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1
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Keeler AM, Zhan W, Ram S, Fitzgerald KA, Gao G. The curious case of AAV immunology. Mol Ther 2025; 33:1946-1965. [PMID: 40156190 DOI: 10.1016/j.ymthe.2025.03.037] [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: 01/31/2025] [Revised: 03/17/2025] [Accepted: 03/24/2025] [Indexed: 04/01/2025] Open
Abstract
Immune responses to adeno-associated virus (AAV) have long been perplexing, from its first discovery to the latest clinical trials of recombinant AAV (rAAV) therapy. Wild-type AAV (wtAAV) does not cause any known disease, making it an ideal vector for gene therapy, as viral vectors retain virus-like properties. Although AAV stimulates only a mild immune response compared with other viruses, it is still recognized by the innate immune system and induces adaptive immune responses. B cell responses against both wtAAV and rAAV are robust and can hinder gene therapy applications and prevent redosing. T cell responses can clear transduced cells or establish tolerance against gene therapy. Immune responses to AAV gene therapy are influenced by many factors. Most clinical immunotoxicities that develop in response to gene therapies have emerged as higher doses of AAV vectors have been utilized and were not properly modeled in preclinical animal studies. Thus, several strategies have been undertaken to reduce or mitigate immune responses to AAV. While we have learned a considerable amount about how the immune system responds to AAV gene therapy since the discovery of AAV virus, it still remains a curious case that requires more investigation to fully understand.
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Affiliation(s)
- Allison M Keeler
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA; NeroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Wei Zhan
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Microbiology, University of Massachusetts Chan Medical School, Worcester, MA, USA; Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Sanjay Ram
- Division of Infectious Diseases and Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Katherine A Fitzgerald
- Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
| | - Guangping Gao
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Microbiology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
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2
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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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3
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Pichard V, Guilbaud M, Devaux M, Jaulin N, Journou M, Cospolite M, Garcia A, Ferry N, Michalak-Provost S, Gernoux G, Adjali O. Incomplete elimination of viral genomes is associated with chronic inflammation in nonhuman primate livers after AAV-mediated gene transfer. Gene Ther 2025:10.1038/s41434-025-00514-z. [PMID: 39838066 DOI: 10.1038/s41434-025-00514-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 12/22/2024] [Accepted: 01/13/2025] [Indexed: 01/23/2025]
Abstract
The liver is a unique organ where immunity can be biased toward ineffective response notably in the context of viral infections. Chronic viral hepatitis depends on the inability of the T-cell immune response to eradicate antigen. In the case of recombinant Adeno-Associated-Virus, used for therapeutic gene transfer, conflicting reports describe tolerance induction to different transgene products while other studies have shown conventional cytotoxic CD8+ T cell responses with a rapid loss of transgene expression. We performed a 1 year follow up of 6 non-human primates after all animals received an rAAV8 vector carrying the GFP transgene at doses of 7×1012 vg/kg. We report that despite anti-GFP peripheral cellular response and loss of hepatic transgene expression, we were still able to detect persisting viral genomes in the liver until 1-year post-injection. These viral genomes were associated with liver inflammation, fibrosis and signs of CD8 T cell exhaustion, including high expression of PD-1. Our study shows that AAV8-mediated gene transfer can results to loss of transgene expression in liver and chronic inflammation several months after gene transfer.
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Affiliation(s)
- Virginie Pichard
- Nantes Université, CHU Nantes, INSERM, TaRGeT-Translational Research in Gene Therapy, UMR1089, F-44200, Nantes, France.
| | - Mickaël Guilbaud
- Nantes Université, CHU Nantes, INSERM, TaRGeT-Translational Research in Gene Therapy, UMR1089, F-44200, Nantes, France
| | - Marie Devaux
- Nantes Université, CHU Nantes, INSERM, TaRGeT-Translational Research in Gene Therapy, UMR1089, F-44200, Nantes, France
| | - Nicolas Jaulin
- Nantes Université, CHU Nantes, INSERM, TaRGeT-Translational Research in Gene Therapy, UMR1089, F-44200, Nantes, France
| | - Malo Journou
- Nantes Université, CHU Nantes, INSERM, TaRGeT-Translational Research in Gene Therapy, UMR1089, F-44200, Nantes, France
| | - Magalie Cospolite
- Nantes Université, CHU Nantes, INSERM, TaRGeT-Translational Research in Gene Therapy, UMR1089, F-44200, Nantes, France
| | - Alexandra Garcia
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000, Nantes, France
| | - Nicolas Ferry
- Nantes Université, CHU Nantes, INSERM, TaRGeT-Translational Research in Gene Therapy, UMR1089, F-44200, Nantes, France
| | - Sophie Michalak-Provost
- HIFIH Laboratory, UPRES 3859, SFR 4208, Angers University, Angers, France
- Pathology Department, Angers University Hospital, Angers, France
| | - Gwladys Gernoux
- Nantes Université, CHU Nantes, INSERM, TaRGeT-Translational Research in Gene Therapy, UMR1089, F-44200, Nantes, France
| | - Oumeya Adjali
- Nantes Université, CHU Nantes, INSERM, TaRGeT-Translational Research in Gene Therapy, UMR1089, F-44200, Nantes, France.
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4
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A Reduction of Calcineurin Inhibitors May Improve Survival in Patients with De Novo Colorectal Cancer after Liver Transplantation. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58121755. [PMID: 36556957 PMCID: PMC9785597 DOI: 10.3390/medicina58121755] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 11/25/2022] [Accepted: 11/28/2022] [Indexed: 12/04/2022]
Abstract
Background and Objectives: After liver transplantation (LT), long-term immunosuppression (IS) is essential. IS is associated with de novo malignancies, and the incidence of colorectal cancer (CRC) is increased in LT patients. We assessed course of disease in patients with de novo CRC after LT with focus of IS and impact on survival in a retrospective, single-center study. Materials and Methods: All patients diagnosed with CRC after LT between 1988 and 2019 were included. The management of IS regimen following diagnosis and the oncological treatment approach were analyzed: Kaplan−Meier analysis as well as univariate and multivariate analysis were performed. Results: A total of 33 out of 2744 patients were diagnosed with CRC after LT. Two groups were identified: patients with restrictive IS management undergoing dose reduction (RIM group, n = 20) and those with unaltered regimen (maintenance group, n = 13). The groups did not differ in clinical and oncological characteristics. Statistically significant improved survival was found in Kaplan−Meier analysis for patients in the RIM group with 83.46 (8.4−193.1) months in RIM and 24.8 (0.5−298.9) months in the maintenance group (log rank = 0.02) and showed a trend in multivariate cox regression (p = 0.054, HR = 14.3, CI = 0.96−213.67). Conclusions: Immunosuppressive therapy should be reduced further in patients suffering from CRC after LT in an individualized manner to enable optimal oncological therapy and enable improved survival.
