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Bondeelle L, Clément S, Bergeron A, Tapparel C. Lung stem cells and respiratory epithelial chimerism in transplantation. Eur Respir Rev 2025; 34:240146. [PMID: 39971397 PMCID: PMC11836672 DOI: 10.1183/16000617.0146-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 11/21/2024] [Indexed: 02/21/2025] Open
Abstract
Stem cells are capable of self-renewal and differentiation into specialised types. They range from totipotent cells to multipotent or somatic stem cells and ultimately to unipotent cells. Some adult multipotent stem cells can have the potential to regenerate and colonise diverse tissues. The respiratory airways and lung mucosa, exposed to ambient air, perform vital roles for all human tissues and organs. They serve as barriers against airborne threats and are essential for tissue oxygenation. Despite low steady-state turnover, lungs are vulnerable to injuries and diseases from environmental exposure. Lung stem cells are crucial due to their regenerative potential and ability to replace damaged cells. Lung repair with extrapulmonary stem cells can occur, leading to the coexistence of respiratory cells with different genetic origins, a phenomenon known as airway epithelial chimerism. The impact of such chimerism in lung repair and disease is actively studied. This review explores different stem cell types, focusing on pulmonary stem cells. It discusses airway epithelium models derived from stem cells for studying lung diseases and examines lung chimerism, particularly in lung transplantation and haematopoietic stem cell transplantation, highlighting its significance in understanding tissue repair and chimerism-mediated repair processes in lung pathology.
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Affiliation(s)
- Louise Bondeelle
- Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
| | - Sophie Clément
- Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
| | - Anne Bergeron
- Pneumology Department, Geneva University Hospitals, Geneva, Switzerland
- Co-last author
| | - Caroline Tapparel
- Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
- Co-last author
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2
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Shahandeh N, Kim JS, Klomhaus AM, Tehrani DM, Hsu JJ, Nsair A, Khush KK, Fearon WF, Parikh RV. Comparison of cardiac allograft vasculopathy incidence between simultaneous multiorgan and isolated heart transplant recipients in the United States. J Heart Lung Transplant 2024; 43:1737-1746. [PMID: 38950666 DOI: 10.1016/j.healun.2024.06.014] [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: 08/19/2023] [Revised: 05/28/2024] [Accepted: 06/25/2024] [Indexed: 07/03/2024] Open
Abstract
BACKGROUND Prior studies have shown reduced development of cardiac allograft vasculopathy (CAV) in multiorgan transplant recipients. The aim of this study was to compare the incidence of CAV between isolated heart transplants and simultaneous multiorgan heart transplants in the contemporary era. METHODS We utilized the Scientific Registry of Transplant Recipients to perform a retrospective analysis of first-time adult heart transplant recipients between January 1, 2010 and December 31, 2019 in the United States. The primary end-point was the development of angiographic CAV within 5 years of follow-up. RESULTS Among 20,591 patients included in the analysis, 1,279 (6%) underwent multiorgan heart transplantation (70% heart-kidney, 16% heart-liver, 13% heart-lung, and 1% triple-organ), and 19,312 (94%) were isolated heart transplant recipients. The average age was 53 years, and 74% were male. There were no significant between-group differences in cold ischemic time. The incidence of acute rejection during the first year after transplant was significantly lower in the multiorgan group (18% vs 33%, p < 0.01). The 5-year incidence of CAV was 33% in the isolated heart group and 27% in the multiorgan group (p < 0.0001); differences in CAV incidence were seen as early as 1 year after transplant and persisted over time. In multivariable analysis, multiorgan heart transplant recipients had a significantly lower likelihood of CAV at 5 years (hazard ratio = 0.76, 95% confidence interval: 0.66-0.88, p < 0.01). CONCLUSIONS Simultaneous multiorgan heart transplantation is associated with a significantly lower long-term risk of angiographic CAV compared with isolated heart transplantation in the contemporary era.
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Affiliation(s)
- Negeen Shahandeh
- Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, California
| | - Juka S Kim
- Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, California
| | - Alexandra M Klomhaus
- Department of Medicine Statistics Core, University of California Los Angeles, Los Angeles, California
| | - David M Tehrani
- Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, California
| | - Jeffrey J Hsu
- Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, California
| | - Ali Nsair
- Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, California
| | - Kiran K Khush
- Division of Cardiovascular Medicine, Stanford University, Stanford, California
| | - William F Fearon
- Division of Cardiovascular Medicine, Stanford University, Stanford, California; Division of Cardiology, VA Palo Alto Health Care Systems, Palo Alto, California
| | - Rushi V Parikh
- Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, California.
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3
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Amin KR, Fildes JE. The contribution of the donor vascularised hand and face allograft in transplant rejection: An immunological perspective. Transpl Immunol 2024; 84:102035. [PMID: 38518826 DOI: 10.1016/j.trim.2024.102035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 03/14/2024] [Accepted: 03/15/2024] [Indexed: 03/24/2024]
Abstract
Overcoming immunological rejection remains a barrier to the safe adoption of Vascularised Composite Allotransplantation (VCA). To mitigate this risk, clinical protocols have been derived from solid organ transplantation, targeting recipient immunomodulation, yet VCA is unique. Face and hand composite allografts are composed of multiple different tissues, each with their own immunological properties. Experimental work suggests that allografts carry variable numbers and populations of donor leukocytes in an organ specific manner. Ordinarily, these passenger leukocytes are transferred from the donor graft into the recipient circulation after transplantation. Whether alloantigen presentation manifests as acute allograft rejection or transplant tolerance is unknown. This review aims to characterise the immunological properties of the constituent parts of the donor face and hand, the potential fate of donor leukocytes and to consider theoretical graft specific interventions to mitigate early rejection.
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Affiliation(s)
- Kavit R Amin
- Department of Plastic Surgery, Manchester University NHS Foundation Trust, Manchester, UK; Division of Cell Matrix, Biology and Regenerative Medicine, University of Manchester, Manchester, UK; The Pebble Institute, Manchester, UK.
| | - James E Fildes
- The Pebble Institute, Manchester, UK; The Healthcare Technologies Institute, University of Birmingham, Birmingham, UK.
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4
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Song S, Zhi Y, Tian G, Sun X, Chen Y, Qiu W, Jiao W, Huang H, Yu Y, Li M, Lv G. Immature and activated phenotype of blood NK cells is associated with acute rejection in adult liver transplant. Liver Transpl 2023; 29:836-848. [PMID: 37002601 DOI: 10.1097/lvt.0000000000000139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 03/08/2023] [Indexed: 05/10/2023]
Abstract
Natural killer (NK) cells contribute to liver transplant (LTx) rejection. However, the blood-circulating NK-cell dynamics of patients who experience acute rejection (AR) are unclear. Herein, we longitudinally profiled the total NK cells and their subsets, along with the expression of activating and inhibitory receptors in sequential peripheral blood mononuclear cell samples, spanning from before LTx to the first year after LTx of 32 patients with AR and 30 patients under a steady immune status. Before transplantation, patients with AR (rejectors) contained a significantly higher proportion of the immature CD56 bright CD16 - subset and a lower cytolytic CD56 dim CD16 + in the total blood-circulating NK cells than patients with steady immunity. Both subsets contained a high NKp30-positive population, and CD56 dim CD16 + additionally exhibited a high NKp46-positive ratio. The NKp30-positive ratio in CD56 dim CD16 + subset showed the most prominent AR predictive ability before LTx and was an independent risk factor of LTx AR. After transplantation, the blood-circulating NK cells in rejectors maintained a higher CD56 bright CD16 - and lower CD56 dim CD16 + composition than the controls throughout the first year after LTx. Moreover, both subsets maintained a high NKp30-positive ratio, and CD56 dim CD16 + retained a high NKp46-positive ratio. The blood-circulating NK cell subset composition was consistent during AR, while the expressions of NKp30 and NKp46 were augmented. Collectively, a more immature CD56 bright CD16 - subset composition and an activated phenotype of high NKp30 expression were the general properties of blood-circulating NK cells in rejected LTx recipients, and the NKp30-positive ratio in CD56 dim CD16 + NK subset before LTx possessed AR predictive potential.
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Affiliation(s)
- Shifei Song
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
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5
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Iske J, Wiegmann B, Ius F, Chichelnitskiy E, Ludwig K, Kühne JF, Hitz AM, Beushausen K, Keil J, Iordanidis S, Rojas SV, Sommer W, Salman J, Haverich A, Warnecke G, Falk CS. Immediate major dynamic changes in the T- and NK-cell subset composition after cardiac transplantation. Eur J Immunol 2023; 53:e2250097. [PMID: 37119053 DOI: 10.1002/eji.202250097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 03/23/2023] [Accepted: 04/28/2023] [Indexed: 04/30/2023]
Abstract
Early kinetics of lymphocyte subsets involved in tolerance and rejection following heart transplantation (HTx) are barely defined. Here, we aimed to delineate the early alloimmune response immediately after HTx. Therefore, blood samples from 23 heart-transplanted patients were collected before (pre-), immediately (T0), 24 hours (T24), and 3 weeks (3 wks) after HTx. Immunophenotyping was performed using flow cytometry. A significant increase was detected for terminally differentiated (TEMRA) CD4+ or CD8+ T cells and CD56dim CD16+ NK cells immediately after HTx linked to a decrease in naïve CD8+ and CM CD4+ T as well as CD56bright CD16- NK cells, returning to baseline levels at T24. More detailed analyses revealed increased CD69+ CD25- and diminished CD69- CD25- CD4+ or CD8+ T-cell proportions at T0 associated with decreasing S1PR1 expression. Passenger T and NK cells were found at low frequencies only in several patients at T0 and did not correlate with lymphocyte alterations. Collectively, these results suggest an immediate, transient shift toward memory T and NK cells following HTx. Opposite migratory properties of naïve versus memory T and NK cells occurring in the early phase after HTx could underlie these observations and may impinge on the development of allo-specific immune responses.
