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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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Bastin DJ, Mount G, Hsia CC, Jarrar M, McCann K, Xenocostas A, Teriaky A, Deotare U. The tale of two organs: allogeneic hematopoietic stem cell transplantation following liver transplantation in a myelofibrosis patient. Hematol Transfus Cell Ther 2023; 45:502-504. [PMID: 34955451 PMCID: PMC10627999 DOI: 10.1016/j.htct.2021.11.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 07/06/2021] [Accepted: 11/02/2021] [Indexed: 11/13/2022] Open
Affiliation(s)
| | | | | | | | - Kit McCann
- Western University, London, ON, Canada; Windsor Regional Hospital, Windsor, ON, Canada
| | - Anargyros Xenocostas
- Western University, London, ON, Canada; Blood and Marrow Transplant Program, London Health Sciences Centre, London, ON, Canada
| | | | - Uday Deotare
- Western University, London, ON, Canada; Blood and Marrow Transplant Program, London Health Sciences Centre, London, ON, Canada; The Centre for Quality, Innovation and Safety, Department of Medicine, Western University, London, ON, Canada.
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3
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Dart SJ, Prosser AC, Huang WH, Liu L, Lucas AD, Delriviere L, Gaudieri S, Jeffrey GP, Lucas M. Subset-specific Retention of Donor Myeloid Cells After Major Histocompatibility Complex-matched and Mismatched Liver Transplantation. Transplantation 2023; 107:1502-1512. [PMID: 36584373 PMCID: PMC10508270 DOI: 10.1097/tp.0000000000004481] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 10/14/2022] [Accepted: 11/03/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND During solid organ transplantation, donor leukocytes, including myeloid cells, are transferred within the organ to the recipient. Both tolerogenic and alloreactive roles have been attributed to donor myeloid cells; however, their subset-specific retention posttransplantation has not been investigated in detail. METHODS Major histocompatibility complex (MHC)-matched and mismatched liver transplants were performed in mice, and the fate of donor and recipient myeloid cells was assessed. RESULTS Following MHC-matched transplantation, a proportion of donor myeloid cells was retained in the graft, whereas others egressed and persisted in the blood, spleen, and bone marrow but not the lymph nodes. In contrast, after MHC-mismatched transplantation, all donor myeloid cells, except Kupffer cells, were depleted. This depletion was caused by recipient T and B cells because all donor myeloid subsets were retained in MHC-mismatched grafts when recipients lacked T and B cells. Recipient myeloid cells rapidly infiltrated MHC-matched and, to a greater extent, MHC-mismatched liver grafts. MHC-mismatched grafts underwent a transient rejection episode on day 7, coinciding with a transition in macrophages to a regulatory phenotype, after which rejection resolved. CONCLUSIONS Phenotypic and kinetic differences in the myeloid cell responses between MHC-matched and mismatched grafts were identified. A detailed understanding of the dynamics of immune responses to transplantation is critical to improving graft outcomes.
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Affiliation(s)
- Sarah J. Dart
- Medical School, The University of Western Australia, Perth, WA, Australia
| | - Amy C. Prosser
- Medical School, The University of Western Australia, Perth, WA, Australia
| | - Wen Hua Huang
- Medical School, The University of Western Australia, Perth, WA, Australia
- Western Australian Liver Transplant Service, Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Liu Liu
- Medical School, The University of Western Australia, Perth, WA, Australia
| | - Andrew D. Lucas
- School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia
| | - Luc Delriviere
- Medical School, The University of Western Australia, Perth, WA, Australia
- Western Australian Liver Transplant Service, Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Silvana Gaudieri
- School of Human Sciences, The University of Western Australia, Perth, WA, Australia
| | - Gary P. Jeffrey
- Medical School, The University of Western Australia, Perth, WA, Australia
- Western Australian Liver Transplant Service, Sir Charles Gairdner Hospital, Perth, WA, Australia
- Department of Hepatology, Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Michaela Lucas
- Medical School, The University of Western Australia, Perth, WA, Australia
- Department of Immunology, Sir Charles Gairdner Hospital and PathWest Laboratory Medicine, Perth, WA, Australia
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Hilscher MB, Wells ML, Venkatesh SK, Cetta F, Kamath PS. Fontan-associated liver disease. Hepatology 2022; 75:1300-1321. [PMID: 35179797 DOI: 10.1002/hep.32406] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 12/21/2021] [Accepted: 12/27/2021] [Indexed: 12/13/2022]
Affiliation(s)
- Moira B Hilscher
- Division of Gastroenterology and HepatologyDepartment of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Michael L Wells
- Division of Abdominal ImagingDepartment of RadiologyMayo ClinicRochesterMinnesotaUSA
| | - Sudhakar K Venkatesh
- Division of Abdominal ImagingDepartment of RadiologyMayo ClinicRochesterMinnesotaUSA
| | - Frank Cetta
- Division of Pediatric CardiologyDepartment of Pediatric and Adolescent MedicineMayo ClinicRochesterMinnesotaUSA
| | - Patrick S Kamath
- Division of Gastroenterology and HepatologyDepartment of MedicineMayo ClinicRochesterMinnesotaUSA