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5
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Ni X, Wang Q, Gu J, Lu L. Clinical and Basic Research Progress on Treg-Induced Immune Tolerance in Liver Transplantation. Front Immunol 2021; 12:535012. [PMID: 34093514 PMCID: PMC8173171 DOI: 10.3389/fimmu.2021.535012] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 04/26/2021] [Indexed: 12/29/2022] Open
Abstract
Rejection after organ transplantation is a cause of graft failure. Effectively reducing rejection and inducing tolerance is a challenge in the field of transplantation immunology. The liver, as an immunologically privileged organ, has high rates of spontaneous and operational tolerance after transplantation, allowing it to maintain its normal function for long periods. Although modern immunosuppression regimens have serious toxicity and side effects, it is very risky to discontinue immunosuppression regimens blindly. A more effective treatment to induce immune tolerance is the most sought-after goal in transplant medicine. Tregs have been shown to play a pivotal role in the regulation of immune balance, and infusion of Tregs can also effectively prevent rejection and cure autoimmune diseases without significant side effects. Given the immune characteristics of the liver, the correct use of Tregs can more effectively induce the occurrence of operational tolerance for liver transplants than for other organ transplants. This review mainly summarizes the latest research advances regarding the characteristics of the hepatic immune microenvironment, operational tolerance, Treg generation in vitro, and the application of Tregs in liver transplantation. It is hoped that this review will provide a deeper understanding of Tregs as the most effective treatment to induce and maintain operational tolerance after liver transplantation.
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Affiliation(s)
- Xuhao Ni
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Qi Wang
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Jian Gu
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Ling Lu
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
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6
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Marfil-Garza BA, Hefler J, Bermudez De Leon M, Pawlick R, Dadheech N, Shapiro AMJ. Progress in Translational Regulatory T Cell Therapies for Type 1 Diabetes and Islet Transplantation. Endocr Rev 2021; 42:198-218. [PMID: 33247733 DOI: 10.1210/endrev/bnaa028] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Indexed: 02/06/2023]
Abstract
Regulatory T cells (Tregs) have become highly relevant in the pathophysiology and treatment of autoimmune diseases, such as type 1 diabetes (T1D). As these cells are known to be defective in T1D, recent efforts have explored ex vivo and in vivo Treg expansion and enhancement as a means for restoring self-tolerance in this disease. Given their capacity to also modulate alloimmune responses, studies using Treg-based therapies have recently been undertaken in transplantation. Islet transplantation provides a unique opportunity to study the critical immunological crossroads between auto- and alloimmunity. This procedure has advanced greatly in recent years, and reports of complete abrogation of severe hypoglycemia and long-term insulin independence have become increasingly reported. It is clear that cellular transplantation has the potential to be a true cure in T1D, provided the remaining barriers of cell supply and abrogated need for immune suppression can be overcome. However, the role that Tregs play in islet transplantation remains to be defined. Herein, we synthesize the progress and current state of Treg-based therapies in T1D and islet transplantation. We provide an extensive, but concise, background to understand the physiology and function of these cells and discuss the clinical evidence supporting potency and potential Treg-based therapies in the context of T1D and islet transplantation. Finally, we discuss some areas of opportunity and potential research avenues to guide effective future clinical application. This review provides a basic framework of knowledge for clinicians and researchers involved in the care of patients with T1D and islet transplantation.
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Affiliation(s)
| | - Joshua Hefler
- Department of Surgery, University of Alberta, Edmonton, Canada
| | - Mario Bermudez De Leon
- Department of Molecular Biology, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey, Nuevo Leon, Mexico
| | - Rena Pawlick
- Department of Surgery, University of Alberta, Edmonton, Canada
| | | | - A M James Shapiro
- Department of Surgery, University of Alberta, Edmonton, Canada.,Clinical Islet Transplant Program, University of Alberta, Edmonton, Canada
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7
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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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8
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Long-Term Tacrolimus Blood Trough Level and Patient Survival in Adult Liver Transplantation. J Pers Med 2021; 11:jpm11020090. [PMID: 33535628 PMCID: PMC7912911 DOI: 10.3390/jpm11020090] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/25/2021] [Accepted: 01/29/2021] [Indexed: 12/30/2022] Open
Abstract
Tacrolimus is the most widely used immunosuppressant in liver transplant (LT) patients. However, the ideal long-term target level for these patients is unknown. This retrospective study aimed to investigate the impact of tacrolimus blood concentration five years after LT on long-term patient survival outcomes in adult LT recipients. Patients who underwent LT between January 2004 and July 2014 at a tertiary medical center were included in this study (n = 189). The mean tacrolimus blood concentrations of each patient during the fifth year after LT were recorded and the overall survival rate was determined. A multivariate analysis of factors associated with long-term survival was conducted using a Cox’s model. The median follow-up period was 9.63 years, and 144 patients (76.2%) underwent live donor LT. Sixteen patients died within 5 years of LT. In the Cox’s model, patients with a mean tacrolimus blood trough level of 4.6–10.2 ng/mL had significantly better long-term survival than those with a mean tacrolimus blood trough level outside this range (estimated hazard ratio = 4.76; 95% confidence interval: 1.34–16.9, p = 0.016). Therefore, a tacrolimus level no lower than 4.6 ng/mL would be recommended in adult LT patients.
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9
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Yu J, Liu Z, Li C, Wei Q, Zheng S, Saeb-Parsy K, Xu X. Regulatory T Cell Therapy Following Liver Transplantation. Liver Transpl 2021; 27:264-280. [PMID: 37160016 DOI: 10.1002/lt.25948] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 10/25/2020] [Accepted: 10/31/2020] [Indexed: 12/17/2022]
Abstract
Liver transplantation (LT) is considered the gold standard of curative treatment for patients with end-stage liver disease or nonresectable hepatic malignant tumors. Rejection after LT is the main nontechnical factor affecting the prognosis of recipients. Medical and surgical advances, combined with improved immunosuppression with drugs such as calcineurin inhibitors (CNIs), have contributed to an increase in 1-year graft survival to around 80%. However, medium- and long-term improvements in LT outcomes have lagged behind. Importantly, CNIs and other classical immunosuppressive drugs are associated with significant adverse effects, including malignancies, cardiovascular disease, and severe renal dysfunction. Immunomodulation using regulatory T cells (Tregs) is emerging as a promising alternative to classical immunosuppression. Since their discovery, the immunomodulatory effects of Tregs have been demonstrated in a range of diseases. This has rejuvenated the interest in using Tregs as a therapeutic strategy to induce immune tolerance after LT. In this review, we first summarize the discovery and development of Tregs. We then review the preclinical data supporting their production, mechanism of action, and therapeutic efficacy followed by a summary of relevant clinical trials. Finally, we discuss the outstanding challenges of Treg therapy and its future prospects for routine use in LT.
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Affiliation(s)
- Jiongjie Yu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Zhikun Liu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Changbiao Li
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Qiang Wei
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China.,Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, China
| | - Kourosh Saeb-Parsy
- Department of Surgery, University of Cambridge, Cambridge, UK.,Cambridge National Institute of Health Research Biomedical Research Centre, Cambridge, UK
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
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10
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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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11
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Jiang Y, Que W, Zhu P, Li XK. The Role of Diverse Liver Cells in Liver Transplantation Tolerance. Front Immunol 2020; 11:1203. [PMID: 32595648 PMCID: PMC7304488 DOI: 10.3389/fimmu.2020.01203] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 05/14/2020] [Indexed: 12/11/2022] Open
Abstract
Liver transplantation is the ideal treatment approach for a variety of end-stage liver diseases. However, life-long, systemic immunosuppressive treatment after transplantation is required to prevent rejection and graft loss, which is associated with severe side effects, although liver allograft is considered more tolerogenic. Therefore, understanding the mechanism underlying the unique immunologically privileged liver organ is valuable for transplantation management and autoimmune disease treatment. The unique hepatic acinus anatomy and a complex cellular network constitute the immunosuppressive hepatic microenvironment, which are responsible for the tolerogenic properties of the liver. The hepatic microenvironment contains a variety of hepatic-resident immobile non-professional antigen-presenting cells, including hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, that are insufficient to optimally prime T cells locally and lead to the removal of alloreactive T cells due to the low expression of major histocompatibility complex (MHC) molecules, costimulatory molecules and proinflammatory cytokines but a rather high expression of coinhibitory molecules and anti-inflammatory cytokines. Hepatic dendritic cells (DCs) are generally immature and less immunogenic than splenic DCs and are also ineffective in priming naïve allogeneic T cells via the direct recognition pathway in recipient secondary lymphoid organs. Although natural killer cells and natural killer T cells are reportedly associated with liver tolerance, their roles in liver transplantation are multifaceted and need to be further clarified. Under these circumstances, T cells are prone to clonal deletion, clonal anergy and exhaustion, eventually leading to tolerance. Other proposed liver tolerance mechanisms, such as soluble donor MHC class I molecules, passenger leukocytes theory and a high-load antigen effect, have also been addressed. We herein comprehensively review the current evidence implicating the tolerogenic properties of diverse liver cells in liver transplantation tolerance.