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Affiliation(s)
- Jasper Iske
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité (DHZC), Berlin, Germany
| | - Bettina Wiegmann
- Department for Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
- German Center for Lung Research, BREATH, Hannover Medical School, Hannover, Germany
| | - Fabio Ius
- Department for Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
- German Center for Lung Research, BREATH, Hannover Medical School, Hannover, Germany
| | | | - Kristina Ludwig
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
| | - Jenny F Kühne
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
| | - Anna Maria Hitz
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
| | - Kerstin Beushausen
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
| | - Jana Keil
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
| | - Susanne Iordanidis
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
| | - Sebastián V Rojas
- Heart and Diabetes Center Nordrhein-Westfalen, University Hospital Ruhr-University Bochum, Bad Oeynhausen, Germany
| | - Wiebke Sommer
- Department of Cardiac Surgery, University Hospital Heidelberg UK-HD, Heidelberg, Germany
| | - Jawad Salman
- Department for Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Axel Haverich
- Department for Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Gregor Warnecke
- Department of Cardiac Surgery, University Hospital Heidelberg UK-HD, Heidelberg, Germany
| | - Christine S Falk
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
- German Center for Lung Research, BREATH, Hannover Medical School, Hannover, Germany
- German Center for Infection Research, TTU-IICH Hannover-Braunschweig site, Germany
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6
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Pérez-Escobar J, Jimenez JV, Rodríguez-Aguilar EF, Servín-Rojas M, Ruiz-Manriquez J, Safar-Boueri L, Carrillo-Maravilla E, Navasa M, García-Juárez I. Immunotolerance in liver transplantation: a primer for the clinician. Ann Hepatol 2023; 28:100760. [PMID: 36179797 DOI: 10.1016/j.aohep.2022.100760] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 09/08/2022] [Indexed: 02/04/2023]
Abstract
The use of immunosuppressive medications for solid organ transplantation is associated with cardiovascular, metabolic, and oncologic complications. On the other hand, the development of graft rejection is associated with increased mortality and graft dysfunction. Liver transplant recipients can withdraw from immunosuppression without developing graft injury while preserving an adequate antimicrobial response - a characteristic known as immunotolerance. Immunotolerance can be spontaneously or pharmacologically achieved. Contrary to the classic dogma, clinical studies have elucidated low rates of true spontaneous immunotolerance (no serologic or histological markers of immune injury) among liver transplant recipients. However, clinical, serologic, and tissue biomarkers can aid in selecting patients in whom immunosuppression can be safely withdrawn. For those who failed an immunosuppression withdrawal trial or are at high risk of rejection, pharmacological interventions for immunotolerance induction are under development. In this review, we provide an overview of the mechanisms of immunotolerance, the clinical studies investigating predictors and biomarkers of spontaneous immunotolerance, as well as the potential pharmacological interventions for inducing it.
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Affiliation(s)
- Juanita Pérez-Escobar
- Department of Hepatology and Liver Transplant, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Jose Victor Jimenez
- Department of Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Erika Faride Rodríguez-Aguilar
- Department of Hepatology and Liver Transplant, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Maximiliano Servín-Rojas
- Department of Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Jesus Ruiz-Manriquez
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Luisa Safar-Boueri
- Comprehensive Transplant Center, Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Eduardo Carrillo-Maravilla
- Department of Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Miquel Navasa
- Liver Transplant Unit, Hepatology Service, Hospital Clínic de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Ignacio García-Juárez
- Department of Hepatology and Liver Transplant, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
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7
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Central tolerance promoted by cell chimerism. Proc Natl Acad Sci U S A 2022; 119:e2214989119. [PMID: 36534805 PMCID: PMC9907097 DOI: 10.1073/pnas.2214989119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Historically, successful allotransplantation was only achieved by utilizing powerful immunosuppressive drugs that were exposing the patient to severe opportunistic infections. The thymus of the transplant recipient renders such therapy obligatory as it constitutively blocks self-reactive T cells while allowing alloreactive T cells to mature and populate the periphery. In 1992, a follow-up study revealed the presence of donor leukocytes in long-term transplant survivors. The stable persistence of recipient and donor leukocytes in the transplanted patient, referred to as "chimerism", was considered the reason why in some cases it was even possible to stop immunosuppressive treatment without damaging the transplanted organ. Unfortunately, it quickly became evident that stable, persistent allogeneic chimerism was not easily achievable by design. Recently, a novel approach has been identified to help address this clinical gap in knowledge: Cotransplantation of a donor graft with a thymic organoid populated with donor precursor cells generates stable, long-term chimerism in the recipient. In humanized mice, the implantation of thymic organoids, populated with human donor inducible pluripotent stem cell (iPSC)-derived thymic epithelial cells (TECs) and the same donor CD34+ bone marrow precursors, induces tolerance to human leukocyte antigen (HLA)-matched donor tissues/organs. This technology will allow successful allotransplantation of cells/organs even between Major Histocompatibility Complex (MHC)-noncompatible individuals and allow getting rid of immunosuppressive treatments reducing recipient morbidity.
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8
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Panero AJ, Hirahara AM, Podesta L, Jamali AA, Andersen W, Smith AA. Allograft Tissues. ATLAS OF INTERVENTIONAL ORTHOPEDICS PROCEDURES 2022:89-101. [DOI: 10.1016/b978-0-323-75514-6.00008-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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9
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Toti L, Manzia TM, Sensi B, Blasi F, Baiocchi L, Lenci I, Angelico R, Tisone G. Towards tolerance in liver transplantation. Best Pract Res Clin Gastroenterol 2021; 54-55:101770. [PMID: 34874844 DOI: 10.1016/j.bpg.2021.101770] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 10/08/2021] [Indexed: 02/08/2023]
Abstract
Life-long immunosuppression has always been considered the key in managing liver graft protection from recipient rejection. However, it is associated with severe adverse effects that lead to increased morbidity and mortality, including infections, cardiovascular diseases, kidney failure, metabolic disorders and de novo malignancies. This explains the great interest that has developed in the concept of tolerance in recent years. The liver, thanks to its marked tolerogenicity, is to be considered a privileged organ: up to 60% of selected patients undergoing liver transplantation could safely withdraw immunosuppression.
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Affiliation(s)
- L Toti
- Hepato-Pancreato-Biliary and Transplant Unit, Fondazione Policlinico Tor Vergata, Rome, Italy.
| | - T M Manzia
- University of Rome Tor Vergata, Department of Surgical Science, Italy
| | - B Sensi
- University of Rome Tor Vergata, Department of Surgical Science, Italy
| | - F Blasi
- University of Rome Tor Vergata, Department of Surgical Science, Italy
| | - L Baiocchi
- University of Rome Tor Vergata, Department of Surgical Science, Italy
| | - I Lenci
- Hepatology and Liver Transplant Unit, Fondazione Policlinico Tor Vergata, Rome, Italy
| | - R Angelico
- University of Rome Tor Vergata, Department of Surgical Science, Italy
| | - G Tisone
- University of Rome Tor Vergata, Department of Surgical Science, Italy
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10
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Safinia N, Vaikunthanathan T, Lechler RI, Sanchez‐Fueyo A, Lombardi G. Advances in Liver Transplantation: where are we in the pursuit of transplantation tolerance? Eur J Immunol 2021; 51:2373-2386. [PMID: 34375446 PMCID: PMC10015994 DOI: 10.1002/eji.202048875] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 06/07/2021] [Accepted: 07/23/2021] [Indexed: 12/22/2022]
Abstract
Liver transplantation is the ultimate treatment option for end-stage liver disease. Breakthroughs in surgical practice and immunosuppression have seen considerable advancements in survival after transplantation. However, the intricate management of immunosuppressive regimens, balancing desired immunological quiescence while minimizing toxicity has proven challenging. Diminishing improvements in long-term morbidity and mortality have been inextricably linked with the protracted use of these medications. As such, there is now enormous interest to devise protocols that will allow us to minimize or completely withdraw immunosuppressants after transplantation. Immunosuppression withdrawal trials have proved the reality of tolerance following liver transplantation, however, without intervention will only occur after several years at the risk of potential cumulative immunosuppression-related morbidity. Focus has now been directed at accelerating this phenomenon through tolerance-inducing strategies. In this regard, efforts have seen the use of regulatory cell immunotherapy. Here we focus particularly on regulatory T cells, discussing preclinical data that propagated several clinical trials of adoptive cell therapy in liver transplantation. Furthermore, we describe efforts to further optimize the specificity and survival of regulatory cell therapy guided by concurrent immunomonitoring studies and the development of novel technologies including chimeric antigen receptors and co-administration of low-dose IL-2.
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Affiliation(s)
- Niloufar Safinia
- Division of Transplantation Immunology & Mucosal BiologyKing's College LondonLondonUK
| | | | - Robert Ian Lechler
- Division of Transplantation Immunology & Mucosal BiologyKing's College LondonLondonUK
| | | | - Giovanna Lombardi
- Division of Transplantation Immunology & Mucosal BiologyKing's College LondonLondonUK
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11
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Iske J, Matsunaga T, Zhou H, Tullius SG. Donor and Recipient Age-Mismatches: The Potential of Transferring Senescence. Front Immunol 2021; 12:671479. [PMID: 33995411 PMCID: PMC8113632 DOI: 10.3389/fimmu.2021.671479] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 04/08/2021] [Indexed: 12/15/2022] Open
Abstract
In transplantation, donor and recipients frequently differ in age. Senescent cells accumulate in donor organs with aging and have the potential to promote senescence in adjacent cells when transferred into recipient animals. Characteristically, senescent cells secrete a myriad of pro-inflammatory, soluble molecules as part of their distinct secretory phenotype that have been shown to drive senescence and age-related co-morbidities. Preliminary own data show that the transplantation of old organs limits the physical reserve of recipient animals. Here, we review how organ age may affect transplant recipients and discuss the potential of accelerated aging.
