strict monitoring. We hereby report a post-transplant case who achieved spontaneous operational tolerance after inadvertent immunosuppression withdrawal.
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Affiliation(s)
- Vikrant Sood
- Department of Pediatric Hepatology, New Delhi 110070, India
| | - Bikrant B. Lal
- Department of Pediatric Hepatology, New Delhi 110070, India
| | - N.S. Ashwini
- Department of Hepatopathology, New Delhi 110070, India
| | - Rajeev Khanna
- Department of Pediatric Hepatology, New Delhi 110070, India
| | - Viniyendra Pamecha
- Department of Hepato-pancreato-biliary Surgery and Liver Transplantation, New Delhi 110070, India
| | - Nirupama Trehanpati
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi 110070, India
| | - Seema Alam
- Department of Pediatric Hepatology, New Delhi 110070, India
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14
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Taner T, Bruner J, Emaumaullee J, Bonaccorsi-Riani E, Zarrinpar A. New Approaches to the Diagnosis of Rejection and Prediction of Tolerance in Liver Transplantation. Transplantation 2022; 106:1952-1962. [PMID: 35594482 PMCID: PMC9529763 DOI: 10.1097/tp.0000000000004160] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Immunosuppression after liver transplantation is essential for preventing allograft rejection. However, long-term drug toxicity and associated complications necessitate investigation of immunosuppression minimization and withdrawal protocols. Development of such protocols is hindered by reliance on current paradigms for monitoring allograft function and rejection status. The current standard of care for diagnosis of rejection is histopathologic assessment and grading of liver biopsies in accordance with the Banff Rejection Activity Index. However, this method is limited by cost, sampling variability, and interobserver variation. Moreover, the invasive nature of biopsy increases the risk of patient complications. Incorporating noninvasive techniques may supplement existing methods through improved understanding of rejection causes, hepatic spatial architecture, and the role of idiopathic fibroinflammatory regions. These techniques may also aid in quantification and help integrate emerging -omics analyses with current assessments. Alternatively, emerging noninvasive methods show potential to detect and distinguish between different types of rejection while minimizing risk of adverse advents. Although biomarkers have yet to replace biopsy, preliminary studies suggest that several classes of analytes may be used to detect rejection with greater sensitivity and in earlier stages than traditional methods, possibly when coupled with artificial intelligence. Here, we provide an overview of the latest efforts in optimizing the diagnosis of rejection in liver transplantation.
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Affiliation(s)
- Timucin Taner
- Departments of Surgery & Immunology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Julia Bruner
- Department of Surgery, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Juliet Emaumaullee
- Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Eliano Bonaccorsi-Riani
- Abdominal Transplant Unit, Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Ali Zarrinpar
- Department of Surgery, College of Medicine, University of Florida, Gainesville, FL, USA
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15
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Wozniak LJ, Venick RS, Naini BV, Scapa J, Hickey MJ, Rossetti M, Korin Y, Reed EF, Farmer DG, Busuttil RW, Vargas JH, McDiarmid SV. Operational tolerance is not always permanent: A 10-year prospective study in pediatric liver transplantation recipients. Liver Transpl 2022; 28:1640-1650. [PMID: 35395132 DOI: 10.1002/lt.26474] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/03/2022] [Accepted: 03/02/2022] [Indexed: 12/25/2022]
Abstract
Immunosuppression withdrawal can be safely performed in select liver transplantation recipients, but the long-term outcomes and sustainability of tolerance have not been well studied. We completed a 10-year prospective, observational study of 18 pediatric liver transplantation recipients with operational tolerance to (1) assess the sustainability of tolerance over time, (2) compare the clinical characteristics of patients who maintained versus lost tolerance, (3) characterize liver histopathology findings in surveillance liver biopsies; and (4) describe immunologic markers in patients with tolerance. Comparator patients from two clinical phenotype groups termed "stable" and "nontolerant" patients were used as controls. Of the 18 patients with operational tolerance, the majority of patients were males (n = 14, 78%) who were transplanted for cholestatic liver disease (n = 12, 67%). Median age at transplantation was 1.9 (range, 0.6-8) years. Median time after transplantation that immunosuppression had been discontinued was 13.1 (range, 2.9-22.1) years. As many as 11 (61%) maintained tolerance for a median of 10.4 (range, 1.9-22.1) years, whereas 7 (39%) lost tolerance after a median of 3.2 (range, 1.5-18.6) years. Populations of T regulatory cells (%CD4+ CD25hi CD127lo ) were significantly higher in patients with tolerance (p = 0.02). Our results emphasize that spontaneous operational tolerance is a dynamic and nonpermanent state. It is therefore essential for patients who are clinically stable off immunosuppression to undergo regular follow-up and laboratory monitoring, as well as surveillance biopsies to rule out subclinical rejection.
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Affiliation(s)
- Laura J Wozniak
- Pediatric Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Robert S Venick
- Pediatric Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.,Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Bita V Naini
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Jason Scapa
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Michelle J Hickey
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.,Immunogenetics Center, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - Maura Rossetti
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.,Immunogenetics Center, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - Yael Korin
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.,Immunogenetics Center, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - Elaine F Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.,Immunogenetics Center, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - Douglas G Farmer
- Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Ronald W Busuttil
- Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Jorge H Vargas
- Pediatric Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Sue V McDiarmid
- Pediatric Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.,Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
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16
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Duizendstra AA, De Knegt RJ, Nagtzaam NMA, Betjes MGH, Dik WA, Litjens NHR, Kwekkeboom J. Minimal Development of Liver Fibrosis in Adult Tolerant Liver Transplant Recipients Late After Immunosuppressive Drug Weaning and Transplantation. Transplant Proc 2022; 54:1874-1880. [PMID: 36100485 DOI: 10.1016/j.transproceed.2022.04.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 04/13/2022] [Indexed: 10/14/2022]
Abstract
BACKGROUND Operationally tolerant liver transplant (LTx)-recipients can be weaned off immunosuppressive (IS) drugs without development of graft rejection. However, it is feared that liver fibrosis might develop after complete IS weaning. The purpose of this small single-center study was to assess liver fibrosis in adult tolerant LTx recipients long after LTx and IS weaning. METHODS Liver fibrosis was assessed in adult tolerant LTx-recipients (n = 9) using noninvasive transient elastography and measurements of multiple pro- and antifibrotic serum markers associated with liver fibrosis. The data was collected for 2 subsequent years; 8 and 9 years after IS weaning and 19 and 20 years after transplantation. Healthy individuals (n = 9) matched for age and sex were included as a reference for fibrosis-related serum markers. This study was conducted in accordance with the Declaration of Helsinki and approved by the medical ethics committee of our institution. RESULTS Transient elastography indicated that 7 of 9 tolerant LTx recipients had no or minimal liver fibrosis (F0-F1), whereas 2 recipients had moderate or severe liver fibrosis (F2-F3). Most fibrosis-related serum markers in tolerant LTx recipients were within or close to the range obtained for healthy individuals. CONCLUSIONS The results from this small, single-center study indicated that most adult tolerant LTx recipients have no or minimal liver graft fibrosis long after transplantation and IS weaning, and their fibrosis-related serum marker profile indicates an absence of a profibrotic status.
