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1
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Gabrielli F, Bernasconi E, Toscano A, Avossa A, Cavicchioli A, Andreone P, Gitto S. Side Effects of Immunosuppressant Drugs After Liver Transplant. Pharmaceuticals (Basel) 2025; 18:342. [PMID: 40143120 PMCID: PMC11946649 DOI: 10.3390/ph18030342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 02/18/2025] [Accepted: 02/26/2025] [Indexed: 03/28/2025] Open
Abstract
Liver transplantation (LT) is the standard of care for both end-stage liver failure and hepatocellular carcinoma (HCC). Side effects of the main used immunosuppressive drugs have a noteworthy impact on the long-term outcome of LT recipients. Consequently, to achieve a balance between optimal immunosuppression and minimal side effects is a cornerstone of the post-LT period. Today, there are no validated markers for overimmunosuppression and underimmunosuppression, only a few drugs have therapeutic drug monitoring, and immunosuppression regimens vary from center to center and from country to country. Currently, there are many drugs with different efficacy and safety profiles. Using different agents permits a decrease in the dosage and minimizes the toxicities. A small subset of recipients achieves immunotolerance with the chance to stop immunosuppressive therapy. This article focuses on the side effects of immunosuppressive drugs, which significantly impact long-term outcomes for LT recipients. The primary aim is to highlight the balance between achieving effective immunosuppression and minimizing adverse effects, emphasizing the role of personalized therapeutic strategies. Moreover, this review evaluates the mechanisms of action and specific complications associated with immunosuppressive agents. Finally, special attention is given to strategies for reducing immunosuppressive burdens, improving patient quality of life, and identifying immunotolerant individuals.
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Affiliation(s)
- Filippo Gabrielli
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences for Children & Adults, AOU of Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Elisa Bernasconi
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Arianna Toscano
- Division of Internal Medicine, University Hospital of Policlinico G. Martino, 98124 Messina, Italy
| | - Alessandra Avossa
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Alessia Cavicchioli
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences for Children & Adults, AOU of Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Pietro Andreone
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences for Children & Adults, AOU of Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Postgraduate School of Allergology and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
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2
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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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3
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Zhao Y, Wang L, Xie M, Rao W. Progress in the diagnosis and treatment of graft fibrosis after liver transplantation. PORTAL HYPERTENSION & CIRRHOSIS 2024; 3:22-30. [DOI: 10.1002/poh2.70] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 11/27/2023] [Indexed: 01/04/2025]
Abstract
AbstractLiver transplantation (LT) is considered one of the best treatments for patients with end‐stage liver diseases. However, some patients with no significant clinical manifestations or abnormal laboratory tests still experience graft fibrosis during postoperative follow‐up, which is often recognized by graft histopathology. Graft fibrosis can lead to graft dysfunction, thereby reducing the survival time of the recipient and even requiring re‐transplantation. Currently, noninvasive methods are widely applied in the assessment of hepatic and allograft fibrosis. Although both noninvasive diagnostic models based on laboratory examination indicators and elastography technology that can quantify liver stiffness have some value in the evaluation of fibrosis, the diagnostic accuracy and characteristics of these various methods vary and cannot replace liver biopsy completely. In recent years, some liver‐protective drugs and proprietary Chinese traditional medicines have been proven to delay or reverse chronic liver fibrosis. Nevertheless, their efficacy and safety for LT recipients need to be further verified. This article reviews the diagnosis and treatment of graft fibrosis after LT to provide a reference for improving the overall survival rate of LT recipients.
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Affiliation(s)
- Youwei Zhao
- Department of Gastroenterology Medical College of Qingdao University Qingdao Shandong China
| | - Lijun Wang
- Department of Gastroenterology Medical College of Qingdao University Qingdao Shandong China
| | - Man Xie
- Department of Gastroenterology The Affiliated Hospital of Qingdao University Qingdao Shandong China
| | - Wei Rao
- Division of Hepatology, Liver Disease Center The Affiliated Hospital of Qingdao University Qingdao Shandong China
- Department of Organ Transplantation Center The Affiliated Hospital of Qingdao University Qingdao Shandong China
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4
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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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5
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Pérez-Escobar J, Jimenez JV, Rodríguez-Aguilar EF, Servín-Rojas M, Ruiz-Manriquez J, Safar-Boueri L, Carrillo-Maravilla E, Navasa M, García-Juárez I. Immunotolerance in liver transplantation: a primer for the clinician. Ann Hepatol 2023; 28:100760. [PMID: 36179797 DOI: 10.1016/j.aohep.2022.100760] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 09/08/2022] [Indexed: 02/04/2023]
Abstract
The use of immunosuppressive medications for solid organ transplantation is associated with cardiovascular, metabolic, and oncologic complications. On the other hand, the development of graft rejection is associated with increased mortality and graft dysfunction. Liver transplant recipients can withdraw from immunosuppression without developing graft injury while preserving an adequate antimicrobial response - a characteristic known as immunotolerance. Immunotolerance can be spontaneously or pharmacologically achieved. Contrary to the classic dogma, clinical studies have elucidated low rates of true spontaneous immunotolerance (no serologic or histological markers of immune injury) among liver transplant recipients. However, clinical, serologic, and tissue biomarkers can aid in selecting patients in whom immunosuppression can be safely withdrawn. For those who failed an immunosuppression withdrawal trial or are at high risk of rejection, pharmacological interventions for immunotolerance induction are under development. In this review, we provide an overview of the mechanisms of immunotolerance, the clinical studies investigating predictors and biomarkers of spontaneous immunotolerance, as well as the potential pharmacological interventions for inducing it.
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Affiliation(s)
- Juanita Pérez-Escobar
- Department of Hepatology and Liver Transplant, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Jose Victor Jimenez
- Department of Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Erika Faride Rodríguez-Aguilar
- Department of Hepatology and Liver Transplant, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Maximiliano Servín-Rojas
- Department of Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Jesus Ruiz-Manriquez
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Luisa Safar-Boueri
- Comprehensive Transplant Center, Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Eduardo Carrillo-Maravilla
- Department of Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Miquel Navasa
- Liver Transplant Unit, Hepatology Service, Hospital Clínic de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Ignacio García-Juárez
- Department of Hepatology and Liver Transplant, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
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6
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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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7
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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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8
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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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9
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Toti L, Manzia TM, Sensi B, Blasi F, Baiocchi L, Lenci I, Angelico R, Tisone G. Towards tolerance in liver transplantation. Best Pract Res Clin Gastroenterol 2021; 54-55:101770. [PMID: 34874844 DOI: 10.1016/j.bpg.2021.101770] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 10/08/2021] [Indexed: 02/08/2023]
Abstract
Life-long immunosuppression has always been considered the key in managing liver graft protection from recipient rejection. However, it is associated with severe adverse effects that lead to increased morbidity and mortality, including infections, cardiovascular diseases, kidney failure, metabolic disorders and de novo malignancies. This explains the great interest that has developed in the concept of tolerance in recent years. The liver, thanks to its marked tolerogenicity, is to be considered a privileged organ: up to 60% of selected patients undergoing liver transplantation could safely withdraw immunosuppression.
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Affiliation(s)
- L Toti
- Hepato-Pancreato-Biliary and Transplant Unit, Fondazione Policlinico Tor Vergata, Rome, Italy.
| | - T M Manzia
- University of Rome Tor Vergata, Department of Surgical Science, Italy
| | - B Sensi
- University of Rome Tor Vergata, Department of Surgical Science, Italy
| | - F Blasi
- University of Rome Tor Vergata, Department of Surgical Science, Italy
| | - L Baiocchi
- University of Rome Tor Vergata, Department of Surgical Science, Italy
| | - I Lenci
- Hepatology and Liver Transplant Unit, Fondazione Policlinico Tor Vergata, Rome, Italy
| | - R Angelico
- University of Rome Tor Vergata, Department of Surgical Science, Italy
| | - G Tisone
- University of Rome Tor Vergata, Department of Surgical Science, Italy
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10
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Shizuku M, Kamei H, Yoshizawa A, Ito Y, Ogura Y, Yoshikawa J, Kurata N, Jobara K, Kodera Y. The impact of chronic Epstein-Barr virus infection on the liver graft of pediatric liver transplant recipients: A retrospective observational study. Transpl Infect Dis 2021; 23:e13731. [PMID: 34500501 DOI: 10.1111/tid.13731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/23/2021] [Accepted: 09/01/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Chronic high Epstein-Barr virus loads (CHEBV) are commonly observed in pediatric liver transplant patients. However, it is unclear how CHEBV impacts the liver graft. The aim of this study was to clarify the clinical and pathological impacts of CHEBV on the liver graft. METHODS From 2012 to 2020, we retrospectively investigated 46 pediatric liver transplant patients (under 16 years) who survived ≥6 months. The patients were divided into two groups: CHEBV group (EBV DNA >10 000 IU/ml of whole blood for ≥6 months) and nonchronic high EBV (NCHEBV) group (patients who did not meet CHEBV criteria). Tacrolimus was reduced to <3.0 ng/ml in patients with EBV DNA >5000 IU/ml. Blood biochemistry data and pathological findings, obtained at the time of protocol and episodic biopsies, were compared between the two groups. RESULTS Out of 46 patients, 28 CHEBV and 18 NCHEBV patients were enrolled. The blood biochemical examination did not show a significant difference between the two groups. In addition, no significant differences between the two groups were found in the pathological findings, including frequency of late acute rejection and the progression of fibrosis at the time of both protocol and episodic biopsies. Appropriate adjustment of immunosuppression for CHEBV management may have contributed to the prevention of the progression of fibrosis. CONCLUSION CHEBV had little adverse effect on the liver graft. Graft fibrosis might have been avoided through optimal dose modification of tacrolimus. Further long-term monitoring is necessary because CHEBV may affect the pediatric liver graft in the long term.