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Affiliation(s)
- Jasper Iske
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women´s Hospital, Harvard Medical School, Boston, MA, United States
| | - Tomohisa Matsunaga
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women´s Hospital, Harvard Medical School, Boston, MA, United States.,Department of Urology, Osaka Medical College, Osaka, Japan
| | - Hao Zhou
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women´s Hospital, Harvard Medical School, Boston, MA, United States
| | - Stefan G Tullius
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women´s Hospital, Harvard Medical School, Boston, MA, United States
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12
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Considerations and experience driving expansion of combined heart-liver transplantation. Curr Opin Organ Transplant 2021; 25:496-500. [PMID: 32796180 DOI: 10.1097/mot.0000000000000804] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
PURPOSE OF REVIEW Heart transplantation concomitant with a liver transplant may be warranted when end-stage heart failure results in irreversible liver failure. Previously reported outcomes have been excellent yet the specific immunoprotective role of the liver allograft is not known. We review the current literature about the immunologic benefit for combined heart and liver transplantation (CHLT). RECENT FINDINGS The total number of combined heart and liver transplants continues to increase and accounts for approximately 25 cases per year. Familial amyloid polyneuropathy with cardiac cirrhosis is the most common indication for CHLT while adult congenital heart disease (CHD) with associated cirrhosis is increasing in frequency. The majority of recent registry data suggest a statistically equivalent to modestly improved survival advantage for CHLT compared with isolated heart transplantation. Direct mechanisms accounting for this survival advantage are not proven, but combined heart and liver transplants experience lower rates of acute cardiac rejection and cardiac allograft vasculopathy (CAV). SUMMARY Combined heart and liver transplants remain a small percentage of the total heart transplants worldwide, but the majority of recent literature confirms the safety and viability of this option for patients with end-stage heart and liver disease. Equivalent to modestly improved survival outcomes, lower rates of acute cardiac rejection and CAV warrant further investigation into the liver allograft's immunoprotective effect on the transplanted heart. The key mechanisms of tolerogenicity have important implications for surgical technique and immunosuppression requirements. Future directions include development of criteria for heart-liver transplant candidacy and identification of equitable allocation protocols.
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13
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McCaughan GW, Bowen DG, Bertolino PJ. Induction Phase of Spontaneous Liver Transplant Tolerance. Front Immunol 2020; 11:1908. [PMID: 33013840 PMCID: PMC7516030 DOI: 10.3389/fimmu.2020.01908] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 07/16/2020] [Indexed: 12/30/2022] Open
Abstract
The liver has long been known to possess tolerogenic properties. Early experiments in liver transplantation demonstrated that in animal models, hepatic allografts could be accepted across MHC-mismatch without the use of immunosuppression, and that transplantation of livers from the same donor was capable of inducing tolerance to other solid organs that would normally otherwise be rejected. Although this phenomenon is less pronounced in human liver transplantation, lower levels of immunosuppression are nevertheless required for graft acceptance than for other solid organs, and in a minority of individuals immunosuppression can be discontinued in the longer term. The mechanisms underlying this unique hepatic property have not yet been fully delineated, however it is clear that immunological events in the early period post-liver transplant are key to generation of hepatic allograft tolerance. Both the hepatic parenchyma and the large number of donor passenger leukocytes contained within the liver allograft have been demonstrated to contribute to the generation of donor-specific tolerance in the early post-transplant phase. In particular, the unique nature of hepatic-leukocyte interactions appears to play a crucial role in the ability of the liver to silence the recipient alloimmune response. In this review, we will summarize the evidence regarding the potential mechanisms that mediate the critical early phase in the generation of hepatic allograft tolerance.
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Affiliation(s)
- Geoffrey W McCaughan
- Liver Injury and Cancer Program, The Centenary Institute, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia.,AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - David G Bowen
- AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Liver Immunology Program, The Centenary Institute, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Patrick J Bertolino
- AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Liver Immunology Program, The Centenary Institute, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
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14
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15
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Sullivan JA, AlAdra DP, Olson BM, McNeel DG, Burlingham WJ. Infectious Tolerance as Seen With 2020 Vision: The Role of IL-35 and Extracellular Vesicles. Front Immunol 2020; 11:1867. [PMID: 32983104 PMCID: PMC7480133 DOI: 10.3389/fimmu.2020.01867] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 07/13/2020] [Indexed: 12/26/2022] Open
Abstract
Originally identified as lymphocyte regulation of fellow lymphocytes, our understanding of infectious tolerance has undergone significant evolutions in understanding since being proposed in the early 1970s by Gershon and Kondo and expanded upon by Herman Waldman two decades later. The evolution of our understanding of infectious tolerance has coincided with significant cellular and humoral discoveries. The early studies leading to the isolation and identification of Regulatory T cells (Tregs) and cytokines including TGFβ and IL-10 in the control of peripheral tolerance was a paradigm shift in our understanding of infectious tolerance. More recently, another potential, paradigm shift in our understanding of the "infectious" aspect of infectious tolerance was proposed, identifying extracellular vesicles (EVs) as a mechanism for propagating infectious tolerance. In this review, we will outline the history of infectious tolerance, focusing on a potential EV mechanism for infectious tolerance and a novel, EV-associated form for the cytokine IL-35, ideally suited to the task of propagating tolerance by "infecting" other lymphocytes.
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Affiliation(s)
- Jeremy A Sullivan
- Department of Surgery-Transplant Division, School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
| | - David P AlAdra
- Department of Surgery-Transplant Division, School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
| | - Brian M Olson
- Departments of Hematology and Medical Oncology, Urology, and Surgery, Emory University School of Medicine, Atlanta, GA, United States
| | - Douglas G McNeel
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
| | - William J Burlingham
- Department of Surgery-Transplant Division, School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
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16
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Briasoulis A, Akintoye E, Kuno T, Alvarez P. Characteristics and Outcomes of Patients Undergoing Combined Organ Transplantation (from the United Network for Organ Sharing). Am J Cardiol 2020; 129:42-45. [PMID: 32540168 DOI: 10.1016/j.amjcard.2020.05.034] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/17/2020] [Accepted: 05/19/2020] [Indexed: 11/30/2022]
Abstract
Studies have shown that highly selected patients who underwent combined heart-kidney (HK) and heart-liver transplants (HLv) have short- and long-term outcomes comparable to those observed in primary heart transplantation (HT). Adults patients with stage D heart failure that underwent combined HK, HLv, and heart-lung (HL) were identified in the United Network for Organ Sharing registry from 1991 to 2016, with follow-up through March 2018. We conducted inverse probability of treatment weighting survival analysis of long-term survival stratified by type of combined organ transplant, accounting for donor, recipient, and operative characteristics. We identified 2,300 patients who underwent combined organ transplant (HK 1,257, HLv 212, HL 831). HL recipients were more likely white (77%), women (58%), with congenital heart disease (44.5%), and longer waiting list time (median 195 days). HK transplant increased significantly during the study period where as HL decreased significantly. Median survival was 12.2 years for HK (95% confidence intervals [CI] 10.8 to 12.8), 12 for HLv (95% CI 8.6 to 17.6) but significantly lower at 4.5 years for HL (95% CI 3.6 to 5.8). Combined HK and HLv transplantation rates are increasing and long-term survival is comparable to primary HT, unlike HL which is associated with decreasing trends and significantly lower survival.
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Affiliation(s)
- Alexandros Briasoulis
- Division of Cardiovascular Diseases, Section of Heart Failure and Transplant, University of Iowa Hospitals and Clinics, Iowa City, Iowa.
| | - Emmanuel Akintoye
- Division of Cardiovascular Diseases, Section of Heart Failure and Transplant, University of Iowa Hospitals and Clinics, Iowa City, Iowa
| | - Toshiki Kuno
- Division of Cardiovascular Diseases, Section of Heart Failure and Transplant, University of Iowa Hospitals and Clinics, Iowa City, Iowa
| | - Paulino Alvarez
- Division of Cardiovascular Diseases, Section of Heart Failure and Transplant, University of Iowa Hospitals and Clinics, Iowa City, Iowa
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17
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Levitsky J, Burrell BE, Kanaparthi S, Turka LA, Kurian S, Sanchez-Fueyo A, Lozano JJ, Demetris A, Lesniak A, Kirk AD, Stempora L, Yang GY, Mathew JM. Immunosuppression Withdrawal in Liver Transplant Recipients on Sirolimus. Hepatology 2020; 72:569-583. [PMID: 31721246 PMCID: PMC7217743 DOI: 10.1002/hep.31036] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Accepted: 11/06/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS As conversion from calcineurin inhibitor to sirolimus (SRL), a mechanistic target of rapamycin inhibitor (mTOR-I), has been shown to enhance immunoregulatory profiles in liver transplant (LT) recipients (LTRs), mTOR-I therapy might allow for increased success of immunosuppression (IS) withdrawal. Our aim was to determine if operational tolerance could be observed in LTRs withdrawn from SRL and if blood/graft tolerance biomarkers were predictive of successful withdrawal. APPROACH AND RESULTS We performed a prospective trial of SRL monotherapy withdrawal in nonimmune, nonviremic LTRs > 3 years post-LT. SRL was weaned over ~6 months, and biopsies were performed 12 months postweaning or at concern for acute rejection. Twenty-one LTRs consented; 6 were excluded due to subclinical acute rejection on baseline biopsy or other reasons, and 15 underwent weaning (age 61.3 ± 8.8 years; LT to SRL weaning 6.7 ± 3 years). Eight (53%) achieved operational tolerance (TOL). Of the 7 who were nontolerant (non-TOL), 6 had mild acute rejection on biopsy near the end of weaning or at study end; 1 was removed from the trial due to liver cancer recurrence. At baseline preweaning, there were statistically increased blood tolerogenic dendritic cells and cell phenotypes correlating with chronic antigen presentation in the TOL versus non-TOL groups. A previously identified biopsy gene signature accurately predicted TOL versus non-TOL in 12/14 LTRs before weaning. At study end, biopsy staining revealed statistically significant increases in antigen-presenting cell:leukocyte pairings, FOXP3+ /CD4+ T cells, Tbet+ /CD8+ T cells, and lobular dendritic cells in the non-TOL group. CONCLUSIONS This study evaluated IS withdrawal directly from mTOR-I therapy in LTRs and achieved > 50% operational tolerance. Preweaning gene expression and peripheral blood mononuclear cell profiling may be useful as predictors of successful mTOR-I therapy withdrawal. NCT02062944.