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Assadiasl S, Toosi MN, Mohebbi B, Ansaripour B, Soleimanifar N, Sadr M, Mojtahedi H, Mosharmovahed B, Fazeli F, Nicknam MH. Th17/Treg cell balance in stable liver transplant recipients. Transpl Immunol 2022; 71:101540. [DOI: 10.1016/j.trim.2022.101540] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 01/12/2022] [Accepted: 01/13/2022] [Indexed: 12/23/2022]
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6
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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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7
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Ronca V, Wootton G, Milani C, Cain O. The Immunological Basis of Liver Allograft Rejection. Front Immunol 2020; 11:2155. [PMID: 32983177 PMCID: PMC7492390 DOI: 10.3389/fimmu.2020.02155] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 08/07/2020] [Indexed: 12/15/2022] Open
Abstract
Liver allograft rejection remains a significant cause of morbidity and graft failure in liver transplant recipients. Rejection is caused by the recognition of non-self donor alloantigens by recipient T-cells. Antigen recognition results in proliferation and activation of T-cells in lymphoid tissue before migration to the allograft. Activated T-cells have a variety of effector mechanisms including direct T-cell mediated damage to bile ducts, endothelium and hepatocytes and indirect effects through cytokine production and recruitment of tissue-destructive inflammatory cells. These effects explain the histological appearances of typical acute T-cell mediated rejection. In addition, donor specific antibodies, most typically against HLA antigens, may give rise to antibody-mediated rejection causing damage to the allograft primarily through endothelial injury. However, as an immune-privileged site there are several mechanisms in the liver capable of overcoming rejection and promoting tolerance to the graft, particularly in the context of recruitment of regulatory T-cells and promotors of an immunosuppressive environment. Indeed, around 20% of transplant recipients can be successfully weaned from immunosuppression. Hence, the host immunological response to the liver allograft is best regarded as a balance between rejection-promoting and tolerance-promoting factors. Understanding this balance provides insight into potential mechanisms for novel anti-rejection therapies.
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Affiliation(s)
- Vincenzo Ronca
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy.,National Institute of Health Research Liver Biomedical Research Unit Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Grace Wootton
- National Institute of Health Research Liver Biomedical Research Unit Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Chiara Milani
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
| | - Owen Cain
- Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
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9
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Hann A, Osei-Bordom DC, Neil DAH, Ronca V, Warner S, Perera MTPR. The Human Immune Response to Cadaveric and Living Donor Liver Allografts. Front Immunol 2020; 11:1227. [PMID: 32655558 PMCID: PMC7323572 DOI: 10.3389/fimmu.2020.01227] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 05/15/2020] [Indexed: 12/13/2022] Open
Abstract
The liver is an important contributor to the human immune system and it plays a pivotal role in the creation of both immunoreactive and tolerogenic conditions. Liver transplantation provides the best chance of survival for both children and adults with liver failure or cancer. With current demand exceeding the number of transplantable livers from donors following brain death, improved knowledge, technical advances and the desire to prevent avoidable deaths has led to the transplantation of organs from living, ABO incompatible (ABOi), cardiac death donors and machine based organ preservation with acceptable results. The liver graft is the most well-tolerated, from an immunological perspective, of all solid organ transplants. Evidence suggests successful cessation of immunosuppression is possible in ~20–40% of liver transplant recipients without immune mediated graft injury, a state known as “operational tolerance.” An immunosuppression free future following liver transplantation is an ambitious but perhaps not unachievable goal. The initial immune response following transplantation is a sterile inflammatory process mediated by the innate system and the mechanisms relate to the preservation-reperfusion process. The severity of this injury is influenced by graft factors and can have significant consequences. There are minimal experimental studies that delineate the differences in the adaptive immune response to the various forms of liver allograft. Apart from ABOi transplants, antibody mediated hyperacute rejection is rare following liver transplant. T-cell mediated rejection is common following liver transplantation and its incidence does not differ between living or deceased donor grafts. Transplantation in the first year of life results in a higher rate of operational tolerance, possibly due to a bias toward Th2 cytokines (IL4, IL10) during this period. This review further describes the current understanding of the immunological response toward liver allografts and highlight the areas of this topic yet to be fully understood.