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Affiliation(s)
- Masato Shizuku
- Department of Transplantation Surgery, Nagoya University Hospital, Nagoya, Japan.,Department of Transplantation and Endocrine Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideya Kamei
- Department of Transplantation Surgery, Nagoya University Hospital, Nagoya, Japan
| | - Atsushi Yoshizawa
- Department of Transplantation Surgery, Nagoya University Hospital, Nagoya, Japan.,Department of Gastroenterology Surgery, Kansai Electric Power Hospital, Osaka, Japan
| | - Yoshinori Ito
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Ogura
- Department of Transplantation Surgery, Nagoya University Hospital, Nagoya, Japan
| | - Junichi Yoshikawa
- Department of Transplantation Surgery, Nagoya University Hospital, Nagoya, Japan
| | - Nobuhiko Kurata
- Department of Transplantation Surgery, Nagoya University Hospital, Nagoya, Japan
| | - Kanta Jobara
- Department of Transplantation Surgery, Nagoya University Hospital, Nagoya, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
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11
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Gül-Klein S, Hegermann H, Röhle R, Schmelzle M, Tacke F, Schöning W, Öllinger R, Dziodzio T, Maier P, Plewe JM, Horst D, Sauer IM, Pratschke J, Lachmann N, Eurich D. Donor-Specific Antibodies Against Donor Human Leukocyte Antigen are Associated with Graft Inflammation but Not with Fibrosis Long-Term After Liver Transplantation: An Analysis of Protocol Biopsies. J Inflamm Res 2021; 14:2697-2712. [PMID: 34188517 PMCID: PMC8236257 DOI: 10.2147/jir.s307778] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 05/04/2021] [Indexed: 02/06/2023] Open
Abstract
Background Donor-specific antibodies (DSA) against donor human leukocyte antigen after liver transplantation, which are associated with histological changes, have been widely studied with respect to their sustained impact on transplant function. However, their long-term impact after liver transplantation remains unclear. Methods We performed a cross-sectional analysis from June 2016 to July 2017 that included all patients who presented themselves for scheduled follow-up after receiving a liver transplantation between September 1989 and December 2016. In addition to a liver protocol biopsy, patients were screened for human leukocyte antigen antibodies (HLAab) and donor-specific antibodies. Subsequently, the association between human leukocyte antigen antibodies, donor-specific antibodies, histologic and clinical features, and immunosuppression was analyzed. Results Analysis for human leukocyte antigen antibodies and donor-specific antibodies against donor human leukocyte antigen was performed for 291 and 271 patients. A significant association between higher inflammation grades and the presence of human leukocyte antigen antibodies and donor-specific antibodies was detected, while fibrosis stages remained unaffected. These results were confirmed by multivariate logistic regression for inflammation showing a significant increase for presence of human leukocyte antigen antibodies and donor-specific antibodies (OR: 4.43; 95% CI: 1.67–12.6; p=0.0035). Furthermore, the use of everolimus in combination with tacrolimus was significantly associated with the status of negative human leukocyte antigen antibodies and donor-specific antibodies. Viral etiology for liver disease, hepatocellular carcinoma (HCC) and higher steatosis grades of the graft were significantly associated with a lower rate of human leukocyte antigen antibodies. The impact of human leukocyte antigen antibodies and donor-specific antibodies against donor human leukocyte antigen was associated with higher levels of laboratory parameters, such as transaminases and bilirubin. Conclusion Donor-specific antibodies against donor human leukocyte antigen are associated with histological and biochemical graft inflammation after liver transplantation, while fibrosis seems to be unaffected. Future studies should validate these findings for longer observation periods and specific subgroups.
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Affiliation(s)
- Safak Gül-Klein
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Henriette Hegermann
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Robert Röhle
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Biometry and Clinical Epidemiology, Berlin, Germany.,Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Coordinating Center for Clinical Studies, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany
| | - Moritz Schmelzle
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hepatology & Gastroenterology, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Wenzel Schöning
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Robert Öllinger
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Tomasz Dziodzio
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Patrick Maier
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Julius M Plewe
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - David Horst
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Igor Maximilian Sauer
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Biometry and Clinical Epidemiology, Berlin, Germany
| | - Johann Pratschke
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
| | - Nils Lachmann
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, HLA Laboratory, Institute of Transfusion Medicine, Histocompatibility and Immunogenetics, Charité - Universitätsmedizin, Berlin, Germany
| | - Dennis Eurich
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany
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12
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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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13
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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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14
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Murata K, Ikegawa M, Minatoya K, Masumoto H. Strategies for immune regulation in iPS cell-based cardiac regenerative medicine. Inflamm Regen 2020; 40:36. [PMID: 33005258 PMCID: PMC7523082 DOI: 10.1186/s41232-020-00145-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 09/09/2020] [Indexed: 01/14/2023] Open
Abstract
Cardiac regenerative therapy is expected to be a promising therapeutic option for the treatment of severe cardiovascular diseases. Artificial tissues or organoids made from cardiovascular cell lineages differentiated from human induced pluripotent stem cells (iPSCs) are expected to regenerate the damaged heart. Even though immune rejection rarely occurs when iPSC-derived graft and the recipient have the same HLA type, in some cases, such as tissue transplantation onto hearts, the HLA matching would not be sufficient to fully control immune rejection. The present review introduces recent immunomodulatory strategies in iPSC-based transplantation therapies other than MHC matching including the induction of immune tolerance through iPSC-derived antigen-presenting cells, simultaneous transplantation of syngeneic mesenchymal stem cells, and using the universal donor cells such as gene editing-based HLA modulation in iPSCs to regulate T cell compatibility. In addition, we present future perspectives for proper adjustment of immunosuppression therapy after iPSC-derived tissue/organoid-based cardiac regenerative therapies by identifying biomarkers monitoring immune rejection.
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Affiliation(s)
- Kozue Murata
- Clinical Translational Research Program, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 Japan.,Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - Masaya Ikegawa
- Department of Life and Medical Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan
| | - Kenji Minatoya
- Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.,Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hidetoshi Masumoto
- Clinical Translational Research Program, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 Japan.,Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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15
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Tokodai K, Miyagi S, Nakanishi W, Fujio A, Kashiwadate T, Goto M, Unno M, Kamei T. Effects of re-augmenting maintenance immunosuppression on post-transplant donor-specific HLA antibodies in liver transplantation. Transpl Immunol 2020; 63:101334. [PMID: 32919028 DOI: 10.1016/j.trim.2020.101334] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 09/05/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Donor-specific antibodies (DSAs) have various negative short- and long-term effects after organ transplantation. DSAs are prevalent in patients with insufficient immunosuppression; thus, even patients with stable conditions after liver transplantation should be under optimized immunosuppression. However, the effect of re-augmenting immunosuppression therapy for patients with insufficient immunosuppression remains unclear. In this study, we investigated the long-term changes and the effects of immunosuppression (IS) re-augmentation on the DSA status. METHODS Two DSA screenings were performed in 67 patients during long-term follow-up after liver transplantation. After the first screening, IS re-augmentation was performed in patients with consent. The effects of IS re-augmentation on the DSA status were analyzed using data of the serial DSA screenings. Negative conversion was defined as DSA positivity with MFI > 1000 converted to MFI < 1000. Improvement of DSA status was defined as either a 50% reduction of MFI or negative conversion. RESULTS The median interval between the first and second DSA screening was 50 months. Among 67 patients, 43 were positive for DSAs on the first screening. Among these 43 patients, 30 had minimal to no IS therapy at the time of the first screening. Among the 30 patients, IS re-augmentation was conducted in 19. A comparison between the patients with a re-augmented IS and those with a sustained minimized IS showed that the DSA levels significantly decreased in the former (63% (12/19) vs. 18% (2/11), p = 0.02). CONCLUSIONS The results of this study indicate that post-liver transplant IS re-augmentation had suppressive effects on the DSA status. However, the clinical significance of DSA-negative conversion and/or mean fluorescence intensity reduction needs to be further investigated through histological evaluation and/or graft survival during longer follow-up periods.
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Affiliation(s)
- Kazuaki Tokodai
- Department of Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan.
| | - Shigehito Miyagi
- Department of Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan
| | - Wataru Nakanishi
- Department of Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan
| | - Atsushi Fujio
- Department of Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan
| | - Toshiaki Kashiwadate
- Department of Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan
| | - Masafumi Goto
- Department of Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan; Division of Transplantation and Regenerative Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan
| | - Takashi Kamei
- Department of Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan
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16
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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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17
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Manzia TM, Angelico R, Gazia C, Lenci I, Milana M, Ademoyero OT, Pedini D, Toti L, Spada M, Tisone G, Baiocchi L. De novo malignancies after liver transplantation: The effect of immunosuppression-personal data and review of literature. World J Gastroenterol 2019; 25:5356-5375. [PMID: 31558879 PMCID: PMC6761240 DOI: 10.3748/wjg.v25.i35.5356] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 08/08/2019] [Accepted: 08/24/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Immunosuppression has undoubtedly raised the overall positive outcomes in the post-operative management of solid organ transplantation. However, long-term exposure to immunosuppression is associated with critical systemic morbidities. De novo malignancies following orthotopic liver transplants (OLTs) are a serious threat in pediatric and adult transplant individuals. Data from different experiences were reported and compared to assess the connection between immunosuppression and de novo malignancies in liver transplant patients.
AIM To study the role of immunosuppression on the incidence of de novo malignancies in liver transplant recipients.
METHODS A systematic literature examination about de novo malignancies and immunosuppression weaning in adult and pediatric OLT recipients was described in the present review. Worldwide data were collected from highly qualified institutions performing OLTs. Patient follow-up, immunosuppression discontinuation and incidence of de novo malignancies were reported. Likewise, the review assesses the differences in adult and pediatric recipients by describing the adopted immunosuppression regimens and the different type of diagnosed solid and blood malignancy.
RESULTS Emerging evidence suggests that the liver is an immunologically privileged organ able to support immunosuppression discontinuation in carefully selected recipients. Malignancies are often detected in liver transplant patients undergoing daily immunosuppression regimens. Post-transplant lymphoproliferative diseases and skin tumors are the most detected de novo malignancies in the pediatric and adult OLT population, respectively. To date, immunosuppression withdrawal has been achieved in up to 40% and 60% of well-selected adult and pediatric recipients, respectively. In both populations, a clear benefit of immunosuppression weaning protocols on de novo malignancies is difficult to ascertain because data have not been specified in most of the clinical experiences.