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Affiliation(s)
- Aafke A Duizendstra
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Robert J De Knegt
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Nicole M A Nagtzaam
- Laboratory of Medical Immunology, Department of Immunology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Michiel G H Betjes
- Erasmus MC Transplant Institute, Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Willem A Dik
- Laboratory of Medical Immunology, Department of Immunology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Nicolle H R Litjens
- Erasmus MC Transplant Institute, Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Jaap Kwekkeboom
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
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17
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Barbetta A, Meeberg G, Rocque B, Barhouma S, Weaver C, Gilmour S, Faytrouni F, Guttman O, Zielsdorf S, Etesami K, Kwon Y, Yanni G, Campbell P, Shapiro J, Emamaullee J. Immunologic benefits of maternal living donor allografts in pediatric liver transplantation: fewer rejection episodes and no evidence of de novo allosensitization. Pediatr Transplant 2022; 26:e14197. [PMID: 34806273 PMCID: PMC9053650 DOI: 10.1111/petr.14197] [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: 08/27/2021] [Revised: 10/23/2021] [Accepted: 11/10/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Pediatric liver transplant (LT) recipients of maternal living liver donor (LLD) grafts have been reported to experience fewer rejection episodes. However, it is unclear whether this benefit translates to reduction in developing donor-specific antibody (DSA) among maternal-LLD recipients. The aim of this study was to compare immunologic outcomes among maternal-LLD, non-maternal-LLD, and deceased donor liver transplant (DDLT) recipients. METHODS Children (≤18 years) who underwent LT between 1/1998 and 12/2019 at two high-volume LT centers in North America were evaluated. Patients were divided into three groups by type of graft received (maternal-LLD, non-maternal LLD, and DDLT). Clinical variables and outcomes were compared according to each graft type. RESULTS A total of 450 pediatric primary LT were analyzed: 275 (61.1%) DDLT, 73 (16.2%) maternal-LLD, and 102 (22.6%) non-maternal-LLD. Children receiving LLD grafts were less likely to develop rejection when compared to the DDLT group (DDLT 46.9% vs. maternal-LLD 31.5% vs. non-maternal-LLD 28.4%, p = 0.001). There was no difference in rejection rates between maternal and non-maternal-LLD recipients. A higher percentage of maternal-LLD recipients were on immunosuppression monotherapy compared to non-maternal-LLD and DDLT recipients (6.7% vs. 1.2 vs. 2.4%, respectively). A subgroup of 68 patients were tested for DSA post-LT. Maternal-LLD recipients were less likely to develop de novo DSA (maternal-LLD 11.8% vs. non-maternal-LLD 19.3% vs. DDLT 43%, p = 0.018). None of the maternal-LLD recipients developed antibody-mediated rejection. CONCLUSIONS These data support the concept of immunologic benefit of maternal-LLD in pediatric LT, with lower rates of rejection and allosensitization post-LT when compared to DDLT recipients.
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Affiliation(s)
- Arianna Barbetta
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, Los Angeles, CA, USA
| | | | - Brittany Rocque
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, Los Angeles, CA, USA
| | | | - Carly Weaver
- Division of Hepatobiliary and Abdominal Organ Transplantation Surgery, Children’s Hospital-Los Angeles, Los Angeles, CA USA
| | | | - Farah Faytrouni
- Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
| | - Orlee Guttman
- Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
| | - Shannon Zielsdorf
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, Los Angeles, CA, USA,University of Southern California, Los Angeles, CA, USA,Division of Hepatobiliary and Abdominal Organ Transplantation Surgery, Children’s Hospital-Los Angeles, Los Angeles, CA USA
| | - Kambiz Etesami
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, Los Angeles, CA, USA,University of Southern California, Los Angeles, CA, USA,Division of Hepatobiliary and Abdominal Organ Transplantation Surgery, Children’s Hospital-Los Angeles, Los Angeles, CA USA
| | - Yong Kwon
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, Los Angeles, CA, USA,University of Southern California, Los Angeles, CA, USA,Division of Hepatobiliary and Abdominal Organ Transplantation Surgery, Children’s Hospital-Los Angeles, Los Angeles, CA USA
| | - George Yanni
- University of Southern California, Los Angeles, CA, USA,Department of Pediatrics, Children’s Hospital-Los Angeles, Los Angeles, CA USA
| | - Patricia Campbell
- Alberta Transplant Institute, Edmonton, AB, Canada,Departemtent of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | | | - Juliet Emamaullee
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, Los Angeles, CA, USA,University of Southern California, Los Angeles, CA, USA,Division of Hepatobiliary and Abdominal Organ Transplantation Surgery, Children’s Hospital-Los Angeles, Los Angeles, CA USA
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18
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Ung N, Goldbeck C, Man C, Hoeflich J, Sun R, Barbetta A, Matasci N, Katz J, Lee JSH, Chopra S, Asgharzadeh S, Warren M, Sher L, Kohli R, Akbari O, Genyk Y, Emamaullee J. Adaptation of Imaging Mass Cytometry to Explore the Single Cell Alloimmune Landscape of Liver Transplant Rejection. Front Immunol 2022; 13:831103. [PMID: 35432320 PMCID: PMC9009043 DOI: 10.3389/fimmu.2022.831103] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 03/08/2022] [Indexed: 12/14/2022] Open
Abstract
Rejection continues to be an important cause of graft loss in solid organ transplantation, but deep exploration of intragraft alloimmunity has been limited by the scarcity of clinical biopsy specimens. Emerging single cell immunoprofiling technologies have shown promise in discerning mechanisms of autoimmunity and cancer immunobiology. Within these applications, Imaging Mass Cytometry (IMC) has been shown to enable highly multiplexed, single cell analysis of immune phenotypes within fixed tissue specimens. In this study, an IMC panel of 10 validated markers was developed to explore the feasibility of IMC in characterizing the immune landscape of chronic rejection (CR) in clinical tissue samples obtained from liver transplant recipients. IMC staining was highly specific and comparable to traditional immunohistochemistry. A single cell segmentation analysis pipeline was developed that enabled detailed visualization and quantification of 109,245 discrete cells, including 30,646 immune cells. Dimensionality reduction identified 11 unique immune subpopulations in CR specimens. Most immune subpopulations were increased and spatially related in CR, including two populations of CD45+/CD3+/CD8+ cytotoxic T-cells and a discrete CD68+ macrophage population, which were not observed in liver with no rejection (NR). Modeling via principal component analysis and logistic regression revealed that single cell data can be utilized to construct statistical models with high consistency (Wilcoxon Rank Sum test, p=0.000036). This study highlights the power of IMC to investigate the alloimmune microenvironment at a single cell resolution during clinical rejection episodes. Further validation of IMC has the potential to detect new biomarkers, identify therapeutic targets, and generate patient-specific predictive models of clinical outcomes in solid organ transplantation.
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Affiliation(s)
- Nolan Ung
- Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, United States
| | - Cameron Goldbeck
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Cassandra Man
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Julianne Hoeflich
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Ren Sun
- Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, United States
| | - Arianna Barbetta
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Naim Matasci
- Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, United States
| | - Jonathan Katz
- Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, United States
| | - Jerry S. H. Lee
- Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Chemical Engineering and Material Sciences, University of Southern California, Los Angeles, CA, United States
| | - Shefali Chopra
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pathology, University of Southern California, Los Angeles, CA, United States
| | - Shahab Asgharzadeh
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital-Los Angeles, Los Angeles, CA, United States
| | - Mika Warren
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pathology, Children’s Hospital-Los Angeles, Los Angeles, CA, United States
| | - Linda Sher
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Rohit Kohli
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital-Los Angeles, Los Angeles, CA, United States
| | - Omid Akbari
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
| | - Yuri Genyk
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Juliet Emamaullee
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
- *Correspondence: Juliet Emamaullee,
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19
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Tang Y, Chen J, Chen B, Guo C. Clinical characteristics of immune tolerance after pediatric liver transplantation. BMC Surg 2022; 22:102. [PMID: 35305597 PMCID: PMC8933983 DOI: 10.1186/s12893-021-01402-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 11/10/2021] [Indexed: 12/13/2022] Open
Abstract
Abstract
Background
Clinical operational tolerance is the ultimate goal for liver transplantation. This study aimed to investigate the clinical characteristics of immune tolerance after pediatric liver transplantation and to identify the possible predictors.
Methods
The clinical data from 37 cases of pediatric patients 2 year later after liver transplantation surgery in the Children’s Hospital of Chongqing Medical University, China, were retrospectively analyzed. According to the status of the current immunosuppressant medications of the patients, they were divided into tolerance (n = 15) and Control (n = 22) groups. The current status regarding prope/operational tolerance was reviewed and screened based on the immunosuppressant medications.
Results
The patients in the tolerance group were younger than that of Controls (p < 0.001). The children in the tolerance group experienced no acute rejection episode and exhibited no obvious abnormalities in the liver function during the continuous follow-up period. The primary disease of the tolerance group were more often diagnosed with biliary atresia (p = 0.011), and received with a living donor liver graft (p = 0.005). There were less glomerular function, diabetes mellitus, arterial hypertension events presented in the tolerance group compared with the control group, indicating low toxicity profile.