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Affiliation(s)
- Yanzhi Jiang
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.,Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Weitao Que
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Ping Zhu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xiao-Kang Li
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
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12
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Tolerance studies in liver transplantation: are we fooling ourselves? Curr Opin Organ Transplant 2020; 25:151-157. [DOI: 10.1097/mot.0000000000000738] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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13
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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: 05/02/2019] [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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14
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Oldhafer F, Wittauer EM, Falk CS, DeTemple DE, Beetz O, Timrott K, Kleine M, Vondran FWR. Alloresponses of Mixed Lymphocyte Hepatocyte Culture to Immunosuppressive Drugs as an In-Vitro Model of Hepatocyte Transplantation. Ann Transplant 2019; 24:472-480. [PMID: 31406101 PMCID: PMC6705178 DOI: 10.12659/aot.915982] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Background Hepatocyte transplantation (HCTx) has the potential for the treatment of end-stage liver disease. However, failure of engraftment and the long-term acceptance of cellular allografts remain significant challenges for its clinical application. The aim of this study was to investigate the efficacy of the immunosuppressive agents, Cyclosporine, Everolimus, and Belatacept to suppress the alloresponse of primary human hepatocytes in a mixed lymphocyte-hepatocyte culture (MLHC) and their potential hepatotoxicity in vitro. Material/Methods Primary human hepatocytes were co-cultured with allogeneic peripheral blood mononuclear cells (PBMCs) in an MLHC. Proliferative alloresponses were determined by flow cytometry, and cytokine secretion was measured using Luminex-based multiplex technology. Using an MLHC, the alloresponses of primary human hepatocytes were compared in the presence and absence of Cyclosporine, Everolimus, and Belatacept. Cultured primary human hepatocytes were assessed for the production of albumin, urea, aspartate transaminase (AST) and DNA content. Metabolic activity was determined with the MTT assay. Results Immune responses induced by primary human hepatocytes were effectively suppressed by Cyclosporine, Everolimus, and Belatacept. Everolimus significantly reduced the metabolic activity of primary human hepatocytes in vitro, suggesting impairment of cell viability. However, further functional analysis showed no significant differences between treated and untreated controls. Conclusions Cyclosporine, Everolimus, and Belatacept suppressed the alloresponse of primary human hepatocytes in an MLHC without significant cytotoxicity or functional cell impairment.
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Affiliation(s)
- Felix Oldhafer
- ReMediES, Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Eva-Maria Wittauer
- ReMediES, Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Christine S Falk
- German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany.,Institute of Transplant Immunology, Integrated Research and Treatment Centre Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
| | - Daphne E DeTemple
- ReMediES, Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Oliver Beetz
- ReMediES, Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Kai Timrott
- ReMediES, Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Moritz Kleine
- ReMediES, Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Florian W R Vondran
- ReMediES, Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.,German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
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15
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16
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Whitehouse GP, Hope A, Sanchez-Fueyo A. Regulatory T-cell therapy in liver transplantation. Transpl Int 2018; 30:776-784. [PMID: 28608637 DOI: 10.1111/tri.12998] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 03/27/2017] [Accepted: 06/07/2017] [Indexed: 12/24/2022]
Abstract
Modern immunosuppression drug regimens have produced excellent short-term survival after liver transplantation but it is generally accepted that the side effects of these medications remain a significant contributing factor for less satisfactory long term outcomes. The liver has unique tolerogenic properties as evidenced by the higher rates of operational tolerance seen in liver transplant recipients compared to other solid organ transplants, and therefore, liver transplantation offers an attractive setting in which to study tolerizing therapies. CD4+ CD25+ FOXP3+ regulatory T cells (Tregs) are crucial for maintenance of self-tolerance and prevention of autoimmune disease and are therefore an appealing potential candidate for use as a tolerizing cell therapy. In this review, we summarize the evidence from drug withdrawal trials of spontaneous operational tolerance in liver transplantation, the unique immunology of the hepatic microenvironment, the evidence for the use of CD4+ CD25+ FOXP3+ regulatory T cells as a tolerance inducing therapy in liver transplantation and the challenges in producing clinical grade Treg cell products.
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Affiliation(s)
- Gavin P Whitehouse
- Division of Transplantation Immunology and Mucosal Biology, Institute of Liver Studies, Medical Research Council Centre for Transplantation, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Andrew Hope
- CRF GMP Unit, NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK
| | - Alberto Sanchez-Fueyo
- Division of Transplantation Immunology and Mucosal Biology, Institute of Liver Studies, Medical Research Council Centre for Transplantation, Faculty of Life Sciences and Medicine, King's College London, London, UK
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17
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Chan-On C, Liberto JM, Sarwal MM. Mechanisms and biomarkers of immune quiescence in kidney transplantation. Hum Immunol 2018; 79:356-361. [PMID: 29408630 DOI: 10.1016/j.humimm.2018.01.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 01/26/2018] [Accepted: 01/30/2018] [Indexed: 12/14/2022]
Abstract
This review discusses the current understanding of biomarkers of immune quiescence based on reviews of published literature in kidney transplant operational tolerance and mechanistic studies based on a better characterization of the stable, well-functioning renal allograft.
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Affiliation(s)
- Chitranon Chan-On
- Division of Nephrology, Faculty of Medicine, Department of Internal Medicine, Khon Kaen University, Khon Kaen, Thailand; Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Juliane M Liberto
- Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Minnie M Sarwal
- Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, San Francisco, CA, United States.
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18
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Biomarkers of immune tolerance in liver transplantation. Hum Immunol 2018; 79:388-394. [PMID: 29462637 DOI: 10.1016/j.humimm.2018.02.010] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 02/08/2018] [Accepted: 02/13/2018] [Indexed: 01/01/2023]
Abstract
The liver exhibits intrinsic immune tolerogenic properties that contribute to a unique propensity toward spontaneous acceptance when transplanted, both in animal models and in humans. Thus, in contrast to what happens after transplantation of other solid organs, several years following liver transplantation a significant subset of patients are capable of maintaining normal allograft function with histological integrity in the absence of immunosuppressive drug treatment. Significant efforts have been put into identifying sensitive and specific biomarkers of tolerance in order to stratify liver transplant recipients according to their need for immunosuppressive medication and their likelihood of being able to completely discontinue it. These biomarkers are currently being validated in prospective clinical trials of immunosuppression withdrawal both in Europe and in the United States. These studies have the potential to transform the clinical management of liver transplant recipients by mitigating, at least in part, the burden of lifelong immunosuppression.