CONCLUSION The selected populations of tolerant pediatric and adult liver transplant recipients greatly benefit from immunosuppression weaning. There is still no strong clinical evidence on the usefulness of immunosuppression withdrawal in OLT recipients on malignancies. An interesting focus is represented by the complete reconstitution of the immunological pathways that could help in decreasing the incidence of de novo malignancies and may also help in treating liver transplant patients suffering from cancer.
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Affiliation(s)
- Tommaso Maria Manzia
- HPB and Transplant Unit, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Roberta Angelico
- Division of Abdominal Transplantation and HPB Surgery, Bambino Gesù Children's Hospital IRCCS, Rome 00165, Italy
| | - Carlo Gazia
- HPB and Transplant Unit, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC 27101, United States
| | - Ilaria Lenci
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
| | - Martina Milana
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
| | | | - Domiziana Pedini
- Division of Abdominal Transplantation and HPB Surgery, Bambino Gesù Children's Hospital IRCCS, Rome 00165, Italy
| | - Luca Toti
- HPB and Transplant Unit, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Marco Spada
- Division of Abdominal Transplantation and HPB Surgery, Bambino Gesù Children's Hospital IRCCS, Rome 00165, Italy
| | - Giuseppe Tisone
- HPB and Transplant Unit, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Leonardo Baiocchi
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
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Peng Y, Ye Y, Jia J, He Y, Yang Z, Zhu X, Huang H, Wang W, Geng L, Yin S, Zhou L, Zheng S. Galectin-1-induced tolerogenic dendritic cells combined with apoptotic lymphocytes prolong liver allograft survival. Int Immunopharmacol 2018; 65:470-482. [PMID: 30390594 DOI: 10.1016/j.intimp.2018.10.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 09/25/2018] [Accepted: 10/11/2018] [Indexed: 01/09/2023]
Abstract
Donor-derived tolerogenic dendritic cells (DCs) and apoptotic lymphocytes (ALs) are practical tools for controlling rejection after transplantation by targeting direct and indirect allorecognition pathways, respectively. To date, few studies have investigated the combination of donor-derived tolerogenic DCs and ALs infusion in organ transplantation protection. In the present study, we generated galectin-1-induced tolerogenic DCs (DCgal-1s) and ultraviolet irradiation-induced ALs with stable immune characteristics in vitro and potential immune regulatory activity in vivo. A rat model of acute liver transplant rejection was established, and the intrinsic tolerogenic profiles associated with the short-term alleviation of rejection and the long-term maintenance of tolerance in the absence of immunosuppressive drugs were evaluated. The DCgal-1-AL treatment prolonged allograft survival more significantly than a transfusion of DCgal-1s or ALs alone. This benefit was associated with CD4+ Treg cell expansion and decreased interferon (IFN)-γ+ T cell levels. Moreover, DCgal-1-AL treatment led to different cytokine/chemokine changes in the allograft and peripheral blood, that indicated an alleviation of local and systemic inflammation on day 7 post-transplantation. TGF-β1 and TGF-β2 were significantly increased in the long-term surviving allografts after DCgal-1-AL treatment. Our results indicate that the combination of DCgal-1s with ALs effectively prolongs liver allograft survival and represents a novel therapeutic strategy for liver transplant rejection.
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Affiliation(s)
- Yifan Peng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; NHFPC Key Laboratory of Combined Multi-organ Transplantation, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
| | - Yufu Ye
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; NHFPC Key Laboratory of Combined Multi-organ Transplantation, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
| | - Junjun Jia
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Yong He
- NHFPC Key Laboratory of Combined Multi-organ Transplantation, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China
| | - Zhentao Yang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; NHFPC Key Laboratory of Combined Multi-organ Transplantation, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China
| | - Xiaolu Zhu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; NHFPC Key Laboratory of Combined Multi-organ Transplantation, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China
| | - Hechen Huang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; NHFPC Key Laboratory of Combined Multi-organ Transplantation, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
| | - Wei Wang
- S. Arthur Localio Laboratory, Department of Surgery, NYU School of Medicine, West Tower Alexandria Center, New York 10016, USA
| | - Lei Geng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Shengyong Yin
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; NHFPC Key Laboratory of Combined Multi-organ Transplantation, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; NHFPC Key Laboratory of Combined Multi-organ Transplantation, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; NHFPC Key Laboratory of Combined Multi-organ Transplantation, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China.
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19
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Tokodai K, Miyagi S, Nakanishi C, Hara Y, Nakanishi W, Miyazawa K, Shimizu K, Murakami K, Sasano H, Goto M, Unno M, Kamei T. Association of post-transplant donor-specific HLA antibody with liver graft fibrosis during long-term follow-up after pediatric liver transplantation. Pediatr Transplant 2018. [PMID: 29542229 DOI: 10.1111/petr.13169] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The aim of this study was to evaluate the significance of post-transplant DSA as a predictor of liver fibrosis during long-term follow-up after pediatric LT. We evaluated the histological findings in 18 LT recipients who underwent liver biopsy after DSA screening. Liver fibrosis was scored based on the METAVIR fibrosis staging. Patients were divided into 2 groups based on histological findings, and clinical characteristics among patients with liver fibrosis were assessed. Of 18 patients, 7 were included in the fibrosis group. No significant between-group differences were found regarding peritransplant characteristics, including age, sex, primary disease, ABO incompatibility, and immunosuppressive regimen. Episodes of acute rejection and non-adherence to immunosuppressive drugs were comparable between both groups. The MFI for anti-DR DSA and positive rate were significantly higher in the fibrosis group (1655 vs 216; P = .019, 86% vs 27%; P = .012, respectively). MFI for anti-DQ DSA was higher in the fibrosis group, but non-significantly (2052 vs 384; P = .46). Post-transplant anti-DR DSA is associated with graft fibrosis during long-term follow-up. This finding seems useful for the implementation of valid histological examinations of liver grafts for patients with higher MFI, especially for anti-DR DSA, after pediatric LT.
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Affiliation(s)
- Kazuaki Tokodai
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Shigehito Miyagi
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Chikashi Nakanishi
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuyuki Hara
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Wataru Nakanishi
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Koji Miyazawa
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kenji Shimizu
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Keigo Murakami
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hironobu Sasano
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masafumi Goto
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.,Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
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20
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Feng S, Bucuvalas J. Tolerance after liver transplantation: Where are we? Liver Transpl 2017; 23:1601-1614. [PMID: 28834221 DOI: 10.1002/lt.24845] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 07/24/2017] [Accepted: 08/07/2017] [Indexed: 12/16/2022]
Abstract
Impeccable management of immunosuppression is required to ensure the best longterm outcomes for liver transplant recipients. This is particularly challenging for children who arguably need 8 decades of graft and patient survival. Too little risks chronic, often subclinical allo-immune injury while too much risks insidious and cumulative toxicities. Historically, immunosuppression minimization or withdrawal has been a strategy to optimize the longevity of liver transplant recipients. The literature is sprinkled with single-center reports of operationally tolerant patients - those with apparently normal liver function and liver tests. However, without biopsy evidence of immunological quiescence, confidence in the phenotypic assignment of tolerance is shaky. More recently, multicenter trials of immunosuppression withdrawal for highly selected, stable, longterm adult and pediatric liver recipients have shown tolerance rates, based on both biochemical and histological assessment, of 40% and 60%, respectively. Extended biochemical and histologic follow-up of children over 8 years, equivalent to 7+ years off of drug, suggests that operational tolerance is robust. Therefore, clearly, immunosuppression can be completely and safety withdrawn from highly-selected subsets of adults and children. However, these trials have also confirmed that clinically ideal recipients - those eligible for immunosuppression withdrawal trial - can harbor significant and worrisome inflammation and/or fibrosis. Although the etiology and prognosis of these findings remain unknown, it is reasonable to surmise that they may reflect an anti-donor immune response that is insufficiently controlled. To achieve the outcomes that we are seeking and that our patients are demanding, we desperately need noninvasive but accurate biomarkers that identify whether immunosuppression is neither too much nor too little but "just right." Until these are available, liver histology remains the gold standard to assess allograft health and guide immunosuppression management. Liver Transplantation 23 1601-1614 2017 AASLD.
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Affiliation(s)
- Sandy Feng
- Division of Transplantation, Department of Surgery, University of California, San Francisco, San Francisco, CA
| | - John Bucuvalas
- Division of Gastroenterology, Hepatology and Nutrition, University of Cincinnati, Cincinnati Children's Hospital, Cincinnati, OH
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21
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Levitsky J, Feng S. Tolerance in clinical liver transplantation. Hum Immunol 2017; 79:283-287. [PMID: 29054397 DOI: 10.1016/j.humimm.2017.10.007] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 10/11/2017] [Accepted: 10/17/2017] [Indexed: 12/22/2022]
Abstract
While advances in immunosuppressive therapy have lowered the rate of acute rejection following liver transplantation, the consequence has been an increase in morbidity and mortality related to the lifelong need for maintenance immunosuppression. These complications include an increased risk of malignancy, infection, metabolic disorders, and chronic kidney disease, as well as high health care costs associated with these therapies and the required drug monitoring. Given these issues, most clinicians attempt trial and error dose minimization with variable success rates, and there has been significant interest in full drug withdrawal in select patients through research protocols. These strategies would be more successful if immunomodulatory therapies early after transplantation could be developed and if immune activation biomarkers guiding drug tapering were available to personalize these approaches. This review will review the mechanisms of liver transplant tolerance and potential strategies to achieve immunosuppression withdrawal.