Conclusion
In the current study, there were really certain quantity of recipients following liver transplantation attained long term immune tolerance, with low toxicity and satisfied liver graft function. The younger age of the recipient and maternal donor seems to promote long-term clinical immune tolerance. Further work in larger series should be required to describe the overall perspective of tolerance.
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20
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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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21
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Saunders EA, Engel B, Höfer A, Hartleben B, Vondran FWR, Richter N, Potthoff A, Zender S, Wedemeyer H, Jaeckel E, Taubert R. Outcome and safety of a surveillance biopsy guided personalized immunosuppression program after liver transplantation. Am J Transplant 2022; 22:519-531. [PMID: 34455702 DOI: 10.1111/ajt.16817] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 08/08/2021] [Accepted: 08/19/2021] [Indexed: 01/25/2023]
Abstract
Graft survival beyond year 1 has not changed after orthotopic liver transplantation (OLT) over the last decades. Likewise, OLT causes comorbidities such as infection, renal impairment and cancer. We evaluated our single-center real-world individualized immunosuppression program after OLT, based on 211 baseline surveillance biopsies (svLbx) without any procedural complications. Patients were classified as low, intermediate and high rejection risk based on graft injury in svLbx and anti-HLA donor-specific antibodies. While 32% of patients had minimal histological inflammation, 57% showed histological inflammation and 23% advanced fibrosis (>F2), which was not predicted by lab parameters. IS was modified in 79% of patients after svLbx. After immunosuppression reduction in 69 patients, only 5 patients showed ALT elevations and three of these patients had a biopsy-proven acute rejection, two of them related to lethal comorbidities. The rate of liver enzyme elevation including rejection was not significantly increased compared to a svLbx control cohort prior to the initiation of our structured program. Immunosuppression reduction led to significantly better kidney function compared to this control cohort. In conclusion, a biopsy guided personalized immunosuppression protocol after OLT can identify patients requiring lower immunosuppression or patients with graft injury in which IS should not be further reduced.
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Affiliation(s)
- Emily A Saunders
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Bastian Engel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Anne Höfer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Björn Hartleben
- Institute for Pathology, Hannover Medical School, Hannover, Germany
| | - Florian W R Vondran
- Department for General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Nicolas Richter
- Department for General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Andrej Potthoff
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Steffen Zender
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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22
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Duizendstra AA, de Knegt RJ, Mancham S, Klepper M, Roelen DL, Brand‐Schaaf SH, Boor PP, Doukas M, de Man RA, Sprengers D, Peppelenbosch MP, Betjes MGH, Kwekkeboom J, Litjens NHR. Activated CD4 + T Cells and Highly Differentiated Alloreactive CD4 + T Cells Distinguish Operationally Tolerant Liver Transplantation Recipients. Liver Transpl 2022; 28:98-112. [PMID: 34081828 PMCID: PMC9291234 DOI: 10.1002/lt.26188] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/20/2021] [Accepted: 05/31/2021] [Indexed: 02/06/2023]
Abstract
Spontaneous operational tolerance to the allograft develops in a proportion of liver transplantation (LT) recipients weaned off immunosuppressive (IS) drugs. Several studies have investigated whether peripheral blood circulating T cells could play a role in the development or identify operational tolerance, but never characterized alloreactive T cells in detail due to the lack of a marker for these T cells. In this study, we comprehensively investigated phenotypic and functional characteristics of alloreactive circulating T cell subsets in tolerant LT recipients (n = 15) using multiparameter flow cytometry and compared these with LT recipients on IS drugs (n = 23) and healthy individuals (n = 16). Activation-induced CD137 was used as a marker for alloreactive T cells upon allogenic stimulation. We found that central and effector memory CD4+ T cells were hyporesponsive against donor and third-party splenocyte stimulation in tolerant LT recipients, whereas an overall hyperresponsiveness was observed in alloreactive terminally differentiated effector memory CD4+ T cells. In addition, elevated percentages of circulating activated T helper cells were observed in these recipients. Lastly, tolerant and control LT recipients did not differ in donor-specific antibody formation. In conclusion, a combination of circulating hyperresponsive highly differentiated alloreactive CD4+ T cells and circulating activated T helper cells could discriminate tolerant recipients from a larger group of LT recipients.
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Affiliation(s)
- Aafke A. Duizendstra
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamthe Netherlands
| | - Robert J. de Knegt
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamthe Netherlands
| | - Shanta Mancham
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamthe Netherlands
| | - Mariska Klepper
- Erasmus MC Transplant Institute, Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC University Medical CenterRotterdamthe Netherlands
| | - Dave L. Roelen
- Department of Immunohematology and Blood TransfusionLeiden University Medical CenterLeidenthe Netherlands
| | - Simone H. Brand‐Schaaf
- Department of Immunohematology and Blood TransfusionLeiden University Medical CenterLeidenthe Netherlands
| | - Patrick P. Boor
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamthe Netherlands
| | - Michail Doukas
- Department of PathologyErasmus MC University Medical CenterRotterdamthe Netherlands
| | - Robert A. de Man
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamthe Netherlands
| | - Dave Sprengers
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamthe Netherlands
| | - Maikel P. Peppelenbosch
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamthe Netherlands
| | - Michiel G. H. Betjes
- Erasmus MC Transplant Institute, Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC University Medical CenterRotterdamthe Netherlands
| | - Jaap Kwekkeboom
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamthe Netherlands
| | - Nicolle H. R. Litjens
- Erasmus MC Transplant Institute, Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC University Medical CenterRotterdamthe Netherlands
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23
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Gu LH, Lv ZC, Wu HX, Hou YC, Gao RL, Xi ZF, Fang H, Feng H, Jiang LX, Xia Q. Two-Dimensional Shear Wave Elastography Evaluation of Post-transplantation Complications in Pediatric Receipt: A Retrospective Cohort. Front Pediatr 2022; 10:918145. [PMID: 35967551 PMCID: PMC9363609 DOI: 10.3389/fped.2022.918145] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 06/22/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND The 20-year survival rate in pediatric patients after liver transplantation (LT) was no more than 70%. Hepatic fibrosis is one of the principal factors affecting the long-term prognosis. Imaging evaluation was the first-line examination for pediatric liver graft assessment. However, the sensitivity and specificity were insufficient. Thus, two-dimensional shear wave elastography (2D-SWE) was performed to evaluate liver graft stiffness and complication in post-transplant pediatric receipt. MATERIALS AND METHODS In this retrospective cohort, 343 pediatric recipients who underwent liver graft biopsy in our tertiary LT center were recruited between June 2018 and December 2020. The 2D-SWE evaluation, laboratory examination, routine post-transplant biopsy, and hepatic pathological assessment were performed. RESULTS Ninety-eight of the 343 pediatric patients were included according to the protocol. The Liver Stiffness Measurements (LSM) value of 2D-SWE was significantly elevated in post-transplant fibrosis (p < 0.0001). The LSM value of patients with post-transplant biliary complications (p < 0.0001) and biopsy-proven rejection (BPR, p = 0.0016) also rose compared to regular recovery patients. Concerning the sensitivity and specificity of 2D-SWE in diagnosing liver graft fibrosis, the area under the ROC curve (AUC) was 88%, and the optimal cutoff value was 10.3 kPa. CONCLUSION Pediatric LSM by 2D-SWE was efficient. Routine 2D-SWE evaluation could be optimal to predict significant liver graft fibrosis.