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19
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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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20
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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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21
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Angelico R, Parente A, Manzia TM. Using a weaning immunosuppression protocol in liver transplantation recipients with hepatocellular carcinoma: a compromise between the risk of recurrence and the risk of rejection? Transl Gastroenterol Hepatol 2017; 2:74. [PMID: 29034347 PMCID: PMC5639004 DOI: 10.21037/tgh.2017.08.07] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 08/14/2017] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) recurrence rate after liver transplantation (LT) is still up to 15-20%, despite a careful selection of candidates and optimization of the management within the waiting list. To reduce tumour recurrence, the currently adopted post-transplant strategies are based on the administration of a tailored immunosuppression (IS) regimen. Drug-induced depression of the immune system is essential in preventing graft rejection, however has a well-established association with oncogenesis. The immune system has a key role as a defending mechanism against cancer development, preventing vascular invasion and metastasis. Thus, IS drugs represent one of few modifiable non-oncological risk factors for tumour recurrence. In HCC recipients, a tailored IS therapy, with the aim to minimize drugs' doses, is essential to gain the optimal balance between the risk of rejection and the risk of tumour recurrence. So far, a complete withdrawal of IS drugs after LT is reported to be safely achievable in 25% of patients (defined as "operational tolerant"), without the risk of patient and graft loss. The recent identification of non-invasive "bio-markers of tolerance", which permit to identify patients who could successfully withdraw IS therapies, opens new perspectives in the management of HCC after LT. IS withdrawal could potentially reduce the risk of tumour recurrence, which represents the major drawback in HCC recipients. Herein, we review the current literature on IS weaning in patients who underwent LT for HCC as primary indication and we report the largest experiences on IS withdrawal in HCC recipients.
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Affiliation(s)
- Roberta Angelico
- Department of Experimental Medicine and Surgery, Liver Unit, Tor Vergata University of Rome, Rome, Italy
- Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù Children’s Research Hospital IRCCS, Rome, Italy
| | - Alessandro Parente
- Department of Experimental Medicine and Surgery, Liver Unit, Tor Vergata University of Rome, Rome, Italy
| | - Tommaso Maria Manzia
- Department of Experimental Medicine and Surgery, Liver Unit, Tor Vergata University of Rome, Rome, Italy
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22
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Mechanisms and Strategies for Tolerance in Liver Transplantation. CURRENT TRANSPLANTATION REPORTS 2016. [DOI: 10.1007/s40472-016-0119-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Abstract
PURPOSE OF REVIEW The field of vascularized composite allograft (VCA) to achieve its full potential will require induction of tolerance. This review will introduce a new method of potential inducing tolerance in hand transplantation. RECENT FINDINGS Hand transplantation is never a life-extending transplant. This fact resulted in considerable debate both for and against the use of immunosuppression for nonlife-extending transplants. There is considerable debate about the ethics of hand transplantation. There is now consensus that nonlife-extending transplants are acceptable in properly selected patients. However, ideally, hand transplants should not receive life-long immunosuppression. Therefore, attempts to achieve drug-free tolerance through nonlife-endangering therapies are warranted. To this end, we propose implementation of tolerizing therapy long after periinflammation has subsided and drug minimization has proven successful. Evidence that short-term treatment with low doses of IL-2 or a long-lived IL-2 immunoglobulin (Ig) can tilt the balance of immunity from tissue destructive to tolerance come from preclinical demonstrations in mouse and nonhuman primate models of autoimmunity and/or transplantation and even more recent clinical trials. SUMMARY We believe that with the proper use of low-dose IL-2 given at an opportune time in the inflammatory process of transplant that reduce immunosuppression and even tolerance can be induced in hand transplantation. We propose that tolerance can be inducted after a long period of conventional treatment to avoid 'tolerance-hindering' adverse inflammation that occurs in the posttransplant period. With abatement of posttransplant inflammation and with time, we will institute low-dose IL-2-based therapy to support the proliferation, viability and functional phenotype of regulatory T cells.
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25
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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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26
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Kamran Hejazi Kenari S, Mirzakhani H, Saidi RF. Pediatric transplantation and tolerance: past, present, and future. Pediatr Transplant 2014; 18:435-45. [PMID: 24931282 DOI: 10.1111/petr.12301] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/06/2014] [Indexed: 12/13/2022]
Abstract
Solid organ transplantation is the treatment of choice in children with end-stage organ failure. With improving methods of transplant surgery and post-transplant care, transplantation is more frequently performed worldwide. However, lifelong and non-specific suppression of the recipient's immune system is a cause of significant morbidity in children, including infection, diabetes, and cancer. There is a great need to develop IS minimization/withdrawal and tolerance induction approaches.
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Affiliation(s)
- Seyed Kamran Hejazi Kenari
- Division of Organ Transplantation, Department of Surgery, Alpert Medical School of Brown University, Providence, RI, USA
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27
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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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Briem-Richter A, Leuschner A, Krieger T, Grabhorn E, Fischer L, Nashan B, Haag F, Ganschow R. Peripheral blood biomarkers for the characterization of alloimmune reactivity after pediatric liver transplantation. Pediatr Transplant 2013; 17:757-64. [PMID: 24164827 DOI: 10.1111/petr.12161] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/20/2013] [Indexed: 12/20/2022]
Abstract
Individualization of immunosuppressive medications is an important objective in transplantation medicine. Reliable biomarkers to distinguish between patients dependent from intensive immunosuppressive therapy and those where therapy can be minimized among pediatric transplant recipients receiving immunosuppressive medications are still not established. We evaluated the potential of cross-sectional quantification of regulatory T cells, lymphocyte subsets, and cytokine concentrations as biomarkers in 60 pediatric liver transplant recipients with AR, CR, or normal graft function and in 11 non-transplanted patients. Transplant recipients presenting with AR had significantly higher CD8+ T-cell counts, significantly higher concentrations of IL-2, and increased levels of IFN-γ compared with asymptomatic patients or controls. Regulatory T-cell numbers did not differ between children with rejection and children with good graft function. A tendency toward increased concentrations of IL-4 and TGF-β was detected in transplant recipients with good graft function. Cross-sectional parameters of peripheral regulatory T cells in pediatric liver transplant recipients do not seem to be valuable biomarkers for individualizing immunosuppressive therapy prior to the weaning process. Lymphocyte subsets, IL-2, IFN-γ, IL-4, and TGF-β serum concentrations may be helpful to identify children in whom immunosuppression can be reduced or discontinued.