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Affiliation(s)
- Josh Levitsky
- Division of Gastroenterology & Hepatology, Northwestern University, Chicago, IL, United States.
| | - Sandy Feng
- Division of Transplant Surgery, University of California at San Francisco, San Francisco, CA, United States
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22
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Early and Late Factors Impacting Patient and Graft Outcome in Pediatric Liver Transplantation: Summary of an ESPGHAN Monothematic Conference. J Pediatr Gastroenterol Nutr 2017; 65:e53-e59. [PMID: 28319600 DOI: 10.1097/mpg.0000000000001564] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
As pediatric liver transplantation comes of age, experts gathered to discuss current paradigms and define gaps in knowledge warranting research to further improve patient and graft outcomes. Identified areas ripe for collaborative research include understanding the molecular and cellular mechanisms of tolerance and the role of donor-specific antibodies, considering ways to expand donor pool, minimizing long-term side effects of immunosuppression, and fine-tuning surgical techniques to minimize biliary and vascular complications.
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23
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Impact of the Trough Level of Calcineurin Inhibitor on the Prevalence of Donor-Specific Human Leukocyte Antigen Antibodies During Long-Term Follow-Up After Pediatric Liver Transplantation: Antibody Strength and Complement-Binding Ability. Transplant Direct 2017; 3:e196. [PMID: 28795147 PMCID: PMC5540634 DOI: 10.1097/txd.0000000000000713] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 06/15/2017] [Accepted: 06/17/2017] [Indexed: 12/16/2022] Open
Abstract
Background In pediatric patients, long-term immunosuppression after liver transplantation (LT) is typically minimal. However, posttransplant donor-specific HLA antibodies (DSAs) may be prevalent under these conditions. Here, we evaluated the effects of minimized calcineurin inhibitor (CNI) on DSA development to assess the validity of minimized/withdrawn immunosuppression. Methods We retrospectively examined 66 patients who underwent pediatric LT at our institution between July 1991 and October 2013. Patients were divided into 2 groups based on the CNI trough level. The cutoff trough levels were 3 and 30 ng/mL for tacrolimus and cyclosporine, respectively. Luminex single-antigen bead assays were performed, and the cutoff for a positive reaction was set at a mean fluorescence intensity (MFI) of at least 1000. Results The mean recipient ages at the time of LT were 29.1 and 77.2 months for the low and regular CNI groups, respectively (P = 0.0007). Univariate logistic regression analysis revealed that recipient age at LT younger than 3 years (P = 0.0099) and low CNI (P < 0.0001) were significantly associated with DSA development. In multivariate analysis, low CNI was an independent risk factor of DSA development (P = 0.0011). Of 15 high-MFI DSAs, 3 were anti-DR, and 12 were anti-DQ. Two of 3 anti-DR DSAs and 11 of 12 anti-DQ DSAs had complement-binding ability and high MFIs. Conclusions CNI minimization was an independent risk factor for posttransplant DSA during long-term follow-up after pediatric LT. Adjusting CNI to appropriate levels is a safe first step to prevent the immunological effects of DSA.
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24
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Abstract
Antibody-mediated rejection (AMR) in liver transplants is a field in its infancy compared with its allograft cohorts of the kidney and lung. Acute AMR is diagnosed based on specific clinical and histopathologic criteria: serum donor specific antibodies, C4d staining, histopathologic findings on liver biopsy, and exclusion of other entities. In contrast, the histologic features of chronic AMR are not as specific and it is a more challenging diagnosis to make. Treatments of acute and chronic AMR include some combination of steroids, immune-modulating agents, intravenous immunoglobulin, plasmapheresis, and proteasome inhibitors.
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Affiliation(s)
- Michael Lee
- Department of Pathology and Cell Biology, Columbia University, 630 West 168th Street, VC14-238, New York, NY 10032, USA.
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25
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Feng S, Demetris AJ, Spain KM, Kanaparthi S, Burrell BE, Ekong UD, Alonso EM, Rosenthal P, Turka LA, Ikle D, Tchao NK. Five-year histological and serological follow-up of operationally tolerant pediatric liver transplant recipients enrolled in WISP-R. Hepatology 2017; 65:647-660. [PMID: 27302659 PMCID: PMC5159322 DOI: 10.1002/hep.28681] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 05/15/2016] [Accepted: 05/24/2016] [Indexed: 12/13/2022]
Abstract
UNLABELLED Pediatric liver transplant recipients arguably have the most to gain and the most to lose from discontinuing immunosuppression (IS). Whereas IS undoubtedly exerts a cumulative toll, there is concern that insufficient or no IS may contribute to allograft deterioration. Twelve pediatric recipients of parental living donor liver grafts, identified as operationally tolerant through complete IS withdrawal (WISP-R; NCT00320606), were followed for a total of 5 years (1 year of IS withdrawal and 4 years off IS) with serial liver tests and autoantibody and alloantibody assessments. Liver biopsies were performed 2 and 4 years off IS, and, at these time points, immunoglobulin G (IgG) subclass and C1q binding activity for donor-specific antibodies (DSAs) were determined. There were no cases of chronic rejection, graft loss, or death. Allografts did not exhibit progressive increase in inflammation or fibrosis. Smooth-muscle actin expression by stellate cells and CD34 expression by liver sinusoidal endothelial cells remained stable, consistent with the absence of progressive graft injury. Three subjects never exhibited DSA. However, 3 subjects showed intermittent de novo class I DSA, 4 subjects showed persistent de novo class II DSA, and 5 subjects showed persistent preexisting class II DSA. Class II DSA was predominantly against donor DQ antigens, often of high mean fluorescence intensity, rarely of the IgG3 subclass, and often capable of binding C1q. CONCLUSION Operationally tolerant pediatric liver transplant recipients maintain generally stable allograft histology in spite of apparently active humoral allo-immune responses. The absence of increased inflammation or progressive fibrosis suggests that a subset of liver allografts seem resistant to the chronic injury that is characteristic of antibody-mediated damage. (Hepatology 2017;65:647-660).
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Affiliation(s)
- Sandy Feng
- Department of Surgery, University of California San Francisco, San Francisco, CA
| | | | | | | | | | - Udeme D. Ekong
- Department of Pediatrics, Yale School of Medicine, New Haven, CO
| | - Estella M. Alonso
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Philip Rosenthal
- Department of Surgery, University of California San Francisco, San Francisco, CA,Department of Pediatrics, University of California San Francisco, San Francisco, CA
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26
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Emond JC, Griesemer AD. Tolerance in clinical liver transplantation: The long road ahead. Hepatology 2017; 65:411-413. [PMID: 27718261 DOI: 10.1002/hep.28862] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 09/27/2016] [Accepted: 09/29/2016] [Indexed: 12/15/2022]
Affiliation(s)
- Jean C Emond
- Department of Surgery, Columbia University, New York, NY
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27
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Young JS, Daniels MD, Miller ML, Wang T, Zhong R, Yin D, Alegre ML, Chong AS. Erosion of Transplantation Tolerance After Infection. Am J Transplant 2017; 17:81-90. [PMID: 27273890 PMCID: PMC5938732 DOI: 10.1111/ajt.13910] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 06/01/2016] [Accepted: 06/03/2016] [Indexed: 01/25/2023]
Abstract
Recent clinical studies suggest that operational allograft tolerance can be persistent, but long-term surviving allografts can be rejected in a subset of patients, sometimes after episodes of infection. In this study, we examined the impact of Listeria monocytogenes (Lm) infection on the quality of tolerance in a mouse model of heart allograft transplantation. Lm infection induced full rejection in 40% of tolerant recipients, with the remaining experiencing a rejection crisis or no palpable change in their allografts. In the surviving allografts on day 8 postinfection, graft-infiltrating cell numbers increased and exhibited a loss in the tolerance gene signature. By day 30 postinfection, the tolerance signature was broadly restored, but with a discernible reduction in the expression of a subset of 234 genes that marked tolerance and was down-regulated at day 8 post-Lm infection. We further demonstrated that the tolerant state after Lm infection was functionally eroded, as rejection of the long-term surviving graft was induced with anti-PD-L1 whereas the same treatment had no effect in noninfected tolerant mice. Collectively, these observations demonstrate that tolerance, even if initially robust, exists as a continuum that can be eroded following bystander immune responses that accompany certain infections.
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Affiliation(s)
- James S Young
- Section of Transplantation, Department of Surgery, Chicago State University, Chicago, IL 60628
| | - Melvin D Daniels
- Section of Transplantation, Department of Surgery, Chicago State University, Chicago, IL 60628
- Department of Biological Sciences, Chicago State University, Chicago, IL 60628
| | - Michelle L Miller
- Section of Rheumatology, Department of Medicine, Chicago State University, Chicago, IL 60628
| | - Tongmin Wang
- Section of Transplantation, Department of Surgery, Chicago State University, Chicago, IL 60628
| | - Rong Zhong
- Section of Transplantation, Department of Surgery, Chicago State University, Chicago, IL 60628
| | - Dengping Yin
- Section of Transplantation, Department of Surgery, Chicago State University, Chicago, IL 60628
| | - Maria-Luisa Alegre
- Section of Rheumatology, Department of Medicine, Chicago State University, Chicago, IL 60628
| | - Anita S. Chong
- Section of Transplantation, Department of Surgery, Chicago State University, Chicago, IL 60628
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28
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Conti F, Dahlqvist G, Brisson H, Miyara M, Calmus Y, Gorochov G. Regulatory T cell therapy: An option to induce operational tolerance in liver transplantation. Clin Res Hepatol Gastroenterol 2016; 40:660-665. [PMID: 27288298 DOI: 10.1016/j.clinre.2016.05.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 04/26/2016] [Accepted: 05/02/2016] [Indexed: 02/04/2023]
Abstract
Regulatory T cells (Treg) may play an important role in operational (clinical) tolerance (OT), a stable graft function without immunosuppression in an otherwise immunocompetent host, that is spontaneously observed in some patients many years after transplantation. Several ongoing clinical trials are currently testing the effects of donor-specific or non-specific Treg infusion with the goal to induce this state of OT a few months after liver transplantation (LT). The preliminary results of two of these trials have been recently published, and raise a number of comments and issues: (1) These two papers demonstrate that a 100 to 1000-fold ex-vivo expansion of Treg is possible in humans after 2 weeks of culture. The optimal human Treg dose is however not clearly established, and might be higher than the dose that would be expected from translating murine data. (2) A lot of concerns are remaining regarding the Treg purity before expansion, the Treg stability during in vitro culture and the in vivo fate of infused cells. A strict monitoring of Treg should thus be done at each step. (3) Since Treg may play a detrimental role in some conditions, such as viral diseases and cancer, potential LT recipients with such diseases should probably be excluded from the initial trials of Treg infusion. (4) The follow-up of tolerant liver recipients should include repeated liver biopsies and detection of autoantibodies and humoral response, in addition to conventional liver graft assessment, in order to prevent the development of immune complications related to immunosuppression withdrawal. (5) The final issue raised by Treg therapy in LT is the choice of the immunosuppressive regimen used before tapering or withdrawal, appropriate to preserve OT establishment.