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Affiliation(s)
- Li-Hong Gu
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Department of Ultrasound, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zi-Cheng Lv
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hao-Xiang Wu
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yu-Chen Hou
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Run-Lin Gao
- Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhi-Feng Xi
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hua Fang
- Department of Ultrasound, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hao Feng
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Engineering Research Centre of Transplantation and Immunology, Shanghai, China.,Shanghai Institute of Transplantation, Shanghai, China
| | - Li-Xin Jiang
- Department of Ultrasound, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Engineering Research Centre of Transplantation and Immunology, Shanghai, China.,Shanghai Institute of Transplantation, Shanghai, China
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24
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Angelico R, Sensi B, Manzia TM, Tisone G, Grassi G, Signorello A, Milana M, Lenci I, Baiocchi L. Chronic rejection after liver transplantation: Opening the Pandora’s box. World J Gastroenterol 2021; 27:7771-7783. [PMID: 34963740 PMCID: PMC8661381 DOI: 10.3748/wjg.v27.i45.7771] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/25/2021] [Accepted: 11/21/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic rejection (CR) of liver allografts causes damage to intrahepatic vessels and bile ducts and may lead to graft failure after liver transplantation. Although its prevalence has declined steadily with the introduction of potent immunosuppressive therapy, CR still represents an important cause of graft injury, which might be irreversible, leading to graft loss requiring re-transplantation. To date, we still do not fully appreciate the mechanisms underlying this process. In addition to T cell-mediated CR, which was initially the only recognized type of CR, recently a new form of liver allograft CR, antibody-mediated CR, has been identified. This has indeed opened an era of thriving research and renewed interest in the field. Liver biopsy is needed for a definitive diagnosis of CR, but current research is aiming to identify new non-invasive tools for predicting patients at risk for CR after liver transplantation. Moreover, the minimization or withdrawal of immunosuppressive therapy might influence the establishment of subclinical CR-related injury, which should not be disregarded. Therapies for CR may only be effective in the “early” phases, and a tailored management of the immunosuppression regimen is essential for preventing irreversible liver damage. Herein, we provide an overview of the current knowledge and research on CR, focusing on early detection, identification of non-invasive biomarkers, immunosuppressive management, re-transplantation and future perspectives of CR.
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Affiliation(s)
- Roberta Angelico
- Department of Surgery Sciences, HPB and Transplant Unit, University of Tor Vergata, Rome 00100, Italy
| | - Bruno Sensi
- Department of Surgery Sciences, HPB and Transplant Unit, University of Tor Vergata, Rome 00100, Italy
| | - Tommaso M Manzia
- Department of Surgery Sciences, HPB and Transplant Unit, University of Tor Vergata, Rome 00100, Italy
| | - Giuseppe Tisone
- Department of Surgery Sciences, HPB and Transplant Unit, University of Tor Vergata, Rome 00100, Italy
| | - Giuseppe Grassi
- Hepatology Unit, University of Tor Vergata, Rome 00100, Italy
| | | | - Martina Milana
- Hepatology Unit, University of Tor Vergata, Rome 00100, Italy
| | - Ilaria Lenci
- Hepatology Unit, University of Tor Vergata, Rome 00100, Italy
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25
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Takatsuki M, Eguchi S. Clinical liver transplant tolerance: Recent topics. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 29:369-376. [PMID: 34758514 DOI: 10.1002/jhbp.1077] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 08/27/2021] [Accepted: 10/22/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Immunosuppression is essential after organ transplantation to prevent severe graft injury due to rejection, but in long-term, transplanted organs are generally accepted with minimal dose of immunosuppression, and adverse effects of it such as renal dysfunction, diabetes and development of malignancies might become to exceed over the benefits in majority of the cases. Accordingly, to achieve the immunologic tolerance has been the ultimate goal in organ transplantation, and the liver has been well recognized as the tolerogenic organ compared to other organs. METHODS We referred the reported studies showing the actual protocol to achieve the immunologic tolerance after clinical liver transplantation. RESULTS Actually, two main procedures as "elective weaning of immunosuppression" and/or "cell therapy" using various immune-related cells have been introduced to induce the immunologic tolerance in clinical liver transplantation. The cell therapy, especially using regulatory T-cell has been reported to achieve definitive immunologic tolerance in living donor liver transplantation. CONCLUSION Although it is still developing, the induction of immunologic tolerance in clinical liver transplantation is realistic. Herein, the current topics of immunologic tolerance in liver transplantation is described.
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Affiliation(s)
- Mitsuhisa Takatsuki
- Department of Digestive and General Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan
| | - Susumu Eguchi
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
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26
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Immunosuppression in liver and intestinal transplantation. Best Pract Res Clin Gastroenterol 2021; 54-55:101767. [PMID: 34874848 DOI: 10.1016/j.bpg.2021.101767] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 10/08/2021] [Indexed: 02/07/2023]
Abstract
Immunosuppression handling plays a key role in the early and long-term results of transplantation. The development of multiple immunosuppressive drugs led to numerous clincial trials searching to reach the ideal regimen. Due to heterogeneity of the studied patient cohorts and flaws in many, even randomized controlled, study designs, the answer still stands out. Nowadays triple-drug immunosuppression containing a calcineurin inhibitor (preferentially tacrolimus), an antimetabolite (using mycophenolate moffettil or Azathioprine) and short-term steroids with or without induction therapy (using anti-IL2 receptor blocker or anti-lymphocytic serum) is the preferred option in both liver and intestinal transplantation. This chapter aims, based on a critical review of the definitions of rejection, corticoresistant rejection and standard immunosuppression to give some reflections on how to reach an optimal immunosuppressive status and to conduct trials allowing to draw solid conclusions. Endpoints of future trials should not anymore focus on biopsy proven, acute and chronic, rejection but also on graft and patient survival. Correlation between early- and long-term biologic, immunologic and histopathologic findings will be fundamental to reach in much more patients the status of operational tolerance.
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27
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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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Safinia N, Vaikunthanathan T, Lechler RI, Sanchez‐Fueyo A, Lombardi G. Advances in Liver Transplantation: where are we in the pursuit of transplantation tolerance? Eur J Immunol 2021; 51:2373-2386. [PMID: 34375446 PMCID: PMC10015994 DOI: 10.1002/eji.202048875] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 06/07/2021] [Accepted: 07/23/2021] [Indexed: 12/22/2022]
Abstract
Liver transplantation is the ultimate treatment option for end-stage liver disease. Breakthroughs in surgical practice and immunosuppression have seen considerable advancements in survival after transplantation. However, the intricate management of immunosuppressive regimens, balancing desired immunological quiescence while minimizing toxicity has proven challenging. Diminishing improvements in long-term morbidity and mortality have been inextricably linked with the protracted use of these medications. As such, there is now enormous interest to devise protocols that will allow us to minimize or completely withdraw immunosuppressants after transplantation. Immunosuppression withdrawal trials have proved the reality of tolerance following liver transplantation, however, without intervention will only occur after several years at the risk of potential cumulative immunosuppression-related morbidity. Focus has now been directed at accelerating this phenomenon through tolerance-inducing strategies. In this regard, efforts have seen the use of regulatory cell immunotherapy. Here we focus particularly on regulatory T cells, discussing preclinical data that propagated several clinical trials of adoptive cell therapy in liver transplantation. Furthermore, we describe efforts to further optimize the specificity and survival of regulatory cell therapy guided by concurrent immunomonitoring studies and the development of novel technologies including chimeric antigen receptors and co-administration of low-dose IL-2.