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Affiliation(s)
- Andrea Briem-Richter
- Pediatric Hepatology and Liver Transplantation, Transplantation Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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29
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Barbier L, Garcia S, Cros J, Borentain P, Botta-Fridlund D, Paradis V, Le Treut YP, Hardwigsen J. Assessment of chronic rejection in liver graft recipients receiving immunosuppression with low-dose calcineurin inhibitors. J Hepatol 2013; 59:1223-30. [PMID: 23933266 DOI: 10.1016/j.jhep.2013.07.032] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2013] [Revised: 06/24/2013] [Accepted: 07/16/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Calcineurin inhibitors represent the cornerstone immunosuppressants after liver transplantation despite their side effects. As liver graft is particularly well tolerated, low doses may be proposed. The aim of this study was to assess the prevalence of chronic rejection in patients with low calcineurin inhibitors regimen and to compare their characteristics with patients under standard doses. METHODS All patients with liver transplantation between 1997 and 2004 were divided into two groups. Low-dose patients (n=57) had tacrolimus baseline levels <5ng/ml or cyclosporine levels <50ng/ml at t0 or <100ng/ml at t+2h and were prospectively proposed a liver biopsy, searching for chronic rejection according to Banff criteria. The remaining patients constituted the standard-doses group (n=40). RESULTS Among the low-dose group, 36 patients in the low-dose group were assessed by biopsy. No chronic rejection was found. Fifty-six percent had only calcineurin inhibitors and 8% received other immunosuppressants only. The median time between liver transplantation and biopsy was 90 months (64-157) and between IS regimen decrease and biopsy was 41 months (11-115). Liver tests were normal in 72% of the patients. Low-dose patients had more often hepatitis B (p=0.045), less past acute rejection episodes (p=0.028), and better renal function (p=0.040). Decrease of calcineurin inhibitors failed in 15% of standard-dose patients without impacting the graft function. In the low-dose group, co-prescription of other immunosuppressants facilitated the decrease (p=0.051). CONCLUSIONS The minimization, or even cessation, of calcineurin inhibitors may be an achievable goal in the long term for most of the liver graft recipients.
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Affiliation(s)
- Louise Barbier
- Department of digestive surgery and liver transplantation, Aix-Marseille University, hôpital La Conception, Assistance publique-hôpitaux de Marseille, 13005 Marseille, France.
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30
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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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Kelly DA, Bucuvalas JC, Alonso EM, Karpen SJ, Allen U, Green M, Farmer D, Shemesh E, McDonald RA. Long-term medical management of the pediatric patient after liver transplantation: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Liver Transpl 2013; 19:798-825. [PMID: 23836431 DOI: 10.1002/lt.23697] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Accepted: 06/15/2013] [Indexed: 12/15/2022]
Affiliation(s)
- Deirdre A Kelly
- Liver Unit, Birmingham Children's Hospital, National Health Service Trust, Birmingham, United Kingdom.
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Liu XQ, Hu ZQ, Pei YF, Tao R. Clinical operational tolerance in liver transplantation: state-of-the-art perspective and future prospects. Hepatobiliary Pancreat Dis Int 2013; 12:12-33. [PMID: 23392795 DOI: 10.1016/s1499-3872(13)60002-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Liver transplantation is the definite treatment for end-stage liver diseases with satisfactory results. However, untoward effects of life-long immunosuppression prevent the development of alternative strategies to achieve better long-term outcome. Achieving clinical operational tolerance is the ultimate goal. DATA SOURCES A PubMed and Google Scholar search using terms: "immune tolerance", "liver transplantation", "clinical trial", "operational tolerance" and "immunosuppression withdrawal" was performed, and relevant articles published in English in the past decade were reviewed. Full-text publications relevant to the field were selected and relevant articles from reference lists were also included. Priority was given to those articles which are relevant to the review. RESULTS Because of the inherent tolerogenic property, around 20%-30% of liver transplantation recipients develop spontaneous operational tolerance after immunosuppression withdrawal, and the percentage may be even higher in pediatric living donor liver transplantation recipients. Several natural killer and gammadeltaT cell related markers have been identified to be associated with the tolerant state in liver transplantation patients. Despite the progress, clinical operational tolerance is still rare in liver transplantation. Reprogramming the recipient immune system by creating chimerism and regulatory cell therapies is among newer promising means to achieve clinical liver transplantation tolerance in the future. CONCLUSION Although clinical operational tolerance is still rare in liver transplantation recipients, ongoing basic research and collaborative clinical trials may help to decipher the mystery of transplantation tolerance and extend the potential benefits of drug withdrawal to an increasing number of patients in a more predictable fashion.
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Affiliation(s)
- Xi-Qiang Liu
- Center for Organ Transplantation and Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
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Olson JC, Wiesner RH. Immunomodulating therapy in liver transplantation: principles and practice. Immunotherapy 2013; 4:793-805. [PMID: 22947008 DOI: 10.2217/imt.12.69] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Liver transplantation has enjoyed dramatic success as a treatment option for patients suffering from chronic end-stage liver diseases. It also serves as a definitive treatment for certain genetic conditions such as familial amyloidosis and primary oxalosis, and as a potential curative therapy in selected cases of primary liver cancer. Currently, over 50,000 patients are alive with functioning liver transplants. Liver transplantation owes its success to advances in surgical technique, improvements in anesthesia and critical care, and advances in treatment of post-transplant complications including improved therapies for cytomegalovirus infections. But perhaps the most important advances in liver transplantation arise in the context of improvements in our understanding of the molecular biology of transplant immunology and the development of new agents that allow for manipulation of immunological signaling pathways. These improvements in immunosuppressive therapy have dramatically increased both graft and patient survival.
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Affiliation(s)
- Jody C Olson
- Division of Critical Care Medicine, Mayo Clinic, Rochester, MN 55905, USA
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Importance of liver biopsy findings in immunosuppression management: biopsy monitoring and working criteria for patients with operational tolerance. Liver Transpl 2012; 18:1154-70. [PMID: 22645090 DOI: 10.1002/lt.23481] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Obstacles to morbidity-free long-term survival after liver transplantation (LT) include complications of immunosuppression (IS), recurrence of the original disease and malignancies, and unexplained chronic hepatitis and graft fibrosis. Many programs attempt to minimize chronic exposure to IS by reducing dosages and stopping steroids. A few programs have successfully weaned a highly select group of recipients from all IS without apparent adverse consequences, but long-term follow-up is limited. Patients subjected to adjustments in IS are usually followed by serial liver chemistry tests, which are relatively insensitive methods for detecting allograft damage. Protocol biopsy has largely been abandoned for hepatitis C virus-negative recipients, at least in part because of the inability to integrate routine histopathological findings into a rational clinical management algorithm. Recognizing a need to more precisely categorize and determine the clinical significance of findings in long-term biopsy samples, the Banff Working Group on Liver Allograft Pathology has reviewed the literature, pooled the experience of its members, and proposed working definitions for biopsy changes that (1) are conducive to lowering IS and are compatible with operational tolerance (OT) and (2) raise concern for closer follow-up and perhaps increased IS during or after IS weaning. The establishment of guidelines should help us to standardize analyses of the effects of various treatments and/or weaning protocols and more rigorously categorize patients who are assumed to show OT. Long-term follow-up using standardized criteria will help us to determine the consequences of lowering IS and to define and determine the incidence and robustness of OT in liver allografts.
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Affiliation(s)
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- University of Pittsburgh Medical Center, 3459 5th Avenue, UPMC Montefiore E741, Pittsburgh, PA 15213, USA
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Manzia TM, Angelico R, Toti L, Lai Q, Ciano P, Angelico M, Tisone G. Hepatitis C virus recurrence and immunosuppression-free state after liver transplantation. Expert Rev Clin Immunol 2012; 8:635-644. [PMID: 23078061 DOI: 10.1586/eci.12.66] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
HCV-related disease is the most common indication for liver transplantation (LT). HCV recurrence, which is almost universal, has a significant impact on patient and graft survival after LT and still represents a great unsolved issue for the liver transplant community. Several treatment strategies have been proposed. Since antiviral therapy has limited efficacy and can be administrated only in selected transplant recipients and additionally that immunosuppressive drugs have a negative impact on HCV re-infection, the achievement of an immunosuppression-free state after LT could play a central role in the avoidance of rapid HCV recurrence.