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Affiliation(s)
- F Conti
- AP-HP, Hôpital de la Pitié-Salpêtrière, 75013 Paris, France; France Sorbonne universités, UPMC université Paris 06, 75006 Paris, France
| | - G Dahlqvist
- Cliniques universitaires Saint-Luc, 1200 Bruxelles, Belgium.
| | - H Brisson
- AP-HP, Hôpital de la Pitié-Salpêtrière, 75013 Paris, France.
| | - M Miyara
- AP-HP, Hôpital de la Pitié-Salpêtrière, 75013 Paris, France; France Sorbonne universités, UPMC université Paris 06, 75006 Paris, France.
| | - Y Calmus
- AP-HP, Hôpital de la Pitié-Salpêtrière, 75013 Paris, France; France Sorbonne universités, UPMC université Paris 06, 75006 Paris, France.
| | - G Gorochov
- AP-HP, Hôpital de la Pitié-Salpêtrière, 75013 Paris, France; France Sorbonne universités, UPMC université Paris 06, 75006 Paris, France
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29
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Lau AH, Vitalone MJ, Haas K, Shawler T, Esquivel CO, Berquist WE, Martinez OM, Castillo RO, Krams SM. Mass cytometry reveals a distinct immunoprofile of operational tolerance in pediatric liver transplantation. Pediatr Transplant 2016; 20:1072-1080. [PMID: 27781378 PMCID: PMC5404744 DOI: 10.1111/petr.12795] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/10/2016] [Indexed: 01/24/2023]
Abstract
Long-term IS in transplant patients has significant morbidity, poorer quality of life, and substantial economic costs. TOL, defined as graft acceptance without functional impairment in the absence of IS, has been achieved in some pediatric LT recipients. Using mass cytometry, peripheral blood immunotyping was performed to characterize differences between tolerant patients and patients who are stable on single-agent IS. Single-cell mass cytometry was performed using blood samples from a single-center pediatric LT population of operationally tolerant patients to comprehensively characterize the immune cell populations in the tolerant state compared with patients on chronic low-dose IS. Specific T-cell populations of interest were confirmed by flow cytometry. This high-dimensional phenotypic analysis revealed distinct immunoprofiles between transplant populations as well as a CD4+ TOT (CD4+ CD5+ CD25+ CD38-/lo CD45RA) that correlates with tolerance in pediatric LT recipients. In TOL patients, the TOT was significantly increased as compared to patients stable on low levels of IS. This TOT cell was confirmed by flow cytometry and is distinct from classic Treg cells. These results demonstrate the power of mass cytometry to discover significant immune cell signatures that have diagnostic potential.
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Affiliation(s)
- Audrey H. Lau
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Lucile Packard Children’s Hospital, Stanford, CA, USA,Division of Abdominal Transplantation, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Matthew J. Vitalone
- Division of Abdominal Transplantation, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Kelly Haas
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Lucile Packard Children’s Hospital, Stanford, CA, USA
| | - Todd Shawler
- Division of Abdominal Transplantation, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Carlos O. Esquivel
- Division of Abdominal Transplantation, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - William E. Berquist
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Lucile Packard Children’s Hospital, Stanford, CA, USA
| | - Olivia M. Martinez
- Division of Abdominal Transplantation, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA,Program in Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - Ricardo O. Castillo
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Lucile Packard Children’s Hospital, Stanford, CA, USA
| | - Sheri M. Krams
- Division of Abdominal Transplantation, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA,Program in Immunology, Stanford University School of Medicine, Stanford, CA, USA,Correspondence should be addressed to: Dr. Sheri M. Krams, Transplant Immunobiology Lab, Stanford University School of Medicine, 1201 Welch Road, MSLS P313, Stanford, CA 94305-5492, 650-498-6246, 650-498-6250 (FAX),
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30
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Demetris AJ, Bellamy C, Hübscher SG, O'Leary J, Randhawa PS, Feng S, Neil D, Colvin RB, McCaughan G, Fung JJ, Del Bello A, Reinholt FP, Haga H, Adeyi O, Czaja AJ, Schiano T, Fiel MI, Smith ML, Sebagh M, Tanigawa RY, Yilmaz F, Alexander G, Baiocchi L, Balasubramanian M, Batal I, Bhan AK, Bucuvalas J, Cerski CTS, Charlotte F, de Vera ME, ElMonayeri M, Fontes P, Furth EE, Gouw ASH, Hafezi-Bakhtiari S, Hart J, Honsova E, Ismail W, Itoh T, Jhala NC, Khettry U, Klintmalm GB, Knechtle S, Koshiba T, Kozlowski T, Lassman CR, Lerut J, Levitsky J, Licini L, Liotta R, Mazariegos G, Minervini MI, Misdraji J, Mohanakumar T, Mölne J, Nasser I, Neuberger J, O'Neil M, Pappo O, Petrovic L, Ruiz P, Sağol Ö, Sanchez Fueyo A, Sasatomi E, Shaked A, Shiller M, Shimizu T, Sis B, Sonzogni A, Stevenson HL, Thung SN, Tisone G, Tsamandas AC, Wernerson A, Wu T, Zeevi A, Zen Y. 2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection. Am J Transplant 2016; 16:2816-2835. [PMID: 27273869 DOI: 10.1111/ajt.13909] [Citation(s) in RCA: 404] [Impact Index Per Article: 44.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 06/01/2016] [Accepted: 05/25/2016] [Indexed: 02/06/2023]
Abstract
The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.
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Affiliation(s)
- A J Demetris
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - C Bellamy
- The University of Edinburgh, Edinburgh, Scotland
| | | | - J O'Leary
- Baylor University Medical Center, Dallas, TX
| | - P S Randhawa
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - S Feng
- University of California San Francisco Medical Center, San Francisco, CA
| | - D Neil
- Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | - R B Colvin
- Massachusetts General Hospital, Boston, MA
| | - G McCaughan
- Royal Prince Alfred Hospital, Sydney, Australia
| | | | | | - F P Reinholt
- Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - H Haga
- Kyoto University Hospital, Kyoto, Japan
| | - O Adeyi
- University Health Network and University of Toronto, Toronto, Canada
| | - A J Czaja
- Mayo Clinic College of Medicine, Rochester, MN
| | - T Schiano
- Mount Sinai Medical Center, New York, NY
| | - M I Fiel
- Icahn School of Medicine at Mount Sinai, New York, NY
| | - M L Smith
- Mayo Clinic Health System, Scottsdale, AZ
| | - M Sebagh
- AP-HP Hôpital Paul-Brousse, Paris, France
| | - R Y Tanigawa
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - F Yilmaz
- University of Ege, Faculty of Medicine, Izmir, Turkey
| | | | - L Baiocchi
- Policlinico Universitario Tor Vergata, Rome, Italy
| | | | - I Batal
- Columbia University College of Physicians and Surgeons, New York, NY
| | - A K Bhan
- Massachusetts General Hospital, Boston, MA
| | - J Bucuvalas
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - C T S Cerski
- Universidade Federal do Rio Grande do Sul, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
| | | | | | - M ElMonayeri
- Ain Shams University, Wady El-Neel Hospital, Cairo, Egypt
| | - P Fontes
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - E E Furth
- Hospital of the University of Pennsylvania, Philadelphia, PA
| | - A S H Gouw
- University Medical Center Groningen, Groningen, the Netherlands
| | | | - J Hart
- University of Chicago Hospitals, Chicago, IL
| | - E Honsova
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - W Ismail
- Beni-Suef University, Beni-Suef, Egypt
| | - T Itoh
- Kobe University Hospital, Kobe, Japan
| | | | - U Khettry
- Lahey Hospital and Medical Center, Burlington, MA
| | | | - S Knechtle
- Duke University Health System, Durham, NC
| | - T Koshiba
- Soma Central Hospital, Soma, Fukushima, Japan
| | - T Kozlowski
- University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - C R Lassman
- David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - J Lerut
- Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - J Levitsky
- Northwestern University Feinberg School of Medicine, Chicago, IL
| | - L Licini
- Pope John XXIII Hospital, Bergamo, Italy
| | - R Liotta
- Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, University of Pittsburgh Medical Center, Palermo, Italy
| | - G Mazariegos
- Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA
| | - M I Minervini
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - J Misdraji
- Massachusetts General Hospital, Boston, MA
| | - T Mohanakumar
- St. Joseph's Hospital and Medical Center, Norton Thoracic Institute, Phoenix, AZ
| | - J Mölne
- University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - I Nasser
- Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA
| | - J Neuberger
- Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | - M O'Neil
- University of Kansas Medical Center, Kansas City, KS
| | - O Pappo
- Hadassah Medical Center, Jerusalem, Israel
| | - L Petrovic
- University of Southern California, Los Angeles, CA
| | - P Ruiz
- University of Miami, Miami, FL
| | - Ö Sağol
- School of Medicine, Dokuz Eylul University, Izmir, Turkey
| | | | - E Sasatomi
- University of North Carolina School of Medicine, Chapel Hill, NC
| | - A Shaked
- University of Pennsylvania Health System, Philadelphia, PA
| | - M Shiller
- Baylor University Medical Center, Dallas, TX
| | - T Shimizu
- Toda Chuo General Hospital, Saitama, Japan
| | - B Sis
- University of Alberta Hospital, Edmonton, Canada
| | - A Sonzogni
- Pope John XXIII Hospital, Bergamo, Italy
| | | | - S N Thung
- Icahn School of Medicine at Mount Sinai, New York, NY
| | - G Tisone
- University of Rome-Tor Vergata, Rome, Italy
| | | | - A Wernerson
- Karolinska University Hospital, Stockholm, Sweden
| | - T Wu
- Tulane University School of Medicine, New Orleans, LA
| | - A Zeevi
- University of Pittsburgh, Pittsburgh, PA
| | - Y Zen
- Kobe University Hospital, Kobe, Japan
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Baroja-Mazo A, Revilla-Nuin B, Parrilla P, Martínez-Alarcón L, Ramírez P, Pons JA. Tolerance in liver transplantation: Biomarkers and clinical relevance. World J Gastroenterol 2016; 22:7676-91. [PMID: 27678350 PMCID: PMC5016367 DOI: 10.3748/wjg.v22.i34.7676] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 07/04/2016] [Accepted: 08/05/2016] [Indexed: 02/06/2023] Open
Abstract
Transplantation is the optimal treatment for end-stage organ failure, and modern immunosuppression has allowed important progress in short-term outcomes. However, immunosuppression poorly influences chronic rejection and elicits chronic toxicity in current clinical practice. Thus, a major goal in transplantation is to understand and induce tolerance. It is well established that human regulatory T cells expressing the transcription factor FoxP3 play important roles in the maintenance of immunological self-tolerance and immune homeostasis. The major regulatory T cell subsets and mechanisms of expansion that are critical for induction and long-term maintenance of graft tolerance and survival are being actively investigated. Likewise, other immune cells, such as dendritic cells, monocyte/macrophages or natural killer cells, have been described as part of the process known as "operational tolerance". However, translation of these results towards clinical practice needs solid tools to identify accurately and reliably patients who are going to be tolerant. In this way, a plethora of genetic and cellular biomarkers is raising and being validated worldwide in large multi-center clinical trials. Few of the studies performed so far have provided a detailed analysis of the impact of immunosuppression withdrawal on pre-existing complications derived from the long-term administration of immunosuppressive drugs and the side effects associated with them. The future of liver transplantation is aimed to develop new therapies which increase the actual low tolerant vs non-tolerant recipients ratio.