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Affiliation(s)
- Josh Levitsky
- Northwestern University Feinberg School of Medicine, Chicago, IL
| | | | | | - Laurence A. Turka
- Immune Tolerance Network, Bethesda, MD; Massachusetts General Hospital, Boston, MA
| | - Sunil Kurian
- Scripps Clinic Bio-Repository and Transplantation Research, La Jolla, California, United States
| | | | - Juan J. Lozano
- Biomedical Research Center in Hepatic and Digestive Diseases, Carlos III Health Institute, Barcelona, Spain
| | | | | | | | | | - Guang-Yu Yang
- Northwestern University Feinberg School of Medicine, Chicago, IL
| | - James M. Mathew
- Northwestern University Feinberg School of Medicine, Chicago, IL
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18
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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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19
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Zhang G, Qin W, Yuan J, Ming C, Yue S, Liu Z, Yu L, Yu M, Gao X, Zhou Y, Wang L, Yang X, Dou K, Wang H. A 14-Year Follow-Up of a Combined Liver-Pancreas-Kidney Transplantation: Case Report and Literature Review. Front Med (Lausanne) 2020; 7:148. [PMID: 32411713 PMCID: PMC7198728 DOI: 10.3389/fmed.2020.00148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 04/06/2020] [Indexed: 11/25/2022] Open
Abstract
Objective: To investigate the long-term effect of triple organ transplantation (liver, kidney, and pancreas) in a patient with end-stage liver disease, post chronic hepatitis B, cirrhosis, chronic renal failure, and insulin-dependent diabetes mellitus caused by chronic pancreatitis and to explore the optimal surgical procedure. Case: A 43-year-old man with progressive emaciation and hypourocrinia for 2 months. Results indicated exocrine pancreatic insufficiency and insulin-dependent diabetes related to chronic pancreatitis (CP) after developing end-stage hepatic and renal failure. Simultaneous piggyback orthotopic liver and heterotopic pancreas-duodenum and renal transplantation was performed in 2005. Pancreatic exocrine secretions were drained enterically to the jejunum, and the donor kidney was placed in the left iliac fossa. Patient was prescribed with prednisone, tacrolimus, mycophenolate mofetil, Rabbit Anti-human Thymocyte Immunoglobulin, and simulect for immunosuppression. Results: Satisfactory hepatic and pancreatic functional recovery was achieved within 7 days post-surgery. The kidney was not functional, and continuous renal replacement therapy was used. However, the donor kidney was removed at day 16 post-surgery due to acute rejection reaction. A new renal transplantation at the same position was performed, and satisfactory kidney function from the new graft was achieved 3 days later. In 14 years of follow-up, patient has not had any rejection reactions or other complications such as pancreatitis, thrombosis, and localized infections. The patient is insulin independent with normal liver and renal functions. FK506+Pred was used for immunosuppression, and the tac tough level maintained 3.0–4.5 ng/ml. Lamivudine was prescribed for long-term use to inhibit HBV virus duplication. Conclusion: Simultaneous piggyback orthotopic liver and heterotopic pancreas-duodenum and renal transplantation is a good therapeutic option for patients with exocrine pancreatic insufficiency and insulin-dependent diabetes combined with hepatic and renal failure.
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Affiliation(s)
- Geng Zhang
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Weijun Qin
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Jianlin Yuan
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Changsheng Ming
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuqiang Yue
- Department of Hepatobiliary, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Zhengcai Liu
- Department of Hepatobiliary, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Lei Yu
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Ming Yu
- Department of Ultrasound Diagnostics, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Xiaokang Gao
- Department of Urology, General Hospital of Xinjiang Military Region, Urumqi, China
| | - Yu Zhou
- Department of Urology, Central Theater Command General Hospital of The Chinese People's Liberation Army, Wuhan, China
| | - Longxin Wang
- Urology Department, Maanshan People's Hospital, Maanshan, China
| | - Xiaojian Yang
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Kefeng Dou
- Department of Hepatobiliary, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - He Wang
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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20
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Predicting Outcomes of Rat Vascularized Composite Allotransplants through Quantitative Measurement of Chimerism with PCR-Amplified Short Tandem Repeat. J Immunol Res 2020; 2020:9243531. [PMID: 32090131 PMCID: PMC7024101 DOI: 10.1155/2020/9243531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 12/31/2019] [Accepted: 01/08/2020] [Indexed: 11/17/2022] Open
Abstract
Chimerism has been associated with the induction and maintenance of tolerance to vascularized composite allotransplants (VCA). Although most VCA studies have examined chimerism using flow cytometry, we proposed that precision in the measurement of chimerism may be better approximated when complimentary polymerase chain reaction (PCR) is applied to a specific short tandem repeat (STR). We identified a STR, D10Rat25, which exhibited a ~20 bp difference in length between two rat strains (BN and LEW) often utilized as the donor and recipient in many allotransplantation studies. D10Rat25 was PCR-amplified and quantified with capillary electrophoresis. With pure LEW and BN DNA, a standard curve was constructed to measure chimerism with good linearity. When applied to rat VCA, the relationship between systematic (in peripheral blood) or local (at specific organ/tissues) chimerism to allograft outcomes was noted. We found that peripheral chimerism was elevated by up to ~9% postoperative month 1 (POM 1) but then reduced regardless of the final VCA outcome. However, differences in VCA skin chimerism between early rejection and POM 1 (shown as ΔChimerismPOM1-ER) were notable with respect to VCA outcomes. ROC analysis identified the optimum cutoff value as 17.7%. In summary, we have developed a reliable method to quantify the percentage of BN cells/DNA in BN-LEW chimeras. The detection limit was characterized, and the acquired data were comparable with flow cytometry. This method can be applied to solid organ and composite tissue allotransplantation studies.
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21
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Appenzeller-Herzog C, Hartleif S, Vionnet J. Clinical parameters and biomarkers predicting spontaneous operational tolerance after liver transplantation: a scoping review protocol. F1000Res 2019; 8:2059. [PMID: 32399186 PMCID: PMC7194345 DOI: 10.12688/f1000research.21501.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/28/2019] [Indexed: 12/23/2022] Open
Abstract
Objective: This scoping review aims at systematically identifying prognostic factors for spontaneous immunosuppression (IS) free allograft tolerance (operational tolerance, OT) in non-viral hepatitis and non-autoimmune disease liver transplant (LT) recipients who are undergoing immunosuppression withdrawal (ISW). The results may inform the subsequent conduct of a systematic review with a more specific review question. Background: LT is currently the most effective treatment for end-stage liver diseases. Whereas the short-term outcomes after LT have dramatically improved over the last decades, the long-term outcomes remain unsatisfactory, mainly because of side effects of lifelong IS, such as infections, cardiovascular diseases, malignancies, and nephrotoxicity. ISW studies have shown that OT can be achieved by a subset of LT recipients and recent research has identified biomarkers of OT in these patients. However, an evidence-based selection algorithm for patients that can predictably benefit from ISW is not available to date. The planned review will, therefore, map existing knowledge on prognostic clinical parameters and biomarkers for OT. Inclusion criteria: We will consider studies that record any clinical parameter or biomarker before the initiation of ISW in non-viral hepatitis and non-autoimmune disease LT recipients and analyse their possible association with ISW outcomes (OT or non-tolerance). Studies addressing the effectiveness of OT-inducing treatments will be excluded. Methods: Embase, MEDLINE, and Cochrane Library will be searched for relevant articles or conference abstracts. Full-texts of selected abstracts will be independently screened for inclusion by two reviewers. References and citing articles of included records will be screened for additional relevant records. Clinical trial registries will be searched for ongoing studies, and their investigators contacted for the sharing of unpublished data. Data from included records will be independently extracted by two reviewers using a prespecified data extraction table and presented in both tabular and narrative form.