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Affiliation(s)
- Niloufar Safinia
- Division of Transplantation Immunology & Mucosal BiologyKing's College LondonLondonUK
| | | | - Robert Ian Lechler
- Division of Transplantation Immunology & Mucosal BiologyKing's College LondonLondonUK
| | | | - Giovanna Lombardi
- Division of Transplantation Immunology & Mucosal BiologyKing's College LondonLondonUK
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Menteer J, Goldbeck C, Herrington C, Yanni G, Emamaullee JA. Immunologic and Survival Benefits of Combined Heart-liver Transplantation in Children. Transplantation 2021; 105:e107-e108. [PMID: 34416752 PMCID: PMC8932196 DOI: 10.1097/tp.0000000000003810] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- Jondavid Menteer
- Heart Institute, Children’s Hospital Los Angeles, Los Angeles, CA
- Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Cameron Goldbeck
- Keck School of Medicine, University of Southern California, Los Angeles, CA
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, University of Southern California, Los Angeles, CA
| | - Cynthia Herrington
- Heart Institute, Children’s Hospital Los Angeles, Los Angeles, CA
- Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - George Yanni
- Keck School of Medicine, University of Southern California, Los Angeles, CA
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Children’s Hospital Los Angeles, Los Angeles, CA
| | - Juliet A. Emamaullee
- Keck School of Medicine, University of Southern California, Los Angeles, CA
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, University of Southern California, Los Angeles, CA
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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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Feng S, Bucuvalas JC, Mazariegos GV, Magee JC, Sanchez-Fueyo A, Spain KM, Lesniak A, Kanaparthi S, Perito E, Venkat VL, Burrell BE, Alonso EM, Bridges ND, Doo E, Gupta NA, Himes RW, Ikle D, Jackson AM, Lobritto SJ, Jose Lozano J, Martinez M, Ng VL, Rand EB, Sherker AH, Sundaram SS, Turmelle YP, Wood-Trageser M, Demetris AJ. Efficacy and Safety of Immunosuppression Withdrawal in Pediatric Liver Transplant Recipients: Moving Toward Personalized Management. Hepatology 2021; 73:1985-2004. [PMID: 32786149 DOI: 10.1002/hep.31520] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/13/2020] [Accepted: 07/26/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Tolerance is transplantation's holy grail, as it denotes allograft health without immunosuppression and its toxicities. Our aim was to determine, among stable long-term pediatric liver transplant recipients, the efficacy and safety of immunosuppression withdrawal to identify operational tolerance. APPROACH AND RESULTS We conducted a multicenter, single-arm trial of immunosuppression withdrawal over 36-48 weeks. Liver tests were monitored biweekly (year 1), monthly (year 2), and bimonthly (years 3-4). For-cause biopsies were done at investigators' discretion but mandated when alanine aminotransferase or gamma glutamyltransferase exceeded 100 U/L. All subjects underwent final liver biopsy at trial end. The primary efficacy endpoint was operational tolerance, defined by strict biochemical and histological criteria 1 year after stopping immunosuppression. Among 88 subjects (median age 11 years; 39 boys; 57 deceased donor grafts), 33 (37.5%; 95% confidence interval [CI] 27.4%, 48.5%) were operationally tolerant, 16 were nontolerant by histology (met biochemical but failed histological criteria), and 39 were nontolerant by rejection. Rejection, predicted by subtle liver inflammation in trial entry biopsies, typically (n = 32) occurred at ≤32% of the trial-entry immunosuppression dose and was treated with corticosteroids (n = 32) and/or tacrolimus (n = 38) with resolution (liver tests within 1.5 times the baseline) for all but 1 subject. No death, graft loss, or chronic, severe, or refractory rejection occurred. Neither fibrosis stage nor the expression level of a rejection gene set increased over 4 years for either tolerant or nontolerant subjects. CONCLUSIONS Immunosuppression withdrawal showed that 37.5% of selected pediatric liver-transplant recipients were operationally tolerant. Allograft histology did not deteriorate for either tolerant or nontolerant subjects. The timing and reversibility of failed withdrawal justifies future trials exploring the efficacy, safety, and potential benefits of immunosuppression minimization.
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Affiliation(s)
- Sandy Feng
- Division of Transplantation, Department of Surgery, University of California San Francisco, San Francisco, CA
| | - John C Bucuvalas
- Mount Sinai Kravis Children's Hospital and Recanati/Miller Transplantation Institute, Mount Sinai Health System, New York, NY
| | - George V Mazariegos
- Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - John C Magee
- Section of Transplant Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI
| | | | | | - Andrew Lesniak
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA
| | | | - Emily Perito
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of California San Francisco, San Francisco, CA
| | - Veena L Venkat
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh, Pittsburgh, PA
| | | | - Estella M Alonso
- Siragusa Transplantation Center, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
| | - Nancy D Bridges
- Transplantation Branch, Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, Rockville, MD
| | - Edward Doo
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
| | - Nitika A Gupta
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
| | - Ryan W Himes
- Section of Gastroenterology, Hepatology, and Nutrition, Texas Children's Hospital, Houston, TX
| | | | | | - Steven J Lobritto
- Center for Liver Diseases and Transplantation, Department of Surgery, Columbia University Irving Medical Center, New York, NY
| | - Juan Jose Lozano
- Bioinformatic Platform, Biomedical Research Center in Hepatic and Digestive Diseases, Instituto de Salud Carlos III, Barcelona, Spain
| | - Mercedes Martinez
- Center for Liver Diseases and Transplantation, Department of Surgery, Columbia University Irving Medical Center, New York, NY
| | - Vicky L Ng
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Transplant and Regenerative Medicine Center, The Hospital for Sick Children, University of Toronto, Toronto, OH, Canada
| | - Elizabeth B Rand
- Liver Transplant Program, The Children's Hospital of Pennsylvania, Philadelphia, PA
| | - Averell H Sherker
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
| | - Shikha S Sundaram
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO
| | - Yumirle P Turmelle
- Division of Gastroenterology, Hepatology, and Nutrition, Washington University School of Medicine, St. Louis, MO
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Strategies for Liver Transplantation Tolerance. Int J Mol Sci 2021; 22:ijms22052253. [PMID: 33668238 PMCID: PMC7956766 DOI: 10.3390/ijms22052253] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 02/19/2021] [Accepted: 02/21/2021] [Indexed: 12/13/2022] Open
Abstract
Liver transplant (LT) recipients require life-long immunosuppression (IS) therapy to preserve allograft function. The risks of chronic IS include an increased frequency of malignancy, infection, renal impairment, and other systemic toxicities. Despite advances in IS, long-term LT outcomes have not been improved over the past three decades. Standard-of-care (SoC) therapy can, in rare cases, lead to development of operational tolerance that permits safe withdrawal of maintenance IS. However, successful IS withdrawal cannot be reliably predicted and, in current prospective studies, is attempted several years after the transplant procedure, after considerable exposure to the cumulative burden of maintenance therapy. A recent pilot clinical trial in liver tolerance induction demonstrated that peri-transplant immunomodulation, using a regulatory T-cell (Treg) approach, can reduce donor-specific alloreactivity and allow early IS withdrawal. Herein we review protocols for active tolerance induction in liver transplantation, with a focus on identifying tolerogenic cell populations, as well as barriers to tolerance. In addition, we propose the use of novel IS agents to promote immunomodulatory mechanisms favoring tolerance. With numerous IS withdrawal trials underway, improved monitoring and use of novel immunomodulatory strategies will help provide the necessary knowledge to establish an active liver tolerance induction protocol for widespread use.
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Kroemer A, Khan K, Kaufman SS, Kang J, Weiner J, Duttargi A, Belyayev L, Ashokkumar C, Sindhi R, Timofeeva OA, Zasloff M, Matsumoto CS, Fishbein TM. Operational tolerance in intestinal transplantation. Am J Transplant 2021; 21:876-882. [PMID: 32721092 PMCID: PMC8274367 DOI: 10.1111/ajt.16224] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 06/29/2020] [Accepted: 07/15/2020] [Indexed: 01/25/2023]
Abstract
By presenting the first case report of true operational tolerance in an intestinal transplant patient, we aim to demonstrate that tolerance is possible in a field that has been hampered by suboptimal outcomes. Although operational tolerance has been achieved in liver and kidney transplantation, and some intestinal transplant patients have been able to decrease immunosuppression, this is the first instance of true operational tolerance after complete cessation of immunosuppression. A patient received a deceased-donor small intestinal and colon allograft with standard immunosuppressive treatment, achieving excellent graft function after overcoming a graft-versus-host-disease episode 5 months posttransplant. Four years later, against medical advice, the patient discontinued all immunosuppression. During follow-up visits 2 and 3 years after cessation of immunosuppression, the patient exhibited normal graft function with full enteral autonomy and without histological or endoscopic signs of rejection. Mechanistic analysis demonstrated immune competence against third party antigen, with in vitro evidence of donor-specific hyporesponsiveness in the absence of donor macrochimerism. This proof of principle case can stimulate future mechanistic studies on diagnostic and therapeutic strategies, for example, cellular therapy trials, that can lead to minimization or elimination of immunosuppression and, it is hoped, help revitalize the field of intestinal transplantation.