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Li L, Wozniak LJ, Rodder S, Heish S, Talisetti A, Wang Q, Esquivel C, Cox K, Chen R, McDiarmid SV, Sarwal MM. A common peripheral blood gene set for diagnosis of operational tolerance in pediatric and adult liver transplantation. Am J Transplant 2012; 12:1218-28. [PMID: 22300520 DOI: 10.1111/j.1600-6143.2011.03928.x] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
To identify biomarkers of operational tolerance in pediatric and adult liver transplant recipients, transcriptional profiles were examined from 300 samples by microarrays and Q-PCR measurements of blood specimens from pediatric and adult liver transplant recipients and normal tissues. Tolerance-specific genes were validated in independent samples across two different transplant programs and validated by Q-PCR. A minimal set of 13 unique genes, highly expressed in natural killer cells (p = 0.03), were significantly expressed in both pediatric and adult liver tolerance, irrespective of different clinical and demographic confounders. The performance of this gene set by microarray in independent samples was 100% sensitivity and 83% specificity and the AUC was 0.988 for only three genes by Q-PCR. 26% of adults and 64% of children with excellent liver allograft function, on minimal or dual immunosuppression, showed high prediction scores for tolerance. Novel peripheral transcriptional profiles can be identified in operational tolerance in pediatric and adult recipients of liver allografts, suggesting a high incidence of a pro-tolerogenic phenotype in stable patients on chronic immunosuppression. Given the high incidence of viral infections and malignancies in liver transplant recipients, this gene set provides an important monitoring tool that can move the field toward personalized and predictive medicine in organ transplantation.
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Affiliation(s)
- L Li
- Division of Nephrology, Department of Pediatrics, Stanford University, Palo Alto, CA, USA
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Penninga L, Wettergren A, Chan AW, Steinbrüchel DA, Gluud C. Calcineurin inhibitor minimisation versus continuation of calcineurin inhibitor treatment for liver transplant recipients. Cochrane Database Syst Rev 2012; 2012:CD008852. [PMID: 22419339 PMCID: PMC11441157 DOI: 10.1002/14651858.cd008852.pub2] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND The therapeutic success of liver transplantation has been largely attributable to the development of effective immunosuppressive treatment regimens. In particular, calcineurin inhibitors were essential in reducing acute rejection and improving early survival. Currently, more than 90% of all liver transplant recipients are treated with the calcineurin inhibitor cyclosporine or tacrolimus. Unfortunately, calcineurin inhibitors cause adverse events, such as nephrotoxicity, and because of this, minimisation (reduction and withdrawal) regimens of calcineurin inhibitor have been developed and studied. However, the benefits and harms of these minimisation regimens are unclear. OBJECTIVES To assess the benefits and harms of calcineurin inhibitor minimisation for liver transplant recipients without substitution by another immunosuppressive agent. SEARCH METHODS We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2010), Cochrane Central Register of Controlled Clinical Trials (CENTRAL) in The Cochrane Library, MEDLINE (OvidSP), EMBASE (OvidSP), Science Citation Index Expanded (Royle 2003), and the World Health Organization (WHO) international clinical trials registry platform (www.who.int/ictrp) until August 2011. In addition, we searched bibliographies of relevant articles as well as US Food and Drug Administration (FDA) and European Medicines Agency (EMA) drug approval reviews for additional trials. SELECTION CRITERIA We planned to select all randomised clinical trials investigating calcineurin inhibitor reduction or withdrawal in liver transplant recipients, irrespective of blinding, publication status, or language. Quasi-randomised clinical studies and cohort studies that were obtained through the searches were considered only for the reporting of harms. Trials investigating substitution of one calcineurin inhibitor by another calcineurin inhibitor were excluded. Trials investigating calcineurin inhibitor withdrawal concurrently with switching over to a mammalian target of rapamycin (mTOR) inhibitor-based regimen (everolimus or sirolimus) or mycophenolate mofetil-based regimen are the subject of a separate review. DATA COLLECTION AND ANALYSIS Search strategies were used to obtain titles and abstracts of studies that were relevant for the review. Two authors independently scanned the references and assessed trial eligibility. MAIN RESULTS A total of 1299 references were identified by the searches. After removal of duplicates, 794 references were left. Out of these, two abstract reports of one ongoing randomised trial fulfilled the inclusion criteria of the review. This ongoing trial studies total withdrawal of immunosuppression in patients who receive a calcineurin inhibitor (cyclosporine or tacrolimus) or mycophenolate mofetil as the only immunosuppressive agent. The trial compares withdrawal of calcineurin inhibitor or mycophenolate mofetil with continuation of calcineurin inhibitor or mycophenolate mofetil. However, no trial results on the outcomes of interest to this review were available. AUTHORS' CONCLUSIONS This review shows that strategies regarding calcineurin inhibitor minimisation, that is, reduction or withdrawal, without substitution versus continuation of calcineurin inhibitor treatment lack evidence from randomised trials.More research with calcineurin inhibitor reduction and withdrawal regimens is needed to optimise dosing and timing of calcineurin inhibitor treatment in order to achieve optimal patient and graft survival with a minimum of adverse events.Specifically regarding calcineurin inhibitor reduction versus no reduction, we recommend that randomised trials evaluating calcineurin inhibitor reduction versus continuation of calcineurin inhibitor treatment are conducted.Regarding calcineurin inhibitor withdrawal, we recommend that mechanisms for tolerance and 'graft acceptance' are clarified, and patient groups likely to tolerate calcineurin inhibitor withdrawal are identified in order to select the right patients for total withdrawal of calcineurin inhibitors without substitution with another immunosuppressive drug. The randomised trials should only be performed in highly selected patients.
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Affiliation(s)
- Luit Penninga
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 3344, Rigshospitalet, Copenhagen University Hospital,Copenhagen, Denmark. .
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Alex Bishop G, Bertolino PD, Bowen DG, McCaughan GW. Tolerance in liver transplantation. Best Pract Res Clin Gastroenterol 2012; 26:73-84. [PMID: 22482527 DOI: 10.1016/j.bpg.2012.01.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2011] [Revised: 12/15/2011] [Accepted: 01/13/2012] [Indexed: 01/31/2023]
Abstract
Operational tolerance (OT) in liver transplant patients occurs much more frequently than OT of other transplanted organs; however the rate of OT varies considerably with the centre and patient population. Rates of OT range from 15% of the total liver transplant (LTX) patient population down to less than 5%. This review examines the reports of liver OT and compares the factors that could contribute to this variation. Multiple factors were examined, including the time from transplantation when weaning of immunosuppression (IS) was commenced, the rapidity of weaning, the contribution of maintenance and induction IS and the patient population transplanted. The approaches that might be used to increase the likelihood of OT are discussed and the approaches to monitoring OT in LTX patients are reviewed.
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Affiliation(s)
- G Alex Bishop
- Collaborative Transplantation Laboratory, Royal Prince Alfred Hospital and the University of Sydney, Australia.