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Affiliation(s)
| | - Steffen Hartleif
- University Hospital for Children and Adolescents Tübingen, University Hospital Tubingen, Stuttgart, 70597, Germany
| | - Julien Vionnet
- Institute of Liver Studies, King's College Hospital, London, London, UK
- Transplantation Centre, University of Lausanne, Lausanne, Switzerland
- Service of Gastroenterology and Hepatology, University of Lausanne, Lausanne, Switzerland
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22
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Appenzeller-Herzog C, Hartleif S, Vionnet J. Clinical parameters and biomarkers predicting spontaneous operational tolerance after liver transplantation: a scoping review protocol. F1000Res 2019; 8:2059. [PMID: 32399186 PMCID: PMC7194345 DOI: 10.12688/f1000research.21501.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/27/2020] [Indexed: 02/07/2025] Open
Abstract
Objective: This scoping review aims at systematically mapping reported prognostic factors for spontaneous immunosuppression (IS) free allograft tolerance (operational tolerance, OT) in non-viral hepatitis and non-autoimmune disease liver transplant (LT) recipients who are undergoing immunosuppression withdrawal (ISW). The results may inform the subsequent conduct of a systematic review with a more specific review question. Background: LT is currently the most effective treatment for end-stage liver diseases. Whereas the short-term outcomes after LT have dramatically improved over the last decades, the long-term outcomes remain unsatisfactory, mainly because of side effects of lifelong IS, such as infections, cardiovascular diseases, malignancies, and nephrotoxicity. ISW studies have shown that OT can be achieved by a subset of LT recipients and recent research has identified biomarkers of OT in these patients. However, an evidence-based selection algorithm for patients that can predictably benefit from ISW is not available to date. The planned review will, therefore, map existing knowledge on prognostic clinical parameters and biomarkers for OT. Inclusion criteria: We will consider studies that record any clinical parameter or biomarker before the initiation of ISW in paediatric or adult non-viral hepatitis and non-autoimmune disease LT recipients and analyse their possible association with ISW outcomes (OT or non-tolerance). Studies addressing the effectiveness of OT-inducing treatments will be excluded. Methods: Embase, MEDLINE, and Cochrane Library will be searched for relevant articles or conference abstracts. Full-texts of selected abstracts will be independently screened for inclusion by two reviewers. References and citing articles of included records will be screened for additional relevant records. Clinical trial registries will be searched for ongoing studies, and their investigators contacted for the sharing of unpublished data. Data from included records will be independently extracted by two reviewers using a prespecified data extraction table and presented in both tabular and narrative form.
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Affiliation(s)
| | - Steffen Hartleif
- University Hospital for Children and Adolescents Tübingen, University Hospital Tubingen, Stuttgart, 70597, Germany
| | - Julien Vionnet
- Institute of Liver Studies, King's College Hospital, London, London, UK
- Transplantation Centre, University of Lausanne, Lausanne, Switzerland
- Service of Gastroenterology and Hepatology, University of Lausanne, Lausanne, Switzerland
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23
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Appenzeller-Herzog C, Hartleif S, Vionnet J. Clinical parameters and biomarkers predicting spontaneous operational tolerance after liver transplantation: a scoping review protocol. F1000Res 2019; 8:2059. [PMID: 32399186 PMCID: PMC7194345 DOI: 10.12688/f1000research.21501.3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/23/2020] [Indexed: 11/20/2022] Open
Abstract
Objective: This scoping review aims at systematically mapping reported prognostic factors for spontaneous immunosuppression (IS) free allograft tolerance (operational tolerance, OT) in non-viral hepatitis and non-autoimmune disease liver transplant (LT) recipients who are undergoing immunosuppression withdrawal (ISW). The results may inform the subsequent conduct of a systematic review with a more specific review question. Background: LT is currently the most effective treatment for end-stage liver diseases. Whereas the short-term outcomes after LT have dramatically improved over the last decades, the long-term outcomes remain unsatisfactory, mainly because of side effects of lifelong IS, such as infections, cardiovascular diseases, malignancies, and nephrotoxicity. ISW studies have shown that OT can be achieved by a subset of LT recipients and recent research has identified biomarkers of OT in these patients. However, an evidence-based selection algorithm for patients that can predictably benefit from ISW is not available to date. The planned review will, therefore, map existing knowledge on prognostic clinical parameters and biomarkers for OT. Inclusion criteria: We will consider studies that record any clinical parameter or biomarker before the initiation of ISW in paediatric or adult non-viral hepatitis and non-autoimmune disease LT recipients and analyse their possible association with ISW outcomes (OT or non-tolerance). Studies addressing the effectiveness of OT-inducing treatments will be excluded. Methods: Embase, MEDLINE, and Cochrane Library will be searched for relevant articles or conference abstracts. Full-texts of selected abstracts will be independently screened for inclusion by two reviewers. References and citing articles of included records will be screened for additional relevant records. Clinical trial registries will be searched for ongoing studies, and their investigators contacted for the sharing of unpublished data. Data from included records will be independently extracted by two reviewers using a prespecified data extraction table and presented in both tabular and narrative form.
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Affiliation(s)
| | - Steffen Hartleif
- University Hospital for Children and Adolescents Tübingen, University Hospital Tubingen, Stuttgart, 70597, Germany
| | - Julien Vionnet
- Institute of Liver Studies, King's College Hospital, London, London, UK
- Transplantation Centre, University of Lausanne, Lausanne, Switzerland
- Service of Gastroenterology and Hepatology, University of Lausanne, Lausanne, Switzerland
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24
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Lei H, Reinke P, Volk HD, Lv Y, Wu R. Mechanisms of Immune Tolerance in Liver Transplantation-Crosstalk Between Alloreactive T Cells and Liver Cells With Therapeutic Prospects. Front Immunol 2019; 10:2667. [PMID: 31803188 PMCID: PMC6877506 DOI: 10.3389/fimmu.2019.02667] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 10/28/2019] [Indexed: 12/11/2022] Open
Abstract
Liver transplantation (LTx) is currently the most powerful treatment for end-stage liver disease. Although liver allograft is more tolerogenic compared to other solid organs, the majority of LTx recipients still require long-term immune suppression (IS) to control the undesired alloimmune responses, which can lead to severe side effects. Thus, understanding the mechanism of liver transplant tolerance and crosstalk between immune cells, especially alloreactive T cells and liver cells, can shed light on more specific tolerance induction strategies for future clinical translation. In this review, we focus on alloreactive T cell mediated immune responses and their crosstalk with liver sinusoidal endothelial cells (LSECs), hepatocytes, hepatic stellate cells (HSCs), and cholangiocytes in transplant setting. Liver cells mainly serve as antigen presenting cells (APCs) to T cells, but with low expression of co-stimulatory molecules. Crosstalk between them largely depends on the different expression of adhesion molecules and chemokine receptors. Inflammatory cytokines secreted by immune cells further elaborate this crosstalk and regulate the fate of naïve T cells differentiation within the liver graft. On the other hand, regulatory T cells (Tregs) play an essential role in inducing and keeping immune tolerance in LTx. Tregs based adoptive cell therapy provides an excellent therapeutic option for clinical transplant tolerance induction. However, many questions regarding cell therapy still need to be solved. Here we also address the current clinical trials of adoptive Tregs therapy and other tolerance induction strategies in LTx, together with future challenges for clinical translation from bench to bedside.
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Affiliation(s)
- Hong Lei
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Berlin Institute of Health Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany
| | - Petra Reinke
- Berlin Institute of Health Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany.,Berlin Center of Advanced Therapies, Berlin, Germany
| | - Hans-Dieter Volk
- Berlin Institute of Health Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany.,Institute of Medical Immunology, Charité University Medicine Berlin, Berlin, Germany
| | - Yi Lv
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Rongqian Wu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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25
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Kenyon NS. We Could Use More Tolerance: Role of Intestinal-Allograft-Derived Human Stem Cells. Cell Stem Cell 2019; 24:197-198. [PMID: 30735643 DOI: 10.1016/j.stem.2019.01.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Mixed chimerism is associated with allograft acceptance and tolerance. In this issue of Cell Stem Cell, Fu et al. (2019) provide evidence that functional, donor-derived hematopoietic stem and progenitor cells in the intestinal allograft can persist long-term, contribute to multi-lineage chimerism in the circulation, and result in T cell tolerance through host lymphoid organ selection.
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Affiliation(s)
- Norma Sue Kenyon
- Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
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26
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Combined heart and kidney transplantation—Is there a protective effect against cardiac allograft vasculopathy using intravascular ultrasound? J Heart Lung Transplant 2019; 38:956-962. [DOI: 10.1016/j.healun.2019.06.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 06/14/2019] [Accepted: 06/16/2019] [Indexed: 11/20/2022] Open
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27
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Yu D, Wang L, Wu T, Zhang Y, Tian Y, Wang Y, Cui C, Li H, Zhang J, Zhou L, Yan S, Zheng S. Graft-Versus-Tumor Effect in Major Histocompatibility Complex-Mismatched Mouse Liver Transplantation. Liver Transpl 2019; 25:1251-1264. [PMID: 31152624 PMCID: PMC6771797 DOI: 10.1002/lt.25574] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 05/16/2019] [Indexed: 12/21/2022]
Abstract
Liver transplantation (LT) is currently considered an important method in treating hepatocellular carcinoma (HCC) and an alternative treatment for other liver malignancies. Here, we demonstrated that the graft-versus-tumor (GVT) effect exists in allogeneic liver transplantation (allo LT). Recipient-derived T cells played a critical role in the GVT process of allo LT, as demonstrated by extensive infiltration and significant activation of recipient T cells in the tumor after surgery. Moreover, this process was related to donor-derived T/B cells by improving the immune microenvironment in the tumor, as demonstrated by elevated levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), IL-6, IL-16, chemokine (C-X-C motif) ligand 10 (CXCL10), and CXCL11 and decreased levels of IL-10 and IL-4 at tumor sites. Additionally, tacrolimus (FK506) treatment inhibited the GVT effect on allo LT. Donor liver-derived T/B cells infiltrate extrahepatic tumors to trigger a strong T-cell-mediated immune response and thus improve the tumor immune microenvironment.