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Affiliation(s)
- Alexander Kroemer
- Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Khalid Khan
- Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Stuart S Kaufman
- Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Jiman Kang
- Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Joshua Weiner
- Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Anju Duttargi
- Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Leonid Belyayev
- Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Chethan Ashokkumar
- The Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Rakesh Sindhi
- The Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Olga A Timofeeva
- Department of Pathology and Laboratory Medicine, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Michael Zasloff
- Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Cal S Matsumoto
- Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Thomas M Fishbein
- Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA
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Evaluation of Graft Fibrosis, Inflammation and Donor-specific Antibodies at Protocol Liver Biopsies in Pediatric Liver Transplant Patients: a Single Center Experience. Transplantation 2021; 106:85-95. [PMID: 33496554 DOI: 10.1097/tp.0000000000003649] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND The impact of graft fibrosis and inflammation on the natural history of pediatric liver transplants (LT) is still debated. Our objectives were to evaluate the evolution of posttransplant fibrosis and inflammation over time at protocol liver biopsies (PLBs), risk factors for fibrosis, presence of donor-specific antibodies (DSAs) and/or their correlation with graft and recipient factors. METHODS A single-center, retrospective (2000-2019) cross-sectional study on pediatric LT recipients who had at least one PLB, followed by a longitudinal evaluation in those who had at least two PLBs, was conducted. Fibrosis was assessed by the Liver Allograft Fibrosis Semiquantitative score, inflammation by the Rejection Activity Index, DSAs by Luminex®. RESULTS A total of 134 PLBs from 94 patients were included. Fibrosis was detected in 87% (30% mild, 45% moderate, 12% severe), 80% in the portal tracts. There was an increase in fibrosis between the 1-3 and the 4-6 year group (p=0.01), then it was stable. Inflammation was observed in 44% (30% mild, 13% moderate, 1% severe), 90% in the portal tracts. Anti-HLA II (IgG) DSAs were detected in 14/40 (35%). Portal fibrosis was associated with portal inflammation in the 1-3 year group (p=0.04). Low immunosuppression levels were correlated with sinusoidal fibrosis (p=0.04) and DSA positivity (p-value=0.006). There was no statistically significant correlation between DSA positivity and the presence of graft fibrosis or inflammation. CONCLUSIONS This study corroborates the concept of an early evolution of silent graft fibrosis. Suboptimal immunosuppression may play a role in the development of fibrosis and DSAs.
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Commentary: Late Allograft Fibrosis and Inflammation - An Unexpected Finding with Need for More Aggressive Treatment? Transplantation 2021; 106:16-17. [PMID: 33496559 DOI: 10.1097/tp.0000000000003650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Issa F, Strober S, Leventhal JR, Kawai T, Kaufman DB, Levitsky J, Sykes M, Mas V, Wood KJ, Bridges N, Welniak LA, Chandran S, Madsen JC, Nickerson P, Demetris AJ, Lakkis FG, Thomson AW. The Fourth International Workshop on Clinical Transplant Tolerance. Am J Transplant 2021; 21:21-31. [PMID: 32529725 DOI: 10.1111/ajt.16139] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 05/20/2020] [Accepted: 06/08/2020] [Indexed: 01/25/2023]
Abstract
The International Workshop on Clinical Transplant Tolerance is a biennial meeting that aims to provide an update on the progress of studies of immunosuppression minimization or withdrawal in solid organ transplantation. The Fourth International Workshop on Clinical Tolerance was held in Pittsburgh, Pennsylvania, September 5-6, 2019. This report is a summary of presentations on the status of clinical trials designed to minimize or withdraw immunosuppressive drugs in kidney, liver, and lung transplantation without subsequent evidence of rejection. All protocols had in common the use of donor or recipient cell therapy combined with organ transplantation. The workshop also included presentations of mechanistic studies designed to improve understanding of the cellular and molecular basis of tolerance and to identify potential predictors/biomarkers of tolerance. Strategies to enhance the safety of hematopoietic cell transplantation and to improve patient selection/risk stratification for clinical trials were also discussed.
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Affiliation(s)
- Fadi Issa
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Samuel Strober
- Department of Medicine, Stanford University, Stanford, California, USA
| | - Joseph R Leventhal
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Tatsuo Kawai
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Dixon B Kaufman
- Department of Surgery, University of Wisconsin, Madison, Wisconsin, USA
| | - Josh Levitsky
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Megan Sykes
- Columbia Center for Translational Immunology, Department of Microbiology & Immunology, Columbia University, New York, New York, USA
| | - Valeria Mas
- Transplant Research Institute, James D. Eason Transplant Institute, School of Medicine, The University of Tennessee Health Care Science, Memphis, Tennessee, USA
| | - Kathryn J Wood
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Nancy Bridges
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Lisbeth A Welniak
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Sindhu Chandran
- Department of Medicine, University of California, San Francisco, California, USA
| | - Joren C Madsen
- MGH Transplant Center and Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Peter Nickerson
- Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Anthony J Demetris
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Fadi G Lakkis
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Angus W Thomson
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Factors Associated With 5- and 10-Year Survival After Intestinal Transplantation in Infants and Children. J Pediatr Gastroenterol Nutr 2020; 71:617-623. [PMID: 33093368 DOI: 10.1097/mpg.0000000000002849] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Intestinal transplantation is an option for permanent intestinal failure with parenteral nutrition intolerance. We sought to determine long-term intestinal graft survival in pediatric patients at our center and to identify factors influencing survival. METHODS Retrospective chart review of 86 patients transplanted between 2003 and 2013, targeting potential explanatory variables related to demographics, perioperative factors, and postoperative complications. RESULTS Intestinal graft survival was 71% and 65% after 5 and 10 years, respectively. Five-year graft survival was attained in 79% of patients with a history of anatomic intestinal failure compared with 45% with functional intestinal failure (P = 0.0055). Compared with nonsurvival, 5-year graft survival was also associated with reduced incidences of graft-versus-host disease (2% vs 16%, P = 0.0237), post-transplant lymphoproliferative disorder (3% vs 24%, P = 0.0067), and de novo donor-specific antibodies (19% vs 57%, P = 0.0451) plus a lower donor-recipient weight ratio (median 0.727 vs 0.923, P = 0.0316). Factors not associated with 5-year intestinal graft survival included graft rejection of any severity and inclusion of a liver graft. Factors associated with graft survival at 10 years were similar to those at 5 years. CONCLUSIONS In our experience, outcomes in pediatric intestinal transplantation have improved substantially for anatomic but not functional intestinal failure. Graft survival depends on avoidance of severe infectious and immunological complications including GVHD, whereas inclusion of a liver graft provides no obvious survival benefit. Reduced success with functional intestinal failure may reflect inherently increased susceptibility to complications in this group.
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Stormon MO, Hardikar W, Evans HM, Hodgkinson P. Paediatric liver transplantation in Australia and New Zealand: 1985-2018. J Paediatr Child Health 2020; 56:1739-1746. [PMID: 32649047 DOI: 10.1111/jpc.14969] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 05/12/2020] [Indexed: 01/09/2023]
Abstract
Liver transplantation has become the standard of care for children with end-stage liver disease. In Australia and New Zealand, there are four paediatric liver transplant units, in Sydney, Melbourne, Brisbane and Auckland. Over the past 30 years, there have been significant changes to indications for transplant, as well as medical and surgical advances. In this paper, using retrospective data from the Australia and New Zealand Liver Transplant Registry, we review 977 children (less than 16 years of age) who underwent liver transplant from 1985 to 2018. The most common indication was biliary atresia (54%), although there has been an increase in other indications, including inborn errors of metabolism, fulminant hepatic failure and malignant liver tumours. Over the past 3 decades, areas of change and innovation include: the use of 'split grafts' to enable an adult and a child to receive the same donor liver, live donation, improvements in immunosuppressive regimens and infectious prophylaxis protocols and innovative surgical techniques allowing transplantation in smaller infants. The outcomes for children who undergo liver transplant in ANZ are excellent, with current 10-year patient survival rates of 95%, comparable to other larger centres around the world.