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Abstract
1. Liver allografts exhibit intrinsic tolerogenic properties that result in their spontaneous acceptance in many experimental animal models. 2. In clinical transplantation, liver allografts require milder immunosuppression regimens than other organs, are relatively resistant to antibody-mediated rejection, and only very rarely are lost because of immunological insults. 3. A fraction of stable liver transplant recipients can withdraw from all immunosuppression therapy and then maintain normal graft function and not experience rejection. This phenomenon is known as spontaneous operational tolerance (SOT). 4. The intentional discontinuation of immunosuppression in stable liver transplant recipients has led to successful weaning in almost 20% of recipients, but the true prevalence of SOT in unselected recipients is still unknown. 5. The prevalence could be higher in pediatric recipients undergoing transplantation before 1 year of age and in adult recipients with more than 10 years of posttransplant follow-up. 6. Rejection occurring during medically supervised immunosuppression weaning trials tends to be mild and, in the overwhelming majority of cases, can be easily resolved without the administration of high-dose immunosuppression. 7. Tolerant liver recipients exhibit specific transcriptional patterns in peripheral blood and liver tissue that may constitute future diagnostic markers of tolerance. 8. There is still no formal proof that the discontinuation of low-dose immunosuppression in long-term survivors of liver transplantation improves the morbidity and mortality rates associated with immunosuppression therapy.
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Affiliation(s)
- Alberto Sánchez-Fueyo
- Liver Transplant Unit, Hospital Clinic of Barcelona, University of Barcelona, August Pi i Sunyer Institute for Biomedical Research, Center for Biomedical Research in Hepatic and Digestive Diseases (CIBEREHD), Barcelona, Spain.
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Porrett P, Shaked A. The failure of immunosuppression withdrawal: patient benefit is not detectable, inducible, or reproducible. Liver Transpl 2011; 17 Suppl 3:S66-8. [PMID: 21748844 DOI: 10.1002/lt.22377] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
(1) Immunosuppression is responsible for excellent patient outcomes. (2) Immunosuppression withdrawal fails in most patients. (3) Patients who may benefit from immunosuppression withdrawal cannot currently be identified. (4) No data suggest that immunosuppression withdrawal decreases patient morbidity (ie, nephrotoxicity). (5) The minimization of immunosuppression instead of withdrawal may be adequate for improving patient outcomes.
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Affiliation(s)
- Paige Porrett
- Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA
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41
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Orlando G. Finding the right time for weaning off immunosuppression in solid organ transplant recipients. Expert Rev Clin Immunol 2011; 6:879-92. [PMID: 20979553 DOI: 10.1586/eci.10.71] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Solid organ transplantation (SOT) requires lifelong immunosuppression (IS) to prevent rejection and graft loss. The currently adopted immunosuppressive protocols are numerous and are based on the administration of at least two molecules with diverse mechanisms of action. Owing to the fact that the majority of immunosuppressants act non-selectively, the immune system is normally oversuppressed, and as a result is less able to both defend the host against infection and to control the spread of malignant cells. Consequently, long-term IS is burdened by chronic toxicity, which may be highly invalidating and may significantly influence patient's quality of life, compliance to treatment, overall success rate, and patient and graft survival. In an ideal scenario, SOT recipients should initially receive just enough IS to favor the onset of clinical operational tolerance (COT), a condition where the immune system of the host does not attack the graft in the absence of any immunosuppressant. COT has been documented after liver transplantation (LT) and renal transplantation (RT). First, COT was accidentally detected in patients who were nonadherent to treatment and who spontaneously decided to stop all IS without any medical guidance or surveillance. Later, it was described in recipients who required IS withdrawal following the occurrence of malignant diseases. Based on strikingly convincing experimental data, several tolerogenic protocols have recently been applied in patients but overall the results have been disappointing. The current literature demonstrates that COT can be safely achieved in stable LT recipients, with completely different strategies. Importantly, the onset of an episode of acute rejection during the attempt of IS withdrawal would not worsen the clinical outcome. On the contrary, COT remains a major challenge after RT because the onset of acute rejection will substantiate in graft loss. Currently, a major field of investigation aims to define markers of COT, which will allow the selection of individuals who are more prone to develop COT. Preliminary results in both RT and LT have just been announced; however, these markers will require validation in prospective studies.
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Affiliation(s)
- Giuseppe Orlando
- Nuffield Department of Surgery, University of Oxford, Oxford, UK.
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Fändrich F. Tolerance in clinical transplantation: progress, challenge or just a dream? Langenbecks Arch Surg 2011; 396:475-87. [DOI: 10.1007/s00423-011-0757-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2011] [Accepted: 02/16/2011] [Indexed: 12/29/2022]
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Abstract
Every liver transplant (LT) center has had patients who either self-discontinue immunosuppressive (IS) therapy or are deliberately withdrawn due to a research protocol or clinical concern (ie, lymphoproliferative disorder [LPD], overwhelming infection). This is understandable because maintenance IS therapy, particularly calcineurin inhibitors (CNI), is associated with significant cost, side effects, and considerable long-term morbidity and mortality. Detrimental effects of IS therapy include increased risk of cardiovascular disease, metabolic syndrome, bone loss, opportunistic and community-acquired infections, and malignancy. In fact, LT recipients have among the highest rates of chronic kidney disease and associated mortality among all nonkidney solid organ recipients. This mortality is only ameliorated by undergoing a curative kidney transplant, usurping costs and valuable organ resources. The search for improved treatment algorithms includes trial and error CNI dose minimization, the use of alternative IS agents (antimetabolites, mammalian target of rapamycin [mTOR] inhibitors), or even complete CNI withdrawal. Yet those who are successful in achieving such operational tolerance (no immunosuppression and normal allograft function) are considered lucky. The vast majority of recipients will fail this approach, develop acute rejection or immune-mediated hepatitis, and require resumption of IS therapy. As such, withdrawal of IS following LT is not standard-of-care, leaving clinicians to currently maintain transplant patients on IS therapy for life. Nonetheless, the long-term complications of all IS therapies highlight the need for strategies to promote immunologic or operational tolerance. Clinically applicable biomarker assays signifying the potential for tolerance as well as tolerogenic IS conditioning are invariably needed if systematic, controlled rather than "hit or miss" approaches to withdrawal are considered. This review will provide an overview of the basic mechanisms of tolerance, particularly in relation to LT, data from previous IS withdrawal protocols and biomarker studies in tolerant recipients, and a discussion on the prospect of increasing the clinical feasibility and success of withdrawal.
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Affiliation(s)
- Josh Levitsky
- Division of Hepatology and Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
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SÁNCHEZ–FUEYO ALBERTO, STROM TERRYB. Immunologic basis of graft rejection and tolerance following transplantation of liver or other solid organs. Gastroenterology 2011; 140:51-64. [PMID: 21073873 PMCID: PMC3866688 DOI: 10.1053/j.gastro.2010.10.059] [Citation(s) in RCA: 172] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2010] [Revised: 10/24/2010] [Accepted: 10/26/2010] [Indexed: 12/13/2022]
Abstract
Transplantation of organs between genetically different individuals of the same species causes a T cell-mediated immune response that, if left unchecked, results in rejection and graft destruction. The potency of the alloimmune response is determined by the antigenic disparity that usually exists between donors and recipients and by intragraft expression of proinflammatory cytokines in the early period after transplantation. Studies in animal models have identified many molecules that, when targeted, inhibit T-cell activation. In addition, some of these studies have shown that certain immunologic interventions induce transplantation tolerance, a state in which the allograft is specifically accepted without the need for chronic immunosuppression. Tolerance is an important aspect of liver transplantation, because livers have a unique microenvironment that promotes tolerance rather than immunity. In contrast to the progress achieved in inducing tolerance in animal models, patients who receive transplanted organs still require nonspecific immunosuppressant drugs. The development of calcineurin inhibitors has reduced the acute rejection rate and improved short-term, but not long-term, graft survival. However, long-term use of immunosuppressive drugs leads to nephrotoxicity and metabolic disorders, as well as manifestations of overimmunosuppression such as opportunistic infections and cancers. The status of pharmacologic immunosuppression in the clinic is therefore not ideal. We review recently developed therapeutic strategies to promote tolerance to transplanted livers and other organs and diagnostic tools that might be used to identify patients most likely to accept or reject allografts.