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Affiliation(s)
- Dongdong Yu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated HospitalZhejiang UniversityHangzhouChina,National Health and Family Planning Commission of China Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationHangzhouChina,Collaborative Innovation Center for Diagnosis Treatment of Infectious DiseaseHangzhouChina
| | - Lidong Wang
- Department of Hepatobiliary and Pancreatic SurgeryShulan (Hangzhou) HospitalHangzhouChina
| | - Tianchun Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated HospitalZhejiang UniversityHangzhouChina,National Health and Family Planning Commission of China Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationHangzhouChina,Collaborative Innovation Center for Diagnosis Treatment of Infectious DiseaseHangzhouChina
| | - Yaohui Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated HospitalZhejiang UniversityHangzhouChina,National Health and Family Planning Commission of China Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationHangzhouChina,Collaborative Innovation Center for Diagnosis Treatment of Infectious DiseaseHangzhouChina
| | - Yang Tian
- National Health and Family Planning Commission of China Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationHangzhouChina,Collaborative Innovation Center for Diagnosis Treatment of Infectious DiseaseHangzhouChina,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Second Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Yan Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated HospitalZhejiang UniversityHangzhouChina,National Health and Family Planning Commission of China Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationHangzhouChina,Collaborative Innovation Center for Diagnosis Treatment of Infectious DiseaseHangzhouChina
| | - Chenwei Cui
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated HospitalZhejiang UniversityHangzhouChina,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang ProvinceHangzhouChina
| | - Hui Li
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated HospitalZhejiang UniversityHangzhouChina,National Health and Family Planning Commission of China Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationHangzhouChina,Collaborative Innovation Center for Diagnosis Treatment of Infectious DiseaseHangzhouChina
| | - Jinhua Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated HospitalZhejiang UniversityHangzhouChina,National Health and Family Planning Commission of China Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationHangzhouChina,Collaborative Innovation Center for Diagnosis Treatment of Infectious DiseaseHangzhouChina
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated HospitalZhejiang UniversityHangzhouChina,National Health and Family Planning Commission of China Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationHangzhouChina,Collaborative Innovation Center for Diagnosis Treatment of Infectious DiseaseHangzhouChina
| | - Sheng Yan
- National Health and Family Planning Commission of China Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationHangzhouChina,Collaborative Innovation Center for Diagnosis Treatment of Infectious DiseaseHangzhouChina,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Second Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated HospitalZhejiang UniversityHangzhouChina,National Health and Family Planning Commission of China Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationHangzhouChina,Collaborative Innovation Center for Diagnosis Treatment of Infectious DiseaseHangzhouChina
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Abrol N, Jadlowiec CC, Taner T. Revisiting the liver's role in transplant alloimmunity. World J Gastroenterol 2019; 25:3123-3135. [PMID: 31333306 PMCID: PMC6626728 DOI: 10.3748/wjg.v25.i25.3123] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/25/2019] [Accepted: 05/18/2019] [Indexed: 02/06/2023] Open
Abstract
The transplanted liver can modulate the recipient immune system to induce tolerance after transplantation. This phenomenon was observed nearly five decades ago. Subsequently, the liver's role in multivisceral transplantation was recognized, as it has a protective role in preventing rejection of simultaneously transplanted solid organs such as kidney and heart. The liver has a unique architecture and is home to many cells involved in immunity and inflammation. After transplantation, these cells migrate from the liver into the recipient. Early studies identified chimerism as an important mechanism by which the liver modulates the human immune system. Recent studies on human T-cell subtypes, cytokine expression, and gene expression in the allograft have expanded our knowledge on the potential mechanisms underlying immunomodulation. In this article, we discuss the privileged state of liver transplantation compared to other solid organ transplantation, the liver allograft's role in multivisceral transplantation, various cells in the liver involved in immune responses, and the potential mechanisms underlying immunomodulation of host alloresponses.
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Affiliation(s)
- Nitin Abrol
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Massyo Clinic, Rochester, MN 55905, United States
| | | | - Timucin Taner
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Massyo Clinic, Rochester, MN 55905, United States
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Abstract
PURPOSE OF REVIEW Following solid organ transplantation (SOT), populations of donor lymphocytes are frequently found in the recipient circulation. Their impact on host alloimmunity has long been debated but remains unclear, and it has been suggested that transferred donor lymphocytes may either promote tolerance to the graft or hasten its rejection. We discuss possible mechanisms by which the interaction of donor passenger lymphocytes with recipient immune cells may either augment the host alloimmune response or inhibit it. RECENT FINDINGS Recent work has highlighted that donor T lymphocytes are the most numerous of the donor leukocyte populations within a SOT and that these may be transferred to the recipient after transplantation. Surprisingly, graft-versus-host recognition of major histocompatibility complex class II on host B cells by transferred donor CD4 T cells can result in marked augmentation of host humoral alloimmunity and lead to early graft failure. Killing of donor CD4 T cells by host natural killer cells is critical in preventing this augmentation. SUMMARY The ability of passenger donor CD4 T cells to effect long-term augmentation of the host humoral alloimmune response raises the possibility that ex-vivo treatment or modification of the donor organ prior to implantation may improve long-term transplant outcomes.
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Aikawa A. Current status and future aspects of kidney transplantation in Japan. RENAL REPLACEMENT THERAPY 2018. [DOI: 10.1186/s41100-018-0186-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Tissue-Resident Lymphocytes in Solid Organ Transplantation: Innocent Passengers or the Key to Organ Transplant Survival? Transplantation 2018; 102:378-386. [PMID: 29135830 DOI: 10.1097/tp.0000000000002001] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Short-term outcomes of solid organ transplantation have improved dramatically over the past several decades; however, long-term survival has remained static over the same period, and chronic rejection remains a major cause of graft failure. The importance of donor, or "passenger," lymphocytes to the induction of tolerance to allografts was recognized in the 1990s, but their precise contribution to graft acceptance or rejection has not been elucidated. Recently, specialized populations of tissue-resident lymphocytes in nonlymphoid organs have been described. These lymphocytes include tissue-resident memory T cells, regulatory T cells, γδ T cells, invariant natural killer T cells, and innate lymphoid cells. These cells reside in commonly transplanted solid organs, including the liver, kidneys, heart, and lung; however, their contribution to graft acceptance or rejection has not been examined in detail. Similarly, it is unclear whether tissue-resident cells derived from the pool of recipient-derived lymphocytes play a specific role in transplantation biology. This review summarizes the evidence for the roles of tissue-resident lymphocytes in transplant immunology, focussing on their features, functions, and relevance for solid organ transplantation, with specific reference to liver, kidney, heart, and lung transplantation.
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32
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Transplantation and Transfusion. CHIMERISM 2018. [DOI: 10.1007/978-3-319-89866-7_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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33
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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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34
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Abstract
BACKGROUND Nonmyeloablative conditioning followed by donor bone marrow infusion (BMI) to induce tolerance has not been robustly tested in liver transplantation (LT) and may be unsafe at the time of LT. We hypothesized T cell-depleted BMI is effective in inducing tolerance when delayed after LT, resulting in potentially safer future clinical applications. METHODS Nonimmunosuppressed syngeneic (Lewis to Lewis) and allogeneic (ACI to Lewis) rat LT transplants were initially performed as controls. Three experimental allogeneic LT groups were treated with tacrolimus (TAC) for 3 to 4 weeks and then underwent: (1) TAC withdrawal alone; (2) nonmyeloablative conditioning (anti-αβTCR mAb + total body irradiation [300 cGy]) followed by TAC withdrawal; (3) Nonmyeloablative conditioning + donor BMI (100 × 10 T cell-depleted bone marrow cells) followed by TAC withdrawal. RESULTS All group 1 recipients developed chronic rejection. Group 2 had long-term survival but impaired liver function and high donor-specific antibody (DSA) levels. In contrast, group 3 (conditioning + BMI) had long-term TAC-free survival with preserved liver function and histology, high mixed chimerism and blood/liver/spleen CD4 + CD25 + Foxp3+ regulatory T cells, and low DSA titers, similar to syngeneic grafts. While donor-specific tolerance was observed post-BMI, graft-versus-host disease was not. CONCLUSIONS These results support that donor-specific tolerance can be achieved with BMI even when delayed after LT and this tolerance correlates with increased mixed chimerism, regulatory T cell generation, and diminished DSA.
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35
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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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36
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The CD8 T-cell response during tolerance induction in liver transplantation. Clin Transl Immunology 2016; 5:e102. [PMID: 27867515 PMCID: PMC5099425 DOI: 10.1038/cti.2016.53] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 07/20/2016] [Accepted: 07/22/2016] [Indexed: 12/12/2022] Open
Abstract
Both experimental and clinical studies have shown that the liver possesses unique tolerogenic properties. Liver allografts can be spontaneously accepted across complete major histocompatibility mismatch in some animal models. In addition, some liver transplant patients can be successfully withdrawn from immunosuppressive medications, developing ‘operational tolerance'. Multiple mechanisms have been shown to be involved in inducing and maintaining alloimmune tolerance associated with liver transplantation. Here, we focus on CD8 T-cell tolerance in this setting. We first discuss how alloreactive cytotoxic T-cell responses are generated against allografts, before reviewing how the liver parenchyma, donor passenger leucocytes and the host immune system function together to attenuate alloreactive CD8 T-cell responses to promote the long-term survival of liver transplants.