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Affiliation(s)
- Michael O Stormon
- Department of Gastroenterology, Children's Hospital Westmead, Sydney, New South Wales, Australia
| | - Winita Hardikar
- Department of Gastroenterology, Royal Children's Hospital, Melbourne, Victoria, Australia
| | - Helen M Evans
- Department of Gastroenterology, Starship Children's Hospital Auckland, Auckland, New Zealand
| | - Peter Hodgkinson
- Queensland Liver Transplant Unit, Princess Alexandra Hospital, Brisbane, Queensland, Australia
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Wu Y, Huang M, Sun H, Zhou X, Zhou R, Gu G, Xia Q. Role of Innate Immunity in Pediatric Post-transplant Idiopathic Liver Fibrosis. Front Immunol 2020; 11:2111. [PMID: 33193293 PMCID: PMC7642407 DOI: 10.3389/fimmu.2020.02111] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 08/04/2020] [Indexed: 01/22/2023] Open
Abstract
Pediatric post-transplant idiopathic liver fibrosis is an unexplained graft fibrosis that occurs in symptom-free children without acute rejection and surgical complications. Despite a lack of consensus on the subject, the development of pediatric post-transplant idiopathic liver fibrosis is believed to be the result of multiple potential factors, including ischemia-reperfusion injury, allogeneic acute and chronic rejection, viral hepatitis recurrence, opportunistic infection, and drug-induced liver damage. Among them, there is growing evidence that innate immunity may also have a unique role in this progression. This study reviews the features of pediatric post-transplant idiopathic liver fibrosis and discusses current studies illustrating the potential mechanisms of liver allograft tolerance induced by intrahepatic innate immunity, the role of components including Toll-like receptors (TLRs), interferons (IFN), dendritic cells (DC), natural killer cells (NK cells), NKT cells, neutrophils, and Kupffer cells, as well as their possibly relevant role in the development of pediatric post-transplant idiopathic liver fibrosis.
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Affiliation(s)
- Yue Wu
- Department of Liver Surgery, Renji Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mingzhu Huang
- Department of Liver Surgery, Renji Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haojie Sun
- Department of Liver Surgery, Renji Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiying Zhou
- Department of Liver Surgery, Renji Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ruoqiao Zhou
- Department of Liver Surgery, Renji Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guangxiang Gu
- Department of Liver Surgery, Renji Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Two-hour Observation After Liver Biopsy in Children: Clinical and Economic Outcome of a Quality Improvement Intervention. J Pediatr Gastroenterol Nutr 2020; 71:e105-e108. [PMID: 32960537 DOI: 10.1097/mpg.0000000000002821] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Following percutaneous liver biopsy performed at our institution on an outpatient basis, children traditionally were observed for 4 hours then discharged after verifying a stable hematocrit level. In June 2015, we adopted a quality improvement project with shorter 2-hour observation for patients with no known risks and the hematocrit test was abandoned.The purpose of this study is to evaluate the clinical and economic outcomes of early discharge of children following liver biopsy. METHODS We analyzed data on 2 groups of children who underwent ultrasound-guided nontargeted core needle liver biopsy performed on outpatient basis. Group A (100 procedures with 4-hour postprocedural observation time and hematocrit test) was compared with group B (100 procedures with 2-hour observation without hematocrit test). RESULTS Group A consisted of 92 patients (43 boys; 49 girls) with a mean age of 11.1 years and mean weight of 52.6 kg. Group B had 92 patients (47 boys; 45 girls) with a mean age of 8.9 years and mean weight of 40.5 kg. The mean length of observation was 281 minutes (range 204-540 minutes) and 147 minutes (range 86-332 minutes) for groups A and B, respectively. The mean recovery charges were reduced by 35% per procedure in group B. The tissue obtained was sufficient for pathologic diagnosis in all procedures. There were no biopsy-related complications in either group. CONCLUSIONS Enhanced recovery with early discharge of low-risk children after 2-hour observation following percutaneous liver biopsy can be safely implemented without adversely affecting the outcome. Shorter postbiopsy observation can be cost-saving and may potentially improve patient satisfaction.
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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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McCaughan GW, Bowen DG, Bertolino PJ. Induction Phase of Spontaneous Liver Transplant Tolerance. Front Immunol 2020; 11:1908. [PMID: 33013840 PMCID: PMC7516030 DOI: 10.3389/fimmu.2020.01908] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 07/16/2020] [Indexed: 12/30/2022] Open
Abstract
The liver has long been known to possess tolerogenic properties. Early experiments in liver transplantation demonstrated that in animal models, hepatic allografts could be accepted across MHC-mismatch without the use of immunosuppression, and that transplantation of livers from the same donor was capable of inducing tolerance to other solid organs that would normally otherwise be rejected. Although this phenomenon is less pronounced in human liver transplantation, lower levels of immunosuppression are nevertheless required for graft acceptance than for other solid organs, and in a minority of individuals immunosuppression can be discontinued in the longer term. The mechanisms underlying this unique hepatic property have not yet been fully delineated, however it is clear that immunological events in the early period post-liver transplant are key to generation of hepatic allograft tolerance. Both the hepatic parenchyma and the large number of donor passenger leukocytes contained within the liver allograft have been demonstrated to contribute to the generation of donor-specific tolerance in the early post-transplant phase. In particular, the unique nature of hepatic-leukocyte interactions appears to play a crucial role in the ability of the liver to silence the recipient alloimmune response. In this review, we will summarize the evidence regarding the potential mechanisms that mediate the critical early phase in the generation of hepatic allograft tolerance.
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Affiliation(s)
- Geoffrey W McCaughan
- Liver Injury and Cancer Program, The Centenary Institute, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia.,AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - David G Bowen
- AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Liver Immunology Program, The Centenary Institute, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Patrick J Bertolino
- AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Liver Immunology Program, The Centenary Institute, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
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Höfer A, Jonigk D, Hartleben B, Verboom M, Hallensleben M, Manns MP, Jaeckel E, Taubert R. Non-invasive screening for subclinical liver graft injury in adults via donor-specific anti-HLA antibodies. Sci Rep 2020; 10:14242. [PMID: 32859929 PMCID: PMC7455737 DOI: 10.1038/s41598-020-70938-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 07/02/2020] [Indexed: 02/06/2023] Open
Abstract
The majority of liver grafts exhibit abnormal histological findings late after transplantation, even when liver enzymes are normal. Such subclinical graft injuries were associated with rejection and fibrosis progression in recent studies. The identification of non-invasive biomarkers for subclinical graft injury might help to individualize immunosuppression. Therefore, graft injury was assessed in 133 liver biopsies with normal/near normal liver enzymes from a prospective liver biopsy program. Cytokeratin-18 cell death marker (M65) and donor specific anti-HLA antibodies (DSA) were measured as non-invasive markers in paired plasma samples in addition to routine parameters. M65 was associated with subclinical graft injury but this association was too weak for reasonable clinical application. DSA positivity was associated with more graft inflammation (OR = 5.4) and more fibrosis (OR = 4.2). Absence of DSA excluded fibrosis in 87–89%, while presence of DSA excluded histological criteria for immunosuppression minimization attempts in 92–97%. While CK18 cell death marker had no diagnostic value for the detection of subclinical liver graft injury, DSA testing can help to preselect patients for immunosuppression reduction in case of DSA negativity, while DSA positivity should prompt elastography or liver biopsy for the assessment of subclinical graft injury.
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Affiliation(s)
- Anne Höfer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.,European Reference Network On Hepatological Diseases (ERN RARE-LIVER), Hannover, Germany
| | - Danny Jonigk
- Institute for Pathology, Hannover Medical School, Hannover, Germany
| | - Björn Hartleben
- Institute for Pathology, Hannover Medical School, Hannover, Germany
| | - Murielle Verboom
- Institute for Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Michael Hallensleben
- Institute for Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,European Reference Network On Hepatological Diseases (ERN RARE-LIVER), Hannover, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.,European Reference Network On Hepatological Diseases (ERN RARE-LIVER), Hannover, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. .,Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany. .,European Reference Network On Hepatological Diseases (ERN RARE-LIVER), Hannover, Germany.