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Baumann AK, Schlue J, Noyan F, Hardtke-Wolenski M, Lehner F, Barg-Hock H, Klempnauer J, Manns MP, Taubert R, Jaeckel E. Preferential accumulation of T helper cells but not cytotoxic T cells characterizes benign subclinical rejection of human liver allografts. Liver Transpl 2016; 22:943-55. [PMID: 26929119 DOI: 10.1002/lt.24427] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 02/12/2016] [Accepted: 02/16/2016] [Indexed: 12/11/2022]
Abstract
Subclinical rejection (SCR) is a common event in protocol biopsies after liver transplantation (LT). So far the interpretation of the underlying histological changes and clinical significance is limited. Previous studies were restricted to SCR manifestations within the first weeks after transplantation with limited follow-up. We analyzed clinical data from our prospective protocol biopsy program and found late SCR (at least 3 months after transplantation) to be a common event (41/94 patients). SCR manifested much later than acute cellular rejection (ACR). In the second year after transplantation, the SCR incidence in protocol biopsies reached a plateau of approximately 25% and remained at this level until the latest observed manifestations more than 5 years after transplantation. During a median follow-up of 32 months after SCR, no acute or chronic rejection, relevant graft fibrosis, graft loss, or liver-related death occurred even without specific therapy for SCR. Immunophenotyping of liver biopsies during SCR showed that similar to ACR, the composition of intrahepatic T cells depended on the severity of histological rejection. However, SCR showed a different pattern of infiltrating T cells with a stronger accumulation of CD4(+) cells, an increasing CD4(+) /CD8(+) ratio, and an increasing CD4(+) forkhead box P3 (FOXP3)(+) regulatory T cell (Treg)/CD8(+) ratio, which was not seen in ACR. These intrahepatic T cell patterns were not reflected in the peripheral blood. In conclusion, late SCR after LT has a good clinical prognosis, and it seems safe to leave it untreated. This benign clinical course compared to ACR is associated with intrahepatic T cell infiltration patterns showing less cytotoxic T cells and more CD4(+) FOXP3(+) Tregs. Liver Transplantation 22 943-955 2016 AASLD.
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Affiliation(s)
- Anna K Baumann
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Jerome Schlue
- Department of Pathology, Hannover Medical School, Hannover, Germany
| | - Fatih Noyan
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany
| | - Matthias Hardtke-Wolenski
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Frank Lehner
- Department of General, Abdominal, and Transplant Surgery, Hannover Medical School, Hannover, Germany.,Department of Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany
| | - Hannelore Barg-Hock
- Department of General, Abdominal, and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Juergen Klempnauer
- Department of General, Abdominal, and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany
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Nafady-Hego H, Li Y, Ohe H, Elgendy H, Zhao X, Sakaguchi S, Bishop GA, Koshiba T. Utility of CD127 combined with FOXP3 for identification of operational tolerance after liver transplantation. Transpl Immunol 2016; 36:1-8. [PMID: 27105585 DOI: 10.1016/j.trim.2016.04.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 04/17/2016] [Accepted: 04/18/2016] [Indexed: 11/26/2022]
Abstract
Loss of cell surface expression of CD127 on CD4(+)CD25(++) regulatory T-cells (Tregs) may be a useful marker to efficiently isolate Tregs. As FOXP3 was specifically used to identify Tregs, combining these two markers could give better identification for patient with operational tolerance (OT) after liver transplantation. To testify this mixed lymphocyte reaction (MLR), the function of circulating CD4(+)CD25(++)CD127(dim) cells (CD127(dim) cells) was examined in immunosuppression (IS)-free pediatric recipients after liver transplantation (LTx) (group operational tolerance: OT) (Gr-tol n=25) compared to recipients who could not stop IS due to clinically overt rejection (group intolerance) (Gr-intol n=18), recipients who were weaning IS (Gr-weaning n=11) and age-matched healthy volunteers (Gr-vol n=11). In addition, the frequencies of CD127(dim) cells vs CD4(+)CD25(++)CD127(dim)FOXP3(+) (CD127(dim)FOXP3(+)) cells were compared in these four groups by FACS analyses. Our results showed that The proliferation of CD4 cells to donor antigens was reduced compared to third-party antigens only in Gr-tol (P=0.022) but not in other groups (P=NS). Depletion of CD127(dim) cells resulted in a donor antigen-specific abrogation of this MLR hyporesponsiveness in Gr-tol (P<0.001) but not other groups (P=NS). This implied that CD127 efficiently isolated donor antigen-specific Tregs. The frequencies of CD127(dim) cells were significantly lower in Gr-intol (5.2%±1.9%) compared to those in Gr-tol (7.8%±1.8%) (P<0.001) as were the frequencies of CD127(dim) FOXP3(+) cells (Gr-tol: 5.4%±1.7% vs Gr-intol: 2.9%±1.0%, P<0.001). Of interest, there were fewer CD127(dim)FOXP3(+) cells in Gr-intol (2.9%±1%) than in Gr-weaning (5.1%±1.8%) (P=0.002), but no difference in CD127(dim) cells (Gr-intol: 5.2%±1.9% vs Gr-weaning: 6.7%±2.0%) (NS). Thus, combining FOXP3 with CD127 for phenotype analysis demonstrated an unequivocal difference between Gr-intol and Gr-weaning that was not detected by CD127 alone. In conclusion CD127 was a useful surface marker to isolate donor-antigen-specific-Tregs in OT after LTx. The additive effect of its combination with FOXP3 is important in phenotypical Treg analyses of OT patients.
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Affiliation(s)
- Hanaa Nafady-Hego
- Microbiology and Immunology Department, Faculty of Medicine, Assiut University, Assiut 71515, Egypt; Department of Hematology and Immunology, College of Medicine, Umm Al-Qura University, Mecca 50431, Saudi Arabia
| | - Ying Li
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Hidenori Ohe
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Hamed Elgendy
- Department of Anesthesia, Faculty of Medicine, Assiut University, Assiut 71515, Egypt; Department of Anesthesiology, King Abdullah Medical City, Mecca 21955, Saudi Arabia
| | - Xiangdong Zhao
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Shimon Sakaguchi
- World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
| | - G Alex Bishop
- Transplantation Laboratory, The University of Sydney, Sydney, NSW 2006, Australia
| | - Takaaki Koshiba
- Department of Disaster and Comprehensive Medicine, Fukushima Medical University, Fukushima 960-1295, Japan.
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34
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Kamei H, Masuda S, Ishigami M, Nakamura T, Fujimoto Y, Takada Y, Hamajima N. Association of interleukin4 gene polymorphisms of recipients and donors with acute rejection following living donor liver transplantation. Clin Res Hepatol Gastroenterol 2016. [PMID: 26212175 DOI: 10.1016/j.clinre.2015.06.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Little is known as to whether the interleukin4 (IL4) gene polymorphisms in recipients or donors affect the incidence of acute cellular rejection (ACR) following living donor liver transplantation (LDLT). Therefore, we determined the effect of IL4 T-33C polymorphisms in recipients and donors on ACR in a large cohort of patients that underwent LDLT. METHODS We examined 155 LDLT cases treated at Nagoya University or Kyoto University, Japan, between 2004 and 2009. IL4 T-33C polymorphisms were analyzed in recipients and donors. RESULTS Forty-seven recipients (30.3%) developed early ACR. The genotype frequency of IL4 T-33C in the recipients was associated with ACR incidence (P=0.008, P<0.0125 considered significant). Patients with the IL4-33C carrier genotype (C/C or C/T) were significantly associated with a higher incidence of ACR relative to those with the T/T genotype (OR=3.27, 95% CI: 1.56-6.88, P=0.002). The genotype frequencies of IL4 T-33C in the donors were not associated with rejection incidence. In addition, there was no significant effect of IL4 T-33C genotype combinations on ACR incidence in donors and recipients. CONCLUSIONS Genotyping of IL4 T-33C in recipients might be useful to stratify the liver transplant recipients according to their risk of ACR.