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37
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Burlingham WJ. Clinical Implications of Basic Science Discoveries: Microchimerism Finds a Major Role in Reproductive Success; but Does It Also Contribute to Transplant Success? Am J Transplant 2016; 16:2795-2799. [PMID: 26988284 DOI: 10.1111/ajt.13785] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 02/16/2016] [Accepted: 03/04/2016] [Indexed: 01/25/2023]
Abstract
Conventional wisdom argues against inbreeding, to maintain hybrid vigor and increase MHC diversity in response to pathogens. A recent report from the laboratory of Sing-Sing Way uses a mouse model to test a hypothesis put forward by Ray D. Owen more than 60 years ago: that a certain amount of inbreeding is a good thing. Owen proposed that antigens not inherited from the mother (noninherited maternal antigens), when replicated on the mate of the daughter, could protect the latter's developing child from fetal wastage due to immune attack during her pregnancy. Kinder et al use elegant mouse breeding models and MHC class II peptide tetramers to show that Owen's hypothesis, based only on humoral (anti-Rh IgG) data and a small sample size, was indeed correct. The mediators of this cross-generational protection turn out to be a special kind of Foxp3+ T regulatory cell, the development of which requires the persistence of maternal microchimerism into adulthood. The implications of this discovery for the role of microchimerism in tolerance to transplants are discussed.
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Affiliation(s)
- W J Burlingham
- Department of Surgery, University of Wisconsin Medical School, Madison, WI
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38
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Demetris AJ, Bellamy COC, Gandhi CR, Prost S, Nakanuma Y, Stolz DB. Functional Immune Anatomy of the Liver-As an Allograft. Am J Transplant 2016; 16:1653-80. [PMID: 26848550 DOI: 10.1111/ajt.13749] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 01/26/2016] [Accepted: 01/28/2016] [Indexed: 01/25/2023]
Abstract
The liver is an immunoregulatory organ in which a tolerogenic microenvironment mitigates the relative "strength" of local immune responses. Paradoxically, necro-inflammatory diseases create the need for most liver transplants. Treatment of hepatitis B virus, hepatitis C virus, and acute T cell-mediated rejection have redirected focus on long-term allograft structural integrity. Understanding of insults should enable decades of morbidity-free survival after liver replacement because of these tolerogenic properties. Studies of long-term survivors show low-grade chronic inflammatory, fibrotic, and microvascular lesions, likely related to some combination of environment insults (i.e. abnormal physiology), donor-specific antibodies, and T cell-mediated immunity. The resultant conundrum is familiar in transplantation: adequate immunosuppression produces chronic toxicities, while lightened immunosuppression leads to sensitization, immunological injury, and structural deterioration. The "balance" is more favorable for liver than other solid organ allografts. This occurs because of unique hepatic immune physiology and provides unintended benefits for allografts by modulating various afferent and efferent limbs of allogenic immune responses. This review is intended to provide a better understanding of liver immune microanatomy and physiology and thereby (a) the potential structural consequences of low-level, including allo-antibody-mediated injury; and (b) how liver allografts modulate immune reactions. Special attention is given to the microvasculature and hepatic mononuclear phagocytic system.
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Affiliation(s)
- A J Demetris
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - C O C Bellamy
- Department of Pathology, University of Edinburgh, Edinburgh, Scotland, UK
| | - C R Gandhi
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center and Department of Surgery, University of Cincinnati, Cincinnati, OH
| | - S Prost
- Department of Pathology, University of Edinburgh, Edinburgh, Scotland, UK
| | - Y Nakanuma
- Department of Diagnostic Pathology, Shizuoka Cancer Center, Shizuoka, Japan
| | - D B Stolz
- Center for Biologic Imaging, Cell Biology, University of Pittsburgh, Pittsburgh, PA
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39
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Harper IG, Ali JM, Harper SJF, Wlodek E, Alsughayyir J, Negus MC, Qureshi MS, Motalleb-Zadeh R, Saeb-Parsy K, Bolton EM, Bradley JA, Clatworthy MR, Conlon TM, Pettigrew GJ. Augmentation of Recipient Adaptive Alloimmunity by Donor Passenger Lymphocytes within the Transplant. Cell Rep 2016; 15:1214-27. [PMID: 27134179 PMCID: PMC4870521 DOI: 10.1016/j.celrep.2016.04.009] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2015] [Revised: 01/29/2016] [Accepted: 03/28/2016] [Indexed: 01/18/2023] Open
Abstract
Chronic rejection of solid organ allografts remains the major cause of transplant failure. Donor-derived tissue-resident lymphocytes are transferred to the recipient during transplantation, but their impact on alloimmunity is unknown. Using mouse cardiac transplant models, we show that graft-versus-host recognition by passenger donor CD4 T cells markedly augments recipient cellular and humoral alloimmunity, resulting in more severe allograft vasculopathy and early graft failure. This augmentation is enhanced when donors were pre-sensitized to the recipient, is dependent upon avoidance of host NK cell recognition, and is partly due to provision of cognate help for allo-specific B cells from donor CD4 T cells recognizing B cell MHC class II in a peptide-degenerate manner. Passenger donor lymphocytes may therefore influence recipient alloimmune responses and represent a therapeutic target in solid organ transplantation.
Donor CD4 T cells provide cognate, but peptide-degenerate, help to all host B cells Antibody specificity is determined by concurrent B cell receptor ligation Passenger donor CD4 T cells can therefore augment host alloantibody responses Host NK cell allorecognition is critical for preventing this augmentation
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Affiliation(s)
- Ines G Harper
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Jason M Ali
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Simon J F Harper
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Elizabeth Wlodek
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
| | | | - Margaret C Negus
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
| | - M Saeed Qureshi
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
| | | | - Kourosh Saeb-Parsy
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Eleanor M Bolton
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
| | - J Andrew Bradley
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Menna R Clatworthy
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Thomas M Conlon
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Gavin J Pettigrew
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
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40
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Patterns of Immune Regulation in Rhesus Macaque and Human Families. Transplant Direct 2015; 1:e20. [PMID: 27500222 PMCID: PMC4946471 DOI: 10.1097/txd.0000000000000530] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 06/03/2015] [Indexed: 12/29/2022] Open
Abstract
Supplemental digital content is available in the text. Naturally acquired immune regulation amongst family members can result in mutual regulation between living related renal transplant donor and recipients. Pretransplant bidirectional regulation predisposed to superior renal allograft outcome in a CAMPATH-1H protocol. We tested whether Rhesus macaques, a large animal model of choice for preclinical transplant studies, share these immunoregulatory properties.
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Abstract
PURPOSE OF REVIEW Acute rejection is the most common complication after vascularized composite allotransplantation (VCA). This review provides a state-of-the-art analysis of prevention, diagnosis and treatment of acute rejection episodes and highlights recent findings with the potential to improve patient care and enhance understanding of the underlying biologic processes. RECENT FINDINGS Recent reports suggest that maintenance immunosuppression dose reduction and steroid withdrawal are realistic goals in VCA, despite the known high immunogenicity of the skin component. It appears that utilization of sentinel flaps, in-depth histological analyses and application of novel biomarkers have facilitated early diagnosis and characterization of acute rejection episodes, leading to timely institution of appropriate therapy. The successful management of the first highly sensitized face transplant recipient suggests the possibility of carefully considering these high-risk VCA candidates for transplantation. SUMMARY Acute rejection is higher in VCA than in any other organ in the field of transplantation, although most episodes are controlled by high-dose steroids and optimization of maintenance immunosuppression. Because of limitations in patient number and the duration of follow-up, the long-term safety and effectiveness of VCA remain unclear. Moreover, the tests currently used to diagnose acute rejection are of limited value. Better diagnostic tools and a better understanding of the immunologic events during acute rejection are therefore needed to improve diagnosis, treatment and outcomes of this life-changing restorative surgery.
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Loewendorf AI, Csete M, Flake A. Immunological considerations in in utero hematopoetic stem cell transplantation (IUHCT). Front Pharmacol 2015; 5:282. [PMID: 25610396 PMCID: PMC4285014 DOI: 10.3389/fphar.2014.00282] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 12/02/2014] [Indexed: 01/19/2023] Open
Abstract
In utero hematopoietic stem cell transplantation (IUHCT) is an attractive approach and a potentially curative surgery for several congenital hematopoietic diseases. In practice, this application has succeeded only in the context of Severe Combined Immunodeficiency Disorders. Here, we review potential immunological hurdles for the long-term establishment of chimerism and discuss relevant models and findings from both postnatal hematopoietic stem cell transplantation and IUHCT.
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Affiliation(s)
- Andrea I Loewendorf
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles Los Angeles, CA, USA
| | - Marie Csete
- Chief Scientific Officer, The Huntington Medical Research Institutes Pasadena, CA, USA
| | - Alan Flake
- The Children's Hospital of Philadelphia, Children's Institute of Surgical Science Philadelphia, PA, USA
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Karimi MH, Geramizadeh B, Malek-Hosseini SA. Tolerance Induction in Liver. Int J Organ Transplant Med 2015; 6:45-54. [PMID: 26082828 PMCID: PMC4464278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Liver is an exclusive anatomical and immunological organ that displays a considerable tolerance effect. Liver allograft acceptance is shown to occur spontaneously within different species. Although in human transplant patients tolerance is rarely seen, the severity level and cellular mechanisms of transplant rejection vary. Non-paranchymal liver cells, including Kupffer cells, liver sinusoidal endothelial cells, hepatic stellate cells, and resident dendritic cells may participate in liver tolerogenicity. The mentioned cells secret anti-inflammatory cytokines such as TGF-β and IL-10 and express negative co-stimulatory molecules like PD-L1 to mediate immunosuppression. Other mechanisms such as microchimerism, soluble major histocompatibility complex and regulatory T cells may take part in tolerance induction. Understanding the mechanisms involved in liver transplant rejection/tolerance helps us to improve therapeutic options to induce hepatic tolerance.
