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Wang P, Jiang Z, Wang C, Liu X, Li H, Xu D, Zhong L. Immune Tolerance Induction Using Cell-Based Strategies in Liver Transplantation: Clinical Perspectives. Front Immunol 2020; 11:1723. [PMID: 33013824 PMCID: PMC7461870 DOI: 10.3389/fimmu.2020.01723] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 06/29/2020] [Indexed: 12/14/2022] Open
Abstract
Liver transplantation (LT) has become the best chance and a routine practice for patients with end-stage liver disease and small hepatocellular carcinoma. However, life-long immunosuppressive regimens could lead to many post-LT complications, including cancer recurrence, infections, dysmetabolic syndrome, and renal injury. Impeccable management of immunosuppressive regimens is indispensable to ensure the best long-term prognosis for LT recipients. This is challenging for these patients, who probably have a post-LT graft survival of more than 10 or even 20 years. Approximately 20% of patients after LT could develop spontaneous operational tolerance. They could maintain normal graft function and histology without any immunosuppressive regimens. Operational tolerance after transplantation has been an attractive and ultimate goal in transplant immunology. The liver, as an immunoregulatory organ, generates an immune hyporesponsive microenvironment under physiological conditions. In this regard, LT recipients may be ideal candidates for studies focusing on operative tolerance. Cell-based strategies are one of the most promising methods for immune tolerance induction, including chimerism induced by hematopoietic stem cells and adoptive transfer of regulatory T cells, regulatory dendritic cells, regulatory macrophages, regulatory B cells, and mesenchymal stromal cells. The safety and the efficacy of many cell products have been evaluated by prospective clinical trials. In this review, we will summarize the latest perspectives on the clinical application of cell-based strategies in LT and will address a number of concerns and future directions regarding these cell products.
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Affiliation(s)
- Pusen Wang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhongyi Jiang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chunguang Wang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xueni Liu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hao Li
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dingyin Xu
- Department of Hepatobiliary Surgery, Ruian People's Hospital, Ruian, China
| | - Lin Zhong
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Pan H, Gazarian A, Dubernard JM, Belot A, Michallet MC, Michallet M. Transplant Tolerance Induction in Newborn Infants: Mechanisms, Advantages, and Potential Strategies. Front Immunol 2016; 7:116. [PMID: 27092138 PMCID: PMC4823304 DOI: 10.3389/fimmu.2016.00116] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 03/14/2016] [Indexed: 12/26/2022] Open
Abstract
Although several tolerance induction protocols have been successfully implemented in adult renal transplantation, no tolerance induction approach has, as yet, been defined for solid organ transplantations in young infants. Pediatric transplant recipients have a pressing demand for the elaboration of tolerance induction regimens. Indeed, since they display a longer survival time, they are exposed to a higher level of risks linked to long-term immunosuppression (IS) and to chronic rejection. Interestingly, central tolerance induction may be of great interest in newborns, because of their immunological immaturity and the important role of the thymus at this early stage in life. The present review aims to clarify mechanisms and strategies of tolerance induction in these immunologically premature recipients. We first introduce the discovery and mechanisms of neonatal tolerance in murine experimental models and subsequently analyze tolerance induction in human newborn infants. Hematopoietic mixed chimerism in neonates is also discussed based on in utero hematopoietic stem cell (HSC) transplant studies. Then, we review the recent advances in tolerance induction approaches in adults, including the infusion of HSCs associated with less toxic conditioning regimens, regulatory T cells/facilitating cells/mesenchymal stem cells transplantation, costimulatory blockade, and thymus manipulation. Finally, IS withdrawal in pediatric solid organ transplant is discussed. In conclusion, the establishment of transplant tolerance induction in infants is promising and deserves further investigations. Future studies could focus on the selection of patients, on less toxic conditioning regimens, and on biomarkers for IS minimization or withdrawal.