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Affiliation(s)
- Hideya Kamei
- Department of Transplantation Surgery, Nagoya University, 65 Tsurumai, Showa, 466-8550 Nagoya, Japan.
| | - Satohiro Masuda
- Department of Pharmacy, Faculty of Medicine, Kyoto University, Kyoto, Japan
| | | | - Taro Nakamura
- Department of Transplantation Surgery, Nagoya University, 65 Tsurumai, Showa, 466-8550 Nagoya, Japan
| | - Yasuhiro Fujimoto
- Department of Surgery, Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Kyoto University, Kyoto, Japan
| | - Yasutsugu Takada
- Department of Surgery, Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Kyoto University, Kyoto, Japan
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Taubert R, Danger R, Londoño MC, Christakoudi S, Martinez-Picola M, Rimola A, Manns MP, Sánchez-Fueyo A, Jaeckel E. Hepatic Infiltrates in Operational Tolerant Patients After Liver Transplantation Show Enrichment of Regulatory T Cells Before Proinflammatory Genes Are Downregulated. Am J Transplant 2016; 16:1285-93. [PMID: 26603835 DOI: 10.1111/ajt.13617] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Revised: 09/02/2015] [Accepted: 09/26/2015] [Indexed: 01/25/2023]
Abstract
Immunosuppression can be discontinued from selected and stable patients after liver transplantation resulting in spontaneous operational tolerance (SOT), although the underlying mechanisms remain elusive. Thus, we analyzed serial liver biopsy specimens from adult liver recipients enrolled in a prospective multicenter immunosuppression withdrawal trial that used immunophenotyping and transcriptional profiling. Liver specimens were collected before the initiation of weaning, at the time of rejection, or at 1 and 3 years after complete drug discontinuation. Unexpectedly, the tolerated grafts developed portal tract expansion with increased T cell infiltration after immunosuppression withdrawal. This was associated with transient and preferential accumulation of CD4(+) FOXP3(+) cells and a trend toward upregulation of immune activation and regulatory genes, without signs of rejection. At the same time, no markers of endothelial damage or activation were noted. Portal infiltrates persisted at 3 years but were characterized by decreased expression of genes associated with chronic immunological damage. Further, SOT was not associated with a progressive liver fibrosis up to 5 years. These data suggest that SOT involves several mechanisms: a long-lasting local immune cell persistence with a transient regulatory T cells accumulation followed by a downregulation of immune-activated genes over years. These results have important implications for designs and follow-up of weaning trials.
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Affiliation(s)
- R 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
| | - R Danger
- Institute of Liver Studies, Liver Sciences Department, MRC Centre for Transplantation, School of Life Sciences & Medicine, King's College London University, King's College Hospital, London, UK
| | - M-C Londoño
- Liver Unit, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
| | - S Christakoudi
- Department of Biostatistics, Institute of Psychiatry, Psychology & Neuroscience King's College London, London, UK.,Department of Experimental Immunobiology, MRC Centre for Transplantation, King's College London, London, UK
| | - M Martinez-Picola
- Liver Unit, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
| | - A Rimola
- Institute of Liver Studies, Liver Sciences Department, MRC Centre for Transplantation, School of Life Sciences & Medicine, King's College London University, King's College Hospital, London, UK
| | - M P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - A Sánchez-Fueyo
- Institute of Liver Studies, Liver Sciences Department, MRC Centre for Transplantation, School of Life Sciences & Medicine, King's College London University, King's College Hospital, London, UK.,Liver Unit, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
| | - E 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
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36
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Lin NC, Wang HK, Yeh YC, Liu CP, Loong CC, Tsai HL, Chen CY, Chin T, Liu C. Minimization or withdrawal of immunosuppressants in pediatric liver transplant recipients. J Pediatr Surg 2015; 50:2128-33. [PMID: 26377868 DOI: 10.1016/j.jpedsurg.2015.08.043] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 08/24/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND We aimed to minimize the dose of tacrolimus in pediatric patients undergoing liver transplantation prospectively. METHODS Pediatric liver transplant recipients with stable graft function >1year (transplant at <1year of age), or 2years (transplant at >1year of age) post transplant were screened. After baseline graft biopsy, patients were enrolled into our protocol for elective tacrolimus dose reduction. Patients were assessed by liver function test and protocol biopsy during and after tacrolimus dose reduction. RESULTS From January 2011 to December 2012, 16 patients were recruited, of whom 15 completed follow-up at a mean 40.75±5.98months. Six patients were preliminarily weaned off tacrolimus, and five remained tacrolimus-free for more than 2years. Of the 10 patients who were not weaned off tacrolimus, six experienced seven episodes of clinical rejection. Five patients had a reduction in tacrolimus dosage to an undetectable trough level, another five to a trough level <4ng/ml, including one patient who was off the study. At the last patient visit, all of the patients had normal liver function test results with no graft loss. Three patients had low-grade graft fibrosis. The patients with metabolic liver disease (p=0.039) and who were recruited earlier after transplantation (p=0.028) were more likely to be weaned off tacrolimus. CONCLUSION Tacrolimus withdrawal is feasible in select pediatric liver transplant recipients, and long-term follow-up for these patients is suggested.
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Affiliation(s)
- Niang-Cheng Lin
- Divisions of Pediatric Surgery, and Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University, School of Medicine, Taipei, Taiwan
| | - Hsin-Kai Wang
- Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University, School of Medicine, Taipei, Taiwan
| | - Yi-Chen Yeh
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University, School of Medicine, Taipei, Taiwan
| | - Chia-Pei Liu
- Divisions of Pediatric Surgery, and Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University, School of Medicine, Taipei, Taiwan
| | - Che-Chuan Loong
- Divisions of Pediatric Surgery, and Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University, School of Medicine, Taipei, Taiwan
| | - Hsin-Lin Tsai
- Divisions of Pediatric Surgery, and Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University, School of Medicine, Taipei, Taiwan
| | - Cheng-Yen Chen
- Divisions of Pediatric Surgery, and Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University, School of Medicine, Taipei, Taiwan
| | - Taiwai Chin
- Divisions of Pediatric Surgery, and Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University, School of Medicine, Taipei, Taiwan
| | - Chinsu Liu
- Divisions of Pediatric Surgery, and Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University, School of Medicine, Taipei, Taiwan.
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Abstract
PURPOSE OF REVIEW Liver allograft antibody-mediated rejection (AMR) studies have lagged behind parallel efforts in kidney and heart because of a comparative inherent hepatic resistance to AMR. Three developments, however, have increased interest: first, solid phase antibody testing enabled more precise antibody characterization; second, increased expectations for long-term, morbidity-free survival; and third, immunosuppression minimization trials. RECENT FINDINGS Two overlapping liver allograft AMR phenotypic expressions are beginning to emerge: acute and chronic AMR. Acute AMR usually occurs within the several weeks after transplantation and characterized clinically by donor-specific antibodies (DSA) persistence, allograft dysfunction, thrombocytopenia, and hypocomplementemia. Acute AMR appears histopathologically similar to acute AMR in other organs: diffuse microvascular endothelial cell hypertrophy, C4d deposits, neutrophilic, eosinophilic, and macrophag-mediated microvasculitis/capillaritis, along with liver-specific ductular reaction, centrilobular hepatocyte swelling, and hepatocanalicular cholestasis often combined with T-cell-mediated rejection (TCMR). Chronic AMR is less well defined, but strongly linked to serum class II DSA and associated with late-onset acute TCMR, fibrosis, chronic rejection, and decreased survival. Unlike acute AMR, chronic AMR is a slowly evolving insult with a number of potential manifestations, but most commonly appears as low-grade lymphoplasmacytic portal and perivenular inflammation accompanied by unusual fibrosis patterns and variable microvascular C4d deposition; capillaritis can be more difficult to identify than in acute AMR. SUMMARY More precise DSA characterization, increasing expectations for long-term survival, and immunosuppression weaning precipitated a re-emergence of liver allograft AMR interest. Pathophysiological similarities exist between heart, kidney, and liver allografts, but liver-specific considerations may prove critical to our ultimate understanding of all solid organ AMR.
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Is minimal, [almost] steroid-free immunosuppression a safe approach in adult liver transplantation? Long-term outcome of a prospective, double blind, placebo-controlled, randomized, investigator-driven study. Ann Surg 2015; 260:886-91; discussion 891-2. [PMID: 25379858 DOI: 10.1097/sla.0000000000000969] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To investigate the safety of minimal immunosuppression (IS) in liver transplantation (LT). BACKGROUND The lack of long-term follow-up studies, including pathologic data, has led to a protean handling of IS in LT. METHODS Between February 2000 and September 2004, 156 adults were enrolled in a prospective, randomized, double-blind, placebo-controlled minimization trial comparing tacrolimus placebo (TAC-PLAC) and TAC short-term steroid (TAC-STER) IS. All patients had a minimum clinical, biochemical, and histological follow-up of 5 years. RESULTS Five-year actual patient and graft survival rates in TAC-PLAC and TAC-STER groups were 78.1% and 82.1% (P=0.89) and 74.2% and 76.9% (P=0.90), respectively. Five-year biopsies were available in 112 (89.6%) of 125 survivors. Twelve patients refused a biopsy because of their excellent evolution; tissue material was insufficient in 1 patient; 11 had normal liver tests; and 2 patients had developed alcoholic and secondary biliary cirrhosis. Histology was normal in 44 (39.3%) patients; 35 (31.3%) had disease recurrence. The remaining biopsies showed nonspecific chronic hepatitis (14.3%), mild inflammatory infiltrates (10.7%), and steatosis (3.5%). All findings were equally distributed between both groups. In each group, 3 patients (4.8%) presented with acute cellular rejection after the first year and only 1 (0.9%) TAC-PLAC patient developed chronic rejection after IS withdrawal because of pneumonitis. Arterial hypertension, diabetes mellitus, renal insufficiency, hypercholesterolemia, gout, and obesity were equally low in both groups. CONCLUSIONS Excellent long-term results can be obtained under minimal IS and absence of steroids. TAC-based monotherapy is feasible in most adult liver recipients until 5 years of follow-up.