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Affiliation(s)
| | | | - S. A. Malek-Hosseini
- CORRESPONDENCE: SEYED ALI MALEKHOSSEINI, MD, PROFESSOR OF SURGERY AND TRANSPLANTATION, DEPARTMENT OF SURGERY, MEDICAL SCHOOL, SHIRAZ UNIVERSITY OF MEDICAL SCIENCES, SHIRAZ, IRAN ,Fax: +98-71-3647-4308
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44
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Yoshida EM, Devonshire VA, Prout AJE. Remission of Multiple Sclerosis Post-Liver Transplantation. Can J Neurol Sci 2014; 31:539-41. [PMID: 15595263 DOI: 10.1017/s0317167100003772] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background:The effect of liver transplantation on pre-existing multiple sclerosis (MS) has never been reported. We report the three year post-transplant neurological outcome of a patient with MS.Case report:A Caucasian woman with MS received an urgent liver transplant for fulminant liver failure at the age of 59. Her Extended Disability Scale Score (EDSS) pretransplant was 5.0 and clinically she had cerebellar and brainstem dysfunction. Post-transplant immunosuppression consisted of tacrolimus, mycophenolate mofetil and tapering corticosteroids that were discontinued after 1.5 years. Post-transplant her EDSS decreased to 2.0 and after three years she is clinically asymptomatic with only very mild dysarthria on neurologic examination. Long-term maintenance immunosuppression consists of low dose tacrolimus.Conclusion:Combination immunosuppression with tacrolimus may have a beneficial effect on MS although an effect of donor allograft itself can not be excluded.
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Affiliation(s)
- Eric M Yoshida
- Division of Neurology, the Department of Medicine, University of British Columbia, Vancouver, BC, Canada
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45
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Dutta P, Burlingham WJ. Correlation between post transplant maternal microchimerism and tolerance across MHC barriers in mice. CHIMERISM 2014. [DOI: 10.4161/chim.18083] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Sanada Y, Kawano Y, Miki A, Aida J, Nakamura KI, Shimomura N, Ishikawa N, Arai T, Hirata Y, Yamada N, Okada N, Wakiya T, Ihara Y, Urahashi T, Yasuda Y, Takubo K, Mizuta K. Maternal grafts protect daughter recipients from acute cellular rejection after pediatric living donor liver transplantation for biliary atresia. Transpl Int 2014; 27:383-90. [PMID: 24472036 DOI: 10.1111/tri.12273] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 09/23/2013] [Accepted: 01/22/2014] [Indexed: 01/09/2023]
Abstract
Some studies have found that gender mismatch between donors and recipients are related to poor graft prognosis after liver transplantation. However, few studies have investigated the impact of gender mismatch on acute cellular rejection (ACR) in pediatric living donor liver transplantation (LDLT). This retrospective study investigated the clinical significance of these factors in ACR after pediatric LDLT. Between November 2001 and February 2012, 114 LDLTs were performed for recipients with biliary atresia (BA) using parental grafts. We performed univariate and multivariate analyses to identify the factors associated with ACR. The donor-recipient classifications included mother donor to daughter recipient (MD; n = 43), mother to son (n = 18), father to daughter (FD; n = 33), and father to son (n = 20) groups. The overall incidence rate of ACR in the recipients was 36.8%. Multivariate analysis showed that gender mismatch alone was an independent risk factor for ACR (P = 0.012). The FD group had a higher incidence of ACR than the MD group (P = 0.002). In LDLT, paternal grafts with gender mismatch were associated with a higher increased incidence of ACR than maternal grafts with gender match. Our findings support the possibility that maternal antigens may have an important clinical impact on graft tolerance in LDLT for patients with BA.
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Affiliation(s)
- Yukihiro Sanada
- Department of Transplant Surgery, Jichi Medical University, Shimotsuke City, Japan; Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
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Abstract
Large animal models have long served as the proving grounds for advances in transplantation, bridging the gap between inbred mouse experimentation and human clinical trials. Although a variety of species have been and continue to be used, the emergence of highly targeted biologic- and antibody-based therapies has required models to have a high degree of homology with humans. Thus, the nonhuman primate has become the model of choice in many settings. This article will provide an overview of nonhuman primate models of transplantation. Issues of primate genetics and care will be introduced, and a brief overview of technical aspects for various transplant models will be discussed. Finally, several prominent immunosuppressive and tolerance strategies used in primates will be reviewed.
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Affiliation(s)
- Douglas J Anderson
- Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia 30322
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Beneficial effects of pretransplantation microchimerism on rejection-free survival in HLA-haploidentical family donor renal transplantation. Transplantation 2013; 95:1375-82. [PMID: 23519024 DOI: 10.1097/tp.0b013e31828b10a1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Fetal-maternal microchimerism (MC) can develop during pregnancy and may persist for decades. Pretransplantation fetal-maternal MC may be present between mother and child and between siblings; however, its effect on renal transplantation is not known. We investigated the effects of pretransplantation MC on allograft outcomes in human leukocyte antigen (HLA)-haploidentical family donor transplantation. METHODS A total of 106 cases transplanted from 1996 to 2004 were retrospectively studied, with median follow-up of 96 months. The study and control groups included 63 and 43 cases of HLA-haploidentical and HLA-identical donor transplantations, respectively. MC against mismatched donor HLA-DRB1 allele was detected in the recipient's peripheral blood using nested polymerase chain reaction-single-strand conformation polymorphism method. The allograft outcomes of HLA-haploidentical MC (+) and (-) subgroups were compared with those of HLA-identical group. RESULTS Pretransplantation MC in the HLA-haploidentical recipients was detected in 22.2% (14 of 63). Compared with HLA-identical group, MC (-) subgroup showed significantly inferior allograft outcomes: higher acute rejection rate (11.6% vs. 42.9%; P=0.001), higher 5-year serum creatinine level (1.1 vs. 1.4 mg/dL; P=0.009), and lower 10-year rejection-free survival rate (83.7% vs. 54.5%; log-rank P=0.001). In contrast, MC (+) subgroup showed no significant differences from HLA-identical group in acute rejection rate (14.3%), 5-year serum creatinine level (1.1 mg/dL), and 10-year rejection-free survival rate (85.7%). Multivariate analysis revealed that pretransplantation MC is associated with a significantly lower risk of acute rejection (odds ratio=0.10; P=0.021). CONCLUSION Pretransplantation MC present in the recipient may have beneficial effects on rejection-free allograft survival in renal transplantation.
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Solgi G, Gadi V, Paul B, Mytilineos J, Pourmand G, Mehrsai A, Ranjbar M, Mohammadnia M, Nikbin B, Amirzargar AA. Five-year clinical effects of donor bone marrow cells infusions in kidney allograft recipients: improved graft function and higher graft survival. CHIMERISM 2013; 4:87-94. [PMID: 23639966 DOI: 10.4161/chim.24719] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Augmentation of microchimerism in solid organ transplant recipients by donor bone marrow cells (DBMC) infusion may promote immune hyporesponsiveness and consequently improve long-term allograft survival. Between March 2005 and July 2007, outcomes for 20 living unrelated donor (LURD) primary kidney recipients with concurrent DBMC infusion (an average of 2.19 ± 1.13 x 10⁹ donor cells consisting of 2.66 ± 1.70 x 10⁷ CD34⁺ cells) were prospectively compared with 20 non-infused control allograft recipients given similar conventional immunosuppressive regimens. With five years of clinical follow up, a total of 11 cases experienced rejection episodes (3 DBMI patients vs. 8 controls, p = 0.15). One DBMC-infused patient experienced chronic rejection vs. two episodes (1 biopsy-confirmed) in the control patients. Actuarial and death-censored 5-y graft survival was significantly higher in infused patients compared with controls (p = 0.01 and p = 0.03, respectively). Long-term graft survival was significantly associated with pre-transplant anti-HLA antibodies (p = 0.01), slightly with peripheral microchimerism (p = 0.09) and CD4⁺CD25⁺FoxP3⁺ T cells (p = 0.09). Immunosuppressant dosing was lower in infused patients than controls, particularly for mycophenolate mofetil (p = 0.001). The current findings as well as our previous reports on these patients indicates clinical improvement in long-term graft survival of renal transplant patients resulting from low-dose DBMC infusion given without induction therapy.
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Affiliation(s)
- Ghasem Solgi
- Immunology Department; School of Medicine; Hamadan University of Medical Sciences; Hamadan, Iran
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Review of the early diagnoses and assessment of rejection in vascularized composite allotransplantation. Clin Dev Immunol 2013; 2013:402980. [PMID: 23431325 PMCID: PMC3575677 DOI: 10.1155/2013/402980] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Revised: 12/05/2012] [Accepted: 12/16/2012] [Indexed: 11/23/2022]
Abstract
The emerging field of vascular composite allotransplantation (VCA) has become a clinical reality. Building upon cutting edge understandings of transplant surgery and immunology, complex grafts such as hands and faces can now be transplanted with success. Many of the challenges that have historically been limiting factors in transplantation, such as rejection and the morbidity of immunosuppression, remain challenges in VCA. Because of the accessibility of most VCA grafts, and the highly immunogenic nature of the skin in particular, VCA has become the focal point for cross-disciplinary approaches to developing novel approaches for some of the most challenging immunological problems in transplantation, particularly the early diagnoses and assessment of rejection. This paper provides a historically oriented introduction to the field of organ transplantation and the evolution of VCA.
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