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Affiliation(s)
- Hua Pan
- Chair of Transplantation, VetAgro Sup-Campus Vétérinaire de Lyon, Marcy l'Etoile, France; Plastic and Reconstructive Surgery Department, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Aram Gazarian
- Chair of Transplantation, VetAgro Sup-Campus Vétérinaire de Lyon, Marcy l'Etoile, France; Department of Hand Surgery, Clinique du Parc, Lyon, France
| | - Jean-Michel Dubernard
- Chair of Transplantation, VetAgro Sup-Campus Vétérinaire de Lyon, Marcy l'Etoile, France; Department of Transplantation, Hôpital Edouard Herriot, Lyon, France
| | - Alexandre Belot
- International Center for Infectiology Research (CIRI), Université de Lyon , Lyon , France
| | - Marie-Cécile Michallet
- Chair of Transplantation, VetAgro Sup-Campus Vétérinaire de Lyon, Marcy l'Etoile, France; Cancer Research Center Lyon (CRCL), UMR INSERM 1052 CNRS 5286, Centre Leon Berard, Lyon, France
| | - Mauricette Michallet
- Chair of Transplantation, VetAgro Sup-Campus Vétérinaire de Lyon, Marcy l'Etoile, France; Department of Hematology, Centre Hospitalier Lyon-Sud, Pierre Benite, France
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Baron D, Giral M, Brouard S. Reconsidering the detection of tolerance to individualize immunosuppression minimization and to improve long-term kidney graft outcomes. Transpl Int 2015; 28:938-59. [DOI: 10.1111/tri.12578] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Revised: 02/03/2015] [Accepted: 04/02/2015] [Indexed: 01/03/2023]
Affiliation(s)
- Daniel Baron
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
| | - Magali Giral
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
| | - Sophie Brouard
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
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Association of Anti-Human Leukocyte Antigen and Anti-Angiotensin II Type 1 Receptor Antibodies With Liver Allograft Fibrosis After Immunosuppression Withdrawal. Transplantation 2014; 98:1105-11. [DOI: 10.1097/tp.0000000000000185] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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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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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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Wu SL, Pan CE. Tolerance and chimerism and allogeneic bone marrow/stem cell transplantation in liver transplantation. World J Gastroenterol 2013; 19:5981-7. [PMID: 24106398 PMCID: PMC3785619 DOI: 10.3748/wjg.v19.i36.5981] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Revised: 06/05/2013] [Accepted: 07/18/2013] [Indexed: 02/06/2023] Open
Abstract
The liver has particular tolerogenic properties that allow its spontaneous acceptance in some animal species. Liver structure is considered to favor a tolerogenic environment. The peripheral tolerance mechanisms also play a role in spontaneous tolerance to liver graft. In a clinical setting, the main challenge nowadays facing liver transplantation is minimization of immunosuppression with the goal of donor-specific tolerance. Mechanisms involved in tolerance to transplanted organs are complex and partly unknown. A significant mechanism in tolerance induction is chimerism. Chimerism can be induced through transplantation of allogeneic donor bone marrow/stem cells under appropriate host conditioning. This review focuses on the tolerance mechanisms in liver transplantation and highlights the role of chimerism and allogeneic bone marrow/stem cell transplantation in tolerance development.
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Chandrasekharan D, Issa F, Wood KJ. Achieving operational tolerance in transplantation: how can lessons from the clinic inform research directions? Transpl Int 2013; 26:576-89. [PMID: 23517251 DOI: 10.1111/tri.12081] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2012] [Revised: 11/23/2012] [Accepted: 02/04/2013] [Indexed: 01/03/2023]
Abstract
Since the first solid organ transplant between the Herrick twins in 1954, transplantation immunology has sought to move away from harmful immunosuppressive regimens towards tolerogenic strategies that promote long-term graft survival. This has required a concerted multinational effort with scientists and clinicians working towards a common goal. Reports of immunosuppression-free kidney and liver allograft recipients have provided the proof-of-principle, but intentional generation of tolerance in clinical transplantation is still only achieved infrequently. Recently, there have been an increasing number of encouraging developments in the field in both experimental and clinical studies. In this article, we review the latest advances in tolerance research and consider possible future barriers and solutions in achieving reliable graft acceptance in the long term.
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Affiliation(s)
- Deepak Chandrasekharan
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
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Szabolcs P, Burlingham WJ, Thomson AW. Tolerance after solid organ and hematopoietic cell transplantation. Biol Blood Marrow Transplant 2012; 18:S193-200. [PMID: 22226107 DOI: 10.1016/j.bbmt.2011.11.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Paul Szabolcs
- Division of Blood and Marrow Transplantation and Cellular Therapies, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224, USA.
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Abstract
Liver transplantation is the standard of care for children with life-threatening liver disease. Survival rates posttransplantation are rising with current 1-year and 5-year rates being greater than 90% and 85%, respectively. Numerous factors contribute to posttransplant outcomes of graft and patient survival, including improved surgical techniques, immunosuppressive regimens, and posttransplant management. The present review aims to discuss predictors of long-term outcomes of pediatric transplant recipients and identify potential risk factors.
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Abstract
PURPOSE OF REVIEW To outline the rationale of powerful depleting induction therapy with alemtuzumab and minimal maintenance immunosuppression after organ transplantation. RECENT FINDINGS The original observations in principle have been confirmed by many independent centres. SUMMARY Follow-up of the 'prope tolerance' protocol has confirmed a low incidence of rejection, infection and post transplant lymphoproliferative disorder (PTLD). Especially, encouraging results were obtained in African-Americans. There were few side effects and the regimen was well tolerated by patients. Treg cells were observed in the circulation, which could be an important factor in the mechanisms of graft acceptance using a prope tolerance regimen. There was a considerable reduction in the costs of the transplantation procedure. It is suggested that this minimalisation of maintenance immunosuppression is the best therapy currently available that we can offer to our patients.
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Current world literature. Curr Opin Organ Transplant 2011; 16:650-60. [PMID: 22068023 DOI: 10.1097/mot.0b013e32834dd969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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