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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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Levitsky J, Burrell BE, Kanaparthi S, Turka LA, Kurian S, Sanchez-Fueyo A, Lozano JJ, Demetris A, Lesniak A, Kirk AD, Stempora L, Yang GY, Mathew JM. Immunosuppression Withdrawal in Liver Transplant Recipients on Sirolimus. Hepatology 2020; 72:569-583. [PMID: 31721246 PMCID: PMC7217743 DOI: 10.1002/hep.31036] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Accepted: 11/06/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS As conversion from calcineurin inhibitor to sirolimus (SRL), a mechanistic target of rapamycin inhibitor (mTOR-I), has been shown to enhance immunoregulatory profiles in liver transplant (LT) recipients (LTRs), mTOR-I therapy might allow for increased success of immunosuppression (IS) withdrawal. Our aim was to determine if operational tolerance could be observed in LTRs withdrawn from SRL and if blood/graft tolerance biomarkers were predictive of successful withdrawal. APPROACH AND RESULTS We performed a prospective trial of SRL monotherapy withdrawal in nonimmune, nonviremic LTRs > 3 years post-LT. SRL was weaned over ~6 months, and biopsies were performed 12 months postweaning or at concern for acute rejection. Twenty-one LTRs consented; 6 were excluded due to subclinical acute rejection on baseline biopsy or other reasons, and 15 underwent weaning (age 61.3 ± 8.8 years; LT to SRL weaning 6.7 ± 3 years). Eight (53%) achieved operational tolerance (TOL). Of the 7 who were nontolerant (non-TOL), 6 had mild acute rejection on biopsy near the end of weaning or at study end; 1 was removed from the trial due to liver cancer recurrence. At baseline preweaning, there were statistically increased blood tolerogenic dendritic cells and cell phenotypes correlating with chronic antigen presentation in the TOL versus non-TOL groups. A previously identified biopsy gene signature accurately predicted TOL versus non-TOL in 12/14 LTRs before weaning. At study end, biopsy staining revealed statistically significant increases in antigen-presenting cell:leukocyte pairings, FOXP3+ /CD4+ T cells, Tbet+ /CD8+ T cells, and lobular dendritic cells in the non-TOL group. CONCLUSIONS This study evaluated IS withdrawal directly from mTOR-I therapy in LTRs and achieved > 50% operational tolerance. Preweaning gene expression and peripheral blood mononuclear cell profiling may be useful as predictors of successful mTOR-I therapy withdrawal. NCT02062944.
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Affiliation(s)
- Josh Levitsky
- Northwestern University Feinberg School of Medicine, Chicago, IL
| | | | | | - Laurence A. Turka
- Immune Tolerance Network, Bethesda, MD; Massachusetts General Hospital, Boston, MA
| | - Sunil Kurian
- Scripps Clinic Bio-Repository and Transplantation Research, La Jolla, California, United States
| | | | - Juan J. Lozano
- Biomedical Research Center in Hepatic and Digestive Diseases, Carlos III Health Institute, Barcelona, Spain
| | | | | | | | | | - Guang-Yu Yang
- Northwestern University Feinberg School of Medicine, Chicago, IL
| | - James M. Mathew
- Northwestern University Feinberg School of Medicine, Chicago, IL
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Du X, Chang S, Guo W, Zhang S, Chen ZK. Progress in Liver Transplant Tolerance and Tolerance-Inducing Cellular Therapies. Front Immunol 2020; 11:1326. [PMID: 32670292 PMCID: PMC7326808 DOI: 10.3389/fimmu.2020.01326] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 05/26/2020] [Indexed: 12/12/2022] Open
Abstract
Liver transplantation is currently the most effective method for treating end-stage liver disease. However, recipients still need long-term immunosuppressive drug treatment to control allogeneic immune rejection, which may cause various complications and affect the long-term survival of the recipient. Many liver transplant researchers constantly pursue the induction of immune tolerance in liver transplant recipients, immunosuppression withdrawal, and the maintenance of good and stable graft function. Although allogeneic liver transplantation is more tolerated than transplantation of other solid organs, and it shows a certain incidence of spontaneous tolerance, there is still great risk for general recipients. With the gradual progress in our understanding of immune regulatory mechanisms, a variety of immune regulatory cells have been discovered, and good results have been obtained in rodent and non-human primate transplant models. As immune cell therapies can induce long-term stable tolerance, they provide a good prospect for the induction of tolerance in clinical liver transplantation. At present, many transplant centers have carried out tolerance-inducing clinical trials in liver transplant recipients, and some have achieved gratifying results. This article will review the current status of liver transplant tolerance and the research progress of different cellular immunotherapies to induce this tolerance, which can provide more support for future clinical applications.
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Affiliation(s)
- Xiaoxiao Du
- Henan Key Laboratory of Digestive Organ Transplantation, Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Sheng Chang
- Key Laboratory of Organ Transplantation, Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Wenzhi Guo
- Henan Key Laboratory of Digestive Organ Transplantation, Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuijun Zhang
- Henan Key Laboratory of Digestive Organ Transplantation, Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhonghua Klaus Chen
- Key Laboratory of Organ Transplantation, Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
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Enhancing the Value of Histopathological Assessment of Allograft Biopsy Monitoring. Transplantation 2020; 103:1306-1322. [PMID: 30768568 DOI: 10.1097/tp.0000000000002656] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Traditional histopathological allograft biopsy evaluation provides, within hours, diagnoses, prognostic information, and mechanistic insights into disease processes. However, proponents of an array of alternative monitoring platforms, broadly classified as "invasive" or "noninvasive" depending on whether allograft tissue is needed, question the value proposition of tissue histopathology. The authors explore the pros and cons of current analytical methods relative to the value of traditional and illustrate advancements of next-generation histopathological evaluation of tissue biopsies. We describe the continuing value of traditional histopathological tissue assessment and "next-generation pathology (NGP)," broadly defined as staining/labeling techniques coupled with digital imaging and automated image analysis. Noninvasive imaging and fluid (blood and urine) analyses promote low-risk, global organ assessment, and "molecular" data output, respectively; invasive alternatives promote objective, "mechanistic" insights by creating gene lists with variably increased/decreased expression compared with steady state/baseline. Proponents of alternative approaches contrast their preferred methods with traditional histopathology and: (1) fail to cite the main value of traditional and NGP-retention of spatial and inferred temporal context available for innumerable objective analyses and (2) belie an unfamiliarity with the impact of advances in imaging and software-guided analytics on emerging histopathology practices. Illustrative NGP examples demonstrate the value of multidimensional data that preserve tissue-based spatial and temporal contexts. We outline a path forward for clinical NGP implementation where "software-assisted sign-out" will enable pathologists to conduct objective analyses that can be incorporated into their final reports and improve patient care.
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48
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Tolerance studies in liver transplantation: are we fooling ourselves? Curr Opin Organ Transplant 2020; 25:151-157. [DOI: 10.1097/mot.0000000000000738] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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49
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Jackson AM, Kanaparthi S, Burrell BE, Lucas DP, Vega RM, Demetris AJ, Feng S. IgG4 donor-specific HLA antibody profile is associated with subclinical rejection in stable pediatric liver recipients. Am J Transplant 2020; 20:513-524. [PMID: 31561279 DOI: 10.1111/ajt.15621] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 08/25/2019] [Accepted: 09/15/2019] [Indexed: 01/25/2023]
Abstract
The impact of donor-specific HLA antibody (DSA) following liver transplantation remains controversial. We hypothesized DSA IgG subclass characteristics, compared to total DSA IgG, might correlate with specific histopathological phenotype(s) of subclinical graft injury. We therefore studied 129 stable, arguably "clinically ideal," pediatric liver recipients at the time of a screening biopsy to enter an immunosuppression withdrawal trial. Sixty-five (50%) subjects tested positive for class II DSA. IgG subclass profile was characterized by mean fluorescence intensity (MFI) and normalized subclass composition (>5%). A prominent IgG4 DSA profile was strongly correlated with greater HLA mismatch, a histopathological phenotype characterized by the presence of interface activity (with variable degrees of fibrosis), and a transcriptional profile of attenuated T cell-mediated rejection. Specifically, compared to those without class II DSA, those with IgG4 class II DSA MFI sum >2000 exhibited an odds ratio (OR) of 20.79 (95% confidence interval [CI] 4.38-98.69) and IgG4 subclass composition >5% exhibited an OR of 8.99 (95% CI 2.70-29.9). Our data suggest that IgG4 DSA may serve as a useful biomarker to identify, among clinically and biochemically stable liver transplant recipients, a subset with histological and transcriptional features indicative of an active, suboptimally controlled alloimmune response.
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Affiliation(s)
| | | | | | - Donna P Lucas
- Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
| | - Renato M Vega
- Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
| | - Anthony J Demetris
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sandy Feng
- Department of Surgery, University of California San Francisco, San Francisco, California, USA
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50
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Vionnet J, Sempoux C, Pascual M, Sánchez-Fueyo A, Colmenero J. Donor-specific antibodies in liver transplantation. GASTROENTEROLOGIA Y HEPATOLOGIA 2020; 43:34-45. [DOI: 10.1016/j.gastrohep.2019.09.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 09/18/2019] [Accepted: 09/30/2019] [Indexed: 12/22/2022]
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