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39
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Chong AS, Alegre ML. Transplantation tolerance and its outcome during infections and inflammation. Immunol Rev 2015; 258:80-101. [PMID: 24517427 DOI: 10.1111/imr.12147] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Much progress has been made toward understanding the mechanistic basis of transplantation tolerance in experimental models, which implicates clonal deletion of alloreactive T and B cells, induction of cell-intrinsic hyporesponsiveness, and dominant regulatory cells mediating infectious tolerance and linked suppression. Despite encouraging success in the laboratory, achieving tolerance in the clinic remains challenging, although the basis for these challenges is beginning to be understood. Heterologous memory alloreactive T cells generated by infections prior to transplantation have been shown to be a critical barrier to tolerance induction. Furthermore, infections at the time of transplantation and tolerance induction provide a pro-inflammatory milieu that alters the stability and function of regulatory T cells as well as the activation requirements and differentiation of effector T cells. Thus, infections can result in enhanced alloreactivity, resistance to tolerance induction, and destabilization of the established tolerance state. We speculate that these experimental findings have relevance to the clinic, where infections have been associated with allograft rejection and may be a causal event precipitating the loss of grafts after long periods of stable operational tolerance. Understanding the mechanisms by which infections prevent and destabilize tolerance can lead to therapies that promote stable life-long tolerance in transplant recipients.
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Affiliation(s)
- Anita S Chong
- Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL, USA
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40
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Calmus Y, Conti F. Is the liver a tolerogenic organ? Clin Res Hepatol Gastroenterol 2014; 38:655-8. [PMID: 25260569 DOI: 10.1016/j.clinre.2014.08.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 08/20/2014] [Indexed: 02/04/2023]
Affiliation(s)
- Yvon Calmus
- Centre de transplantation hépatique, hôpital Saint-Antoine, AP-HP, 75012 Paris, France.
| | - Filoména Conti
- France Sorbonne universités, UPMC université Paris 06, 75006 Paris, France
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41
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Whitehouse GP, Sanchez-Fueyo A. Immunosuppression withdrawal following liver transplantation. Clin Res Hepatol Gastroenterol 2014; 38:676-80. [PMID: 25281267 DOI: 10.1016/j.clinre.2014.06.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Accepted: 06/10/2014] [Indexed: 02/04/2023]
Abstract
Current immunosuppression regimens in liver transplantation provide excellent short-term survival rates but have many deleterious long-term side effects. They are therefore associated with the higher mortality and morbidity seen in liver transplant recipients compared to the general population and the notion that many liver transplant recipients are over-immunosuppressed is widely accepted. Liver allografts show a greater resistance to alloimmune responses than other solid organ transplants and recent research suggests up to 60% of highly selected recipients could wean off immunosuppression completely. In this review, we look at the evidence from immunosuppression withdrawal trials, the potential benefits of immunosuppression withdrawal and the identification of tolerant transplant recipients.
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Affiliation(s)
- Gavin P Whitehouse
- Institute of Liver Studies, King's College Hospital, Denmark Hill, SE5 9RS, London, UK.
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, King's College Hospital, Denmark Hill, SE5 9RS, London, UK.
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42
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Association of Anti-Human Leukocyte Antigen and Anti-Angiotensin II Type 1 Receptor Antibodies With Liver Allograft Fibrosis After Immunosuppression Withdrawal. Transplantation 2014; 98:1105-11. [DOI: 10.1097/tp.0000000000000185] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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44
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Abstract
Advances in pharmacologic immunosuppression are responsible for the excellent outcomes experienced by recipients of liver transplants. However, long-term follow-up of these patients reveals an increasing burden of morbidity and mortality that is attributable to these drugs. The authors summarize the agents used in contemporary liver transplantation immunosuppression protocols and discuss the emerging trend within the community to minimize or eliminate these agents from use. The authors present recently published data that may provide the foundation for immunosuppression minimization or tolerance induction in the future and review studies that have focused on the utility of biomarkers in guiding immunosuppression management.
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45
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Accelerated telomere reduction and hepatocyte senescence in tolerated human liver allografts. Transpl Immunol 2014; 31:55-9. [DOI: 10.1016/j.trim.2014.06.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2014] [Revised: 06/21/2014] [Accepted: 06/23/2014] [Indexed: 01/03/2023]
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Hirabaru M, Mochizuki K, Takatsuki M, Soyama A, Kosaka T, Kuroki T, Shimokawa I, Eguchi S. Expression of alpha smooth muscle actin in living donor liver transplant recipients. World J Gastroenterol 2014; 20:7067-7074. [PMID: 24966580 PMCID: PMC4051953 DOI: 10.3748/wjg.v20.i22.7067] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 12/31/2013] [Accepted: 02/27/2014] [Indexed: 02/06/2023] Open
Abstract
Recently, there have been reports from liver biopsies that showed the progression of liver fibrosis in liver transplant patients after the cessation of immunosuppression. Herein, we focused on activated hepatic stellate cells expressing alpha smooth muscle actin (α-SMA) to understand the correlation between immunosuppressant medication and liver fibrosis. The study enrolled two pediatric patients who underwent living donor liver transplantation and ceased immunosuppressant therapy. The number of α-SMA-positive cells in the specimens obtained by liver biopsy from these two patients showed a three-fold increase compared with the number from four transplanted pediatric patients who were continuing immunosuppressant therapy. In addition, the α-SMA-positive area evaluated using the WinRooF image processing software program continued to increase over time in three adult transplanted patients with liver fibrosis, and the α-SMA-positive area was increasing even during the pre-fibrotic stage in these adult cases, according to a retrospective review. Therefore, α-SMA could be a useful marker for the detection of early stage fibrosis.
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Minimization of immunosuppression in adult liver transplantation: new strategies and tools. Curr Opin Organ Transplant 2014; 15:685-90. [PMID: 20885324 DOI: 10.1097/mot.0b013e3283402c55] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
PURPOSE OF REVIEW To describe most relevant data regarding strategies to achieve immunosuppression minimization and/or complete withdrawal in liver transplantation and to discuss the development of tolerance biomarkers to predict the success of immunosuppression weaning. RECENT FINDINGS In clinical organ transplantation allograft tolerance has been attained through two different pathways: (1) tolerance or immunosuppression minimization has been attempted by administering induction therapies with or without infusion of donor hematopoietic cells; and (2) the availability of spontaneously tolerant liver and kidney recipients has been exploited to develop biomarkers of allograft tolerance. The use of transcriptional profiling is the most promising approach. Recent publications have identified a gene expression signature in tolerant patients. SUMMARY Current immunosuppressive regimens reduce acute rejection episodes but promote a number of complications that have a negative impact on patient morbidity, mortality and quality of life. In this setting, achievement of tolerance is a major goal. Although there are no reliable markers to identify tolerant patients, recent studies have found that tolerant liver recipients exhibit unique peripheral blood transcriptional patterns. The difference in expression patterns is related to the immune response and could constitute the basis of a future diagnostic test of tolerance.
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Oniscu GC, Diaz G, Levitsky J. Meeting report of the 19th Annual International Congress of the International Liver Transplantation Society (Sydney Convention and Exhibition Centre, Sydney, Australia, June 12-15, 2013). Liver Transpl 2014; 20:7-14. [PMID: 24136728 DOI: 10.1002/lt.23767] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2013] [Accepted: 09/24/2013] [Indexed: 12/21/2022]
Abstract
The International Liver Transplantation Society held its annual meeting from June 12 to 15 in Sydney, Australia. More than 800 registrants attended the congress, which opened with a conference celebrating 50 years of liver transplantation (LT). The program included series of featured symposia, focused topic sessions, and oral and poster presentations. This report is by no means all-inclusive and focuses on specific abstracts on key topics in LT. Similarly to previous reports, this one presents data in the context of the published literature and highlights the current direction of LT.
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Affiliation(s)
- Gabriel C Oniscu
- Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
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Immunosuppression minimization vs. complete drug withdrawal in liver transplantation. J Hepatol 2013; 59:872-9. [PMID: 23578883 DOI: 10.1016/j.jhep.2013.04.003] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Revised: 03/15/2013] [Accepted: 04/02/2013] [Indexed: 12/26/2022]
Abstract
Despite the increase in long-term survival, liver transplant recipients still exhibit higher morbidity and mortality than the general population. This is in part attributed to the lifelong administration of immunosuppression and its associated side effects. Several studies reported in the last decades have evaluated the impact of immunosuppression minimization in liver transplant recipients, but results have been inconsistent due to the heterogeneity of study designs and insufficient sample sizes. On the other hand, complete immunosuppression withdrawal has proven to be feasible in approximately 20% of carefully selected liver transplant recipients, especially in older patients and those with longer duration after transplantation. The long-term risks and clinical benefits of this strategy, however, also need to be clarified. As a consequence, and despite the general perception that a large proportion of liver recipients are over-immunosuppressed, it is currently not possible to derive evidence-based guidelines on how to manage long-term immunosuppression to improve clinical outcomes. Large clinical trials of drug minimization and/or withdrawal focused on clinically-relevant long-term outcomes are required. Development of personalized medicine tools and a deeper understanding of the pathogenesis of idiopathic inflammatory graft lesions will be pre-requisites to achieve these goals.
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50
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McCaughan GW, Bowen DG, Bertolino P. Operational tolerance in liver transplantation: shall we predict or promote? Liver Transpl 2013; 19:933-6. [PMID: 23913809 DOI: 10.1002/lt.23719] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2013] [Accepted: 07/22/2013] [Indexed: 12/13/2022]
Affiliation(s)
- Geoffrey W McCaughan
- A. W. Morrow Gastroenterology and Liver Centre, Centenary Institute, University of Sydney, Sydney, Australia; Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia
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