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Affiliation(s)
- ALBERTO SÁNCHEZ–FUEYO
- Liver Transplant Unit, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
| | - TERRY B. STROM
- Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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Abstract
In the clinical arena of transplantation, tolerance remains, for the most part, a concept rather than a reality. Although modern immunosuppression regimens have effectively handled acute rejection, nearly all organs except the liver commonly suffer chronic immunologic damage that impairs organ function, threatening patient and allograft survival. In addition to the imperfect control of the donor-directed immune response, there are additional costs. First, there is the burden of mortality from infection and malignancy that can be directly attributed to a crippled immune system. Second, there are insidious effects on renal function, cardiovascular profile (hypertension, hyperglycemia, and dyslipidemia), bone health, growth, psychological and neurocognitive development, and overall quality of life. It is likely that the full consequences of lifelong immunosuppression on our pediatric transplant recipients will not be fully appreciated until survival routinely extends beyond 1 or 2 decades after transplantation. Therefore, it can be argued that the holy grail of transplantation tolerance is of the utmost importance to children who undergo solid organ transplantation.
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Abstract
Non-self cells can circulate in the body of an individual after any sort of contact with an allogeneic source of cells, thus creating a situation of chimerism that can be transient or prolonged over time. This situation may appear after stem cell transplantation, pregnancy, transfusion or transplantation. Concerning transplantation, many hypotheses have been formulated regarding the existence, persistence and role of these circulating cells in the host. We will review the principal hypotheses that have been formulated for years since the first description of non-self circulating cells in mammals to the utilization of artificially induced chimerism protocols for the achievement of tolerance.
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Affiliation(s)
- Josep-Maria Pujal
- Translational Research Laboratory, Institut Català d'Oncologia, Hospital Duran i Reynals, Avda Gran Via s/n, Km 2.7, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
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47
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Abstract
OBJECTIVE The aim of this study is to present the largest experience of auxiliary liver transplantation for acute liver failure (ALF) in children over the past 19 years. METHODS Between 1990 and 2009, a total of 128 liver transplants were performed on children with ALF. Of these, 20 received auxiliary liver transplants (19 were cadaveric and 1 living graft). The recipient median age was 12 years (range: 1 -16). Indications for auxiliary partial orthotopic liver transplantation were seronegative non-A non-B hepatitis in 16 children, drug induced in 2, and 1 autoimmune hepatitis and 1 mushroom poisoning. The median waiting time for transplantation was 2 days (range: 1-9). After native liver partial hepatectomy, 20 grafts were implanted orthotopically and included 8 right lobes, 8 left lateral segments, 3 left lobes, and 1 whole liver. Regeneration of the native liver was assessed by radiologic, nuclear medicine imaging, and histology. Follow-up imaging and biopsies were performed at intervals of 3 to 6 months and yearly. RESULTS Patient survival was 85% at 1, 5, and 10 years. There were 3 deaths at a median of 9 days (range: 8-52) post-transplantation. There was 1 retransplant for chronic rejection 15 months post-transplantation. There were no biliary or vascular complications. Of 17 survivors, 14 (82%) have successfully regenerated their native liver and so far 11 children (65% of the survivors) have been withdrawn from immunosuppression at a median time of 23 months (range: 4-106) after transplantation. CONCLUSION Auxiliary partial orthotopic liver transplantation should be considered in children presenting with ALF who fulfill criteria for liver transplantation.
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48
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Abstract
Continued advances in surgical techniques and immunosuppressive therapy have allowed liver transplantation to become an extremely successful treatment option for patients with end-stage liver disease. Beginning with the revolutionary discovery of cyclosporine in the 1970s, immunosuppressive regimens have evolved greatly and current statistics confirm one-year graft survival rates in excess of 80%. Immunosuppressive regimens include calcineurin inhibitors, anti-metabolites, mTOR inhibitors, steroids and antibody-based therapies. These agents target different sites in the T cell activation cascade, usually by inhibiting T cell activation or via T cell depletion. They are used as induction therapy in the immediate peri- and post-operative period, as long-term maintenance medications to preserve graft function and as salvage therapy for acute rejection in liver transplant recipients. This review will focus on existing immunosuppressive agents for liver transplantation and consider newer medications on the horizon.
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49
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Abstract
The achievement of an immunosuppression (IS)-free state after transplantation represents the ultimate goal of any immunosuppressive regimen. While clinical operational tolerance (COT) remains the exception after other types of solid organ transplantation, several cases of COT have been described after liver transplantation (LT). Overall, the experience gained so far worldwide demonstrates that COT can be achieved safely in one quarter of selected individuals, irrespective of the immunological background of donor and recipient, patient age, indication for LT, study endpoint, length of the weaning period and of pre/post-weaning follow-up, presence or not of chimerism. However, most transplant physicians still believe that the achievement of COT is still out of reach for the majority of LT recipients because of the potential risk for transplant survival, the non-randomized nature of most of the studies reported so far, and the selective nature of the patients enrolled in such studies, making them non-representative of the whole population of LT recipients. Despite these concerns, the present article demonstrates that this attitude is potentially no longer justified, given the growing evidence that a permanent and stable IS-free state can be achieved in a proportion of individuals who have received a LT for non-immune mediated liver diseases.
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Affiliation(s)
- Giuseppe Orlando
- Transplantation Research Immunology Group, Nuffield Department of Surgery, University of Oxford, Headington, Oxford OX3 9DU, UK.
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50
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Requirement of protocol biopsy before and after complete cessation of immunosuppression after liver transplantation. Transplantation 2009; 87:606-14. [PMID: 19307800 DOI: 10.1097/tp.0b013e318195a7cb] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Operational tolerance is defined as long-term acceptance of a transplanted organ after complete cessation of immunosuppression (IS), but may not always protect against antigen-dependent changes in graft morphology. METHOD IS free patients after living-donor liver transplantation (LDLT) underwent protocol biopsy (tolerance group [Gr-Tol]) and were evaluated for rejection and fibrosis. The degree of fibrosis was compared with those in the patients on maintenance IS group (Gr-IS) and the base line normal liver group (Gr-BS). When bridging fibrosis or progression of fibrosis was observed, IS was reintroduced or increased in Gr-Tol or in the patients in the weaning process. RESULTS Neither acute nor chronic rejection was observed. The degree of fibrosis, however, was significantly greater in Gr-Tol than those in Gr-IS and Gr-BS. In Gr-Tol, the number of graft infiltrating FOXP3 cells was significantly increased, the interval between LDLT and biopsy plus the donor age was significantly longer, and recipient age at LDLT was significantly younger, compared with those in Gr-IS. However, none of these three parameters correlated with the degree of fibrosis. In 7 of 11 patients in whom IS was reintroduced or increased, the improvement of fibrosis was observed by the subsequent biopsy. CONCLUSION Grafts of operationally tolerant patients after LDLT did not exhibit acute or chronic rejection, but they exhibited fibrosis. It remains elusive whether fibrosis observed in tolerant grafts is antigen dependent. The finding that after [corrected] the reintroduction or the increase of IS fibrosis was improved supported the possibility that fibrosis in operationally tolerant patients was antigen dependent.
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