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Affiliation(s)
- Angus Hann
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | | | - Desley A H Neil
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Vincenzo Ronca
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Suz Warner
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,The Liver Unit, Birmingham Children's Hospital, Birmingham, United Kingdom
| | - M Thamara P R Perera
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.,The Liver Unit, Birmingham Children's Hospital, Birmingham, United Kingdom
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10
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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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11
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Eikmans M, van Halteren AGS, van Besien K, van Rood JJ, Drabbels JJM, Claas FHJ. Naturally acquired microchimerism: implications for transplantation outcome and novel methodologies for detection. CHIMERISM 2015; 5:24-39. [PMID: 24762743 DOI: 10.4161/chim.28908] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Microchimerism represents a condition where one individual harbors genetically distinct cell populations, and the chimeric population constitutes <1% of the total number of cells. The most common natural source of microchimerism is pregnancy. The reciprocal cell exchange between a mother and her child often leads to the stable engraftment of hematopoietic and non-hematopoietic stem cells in both parties. Interaction between cells from the mother and those from the child may result in maternal immune cells becoming sensitized to inherited paternal alloantigens of the child, which are not expressed by the mother herself. Vice versa, immune cells of the child may become sensitized toward the non-inherited maternal alloantigens of the mother. The extent of microchimerism, its anatomical location, and the sensitivity of the techniques used for detecting its presence collectively determine whether microchimerism can be detected in an individual. In this review, we focus on the clinical consequences of microchimerism in solid organ and hematopoietic stem cell transplantation, and propose concepts derived from data of epidemiologic studies. Next, we elaborate on the latest molecular methodology, including digital PCR, for determining in a reliable and sensitive way the extent of microchimerism. For the first time, tools have become available to isolate viable chimeric cells from a host background, so that the challenges of establishing the biologic mechanisms and function of these cells may finally be tackled.
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Affiliation(s)
- Michael Eikmans
- Department of Immunohematology and Blood Transfusion; Leiden University Medical Center; Leiden, the Netherlands
| | - Astrid G S van Halteren
- Immunology Laboratory; Willem Alexander Children's Hospital; Leiden University Medical Center; Leiden, the Netherlands
| | | | - Jon J van Rood
- Department of Immunohematology and Blood Transfusion; Leiden University Medical Center; Leiden, the Netherlands; Europdonor Foundation; Leiden, the Netherlands
| | - Jos J M Drabbels
- Department of Immunohematology and Blood Transfusion; Leiden University Medical Center; Leiden, the Netherlands
| | - Frans H J Claas
- Department of Immunohematology and Blood Transfusion; Leiden University Medical Center; Leiden, the Netherlands
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12
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Gleicher N. Graft-versus-host disease and immunologic rejection: implications for diagnosis and treatments of pregnancy complications. ACTA ACUST UNITED AC 2014. [DOI: 10.1586/17474108.3.1.37] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Muller YD, Gupta S, Morel P, Borot S, Bettens F, Truchetet ME, Villard J, Seebach JD, Holmberg D, Toso C, Lobrinus JA, Bosco D, Berney T. Transplanted human pancreatic islets after long-term insulin independence. Am J Transplant 2013; 13:1093-1097. [PMID: 23398948 DOI: 10.1111/ajt.12138] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Revised: 11/22/2012] [Accepted: 12/10/2012] [Indexed: 01/25/2023]
Abstract
Long-term insulin independence after islets of Langerhans transplantation is rarely achieved. The aims of this study were to identify the histological and immunological features of islets transplanted in a type 1 diabetic patient who died of a cerebral hemorrhage after >13 years insulin independence. Islets were pooled from two donors with respectively one and five HLA mismatches. Insulin-positive islets were found throughout the right and left liver, and absent in the pancreas. Two- and three-dimensional analysis showed that islets lost their initial rounded and compact morphology, had a mean diameter of 136 μm and were constituted of an unfolded epithelial band of 39.1 μm. Leukocyte phenotyping showed no evidence of a tolerogenic environment in the islet-containing portal spaces. Finally, HLA typing of microdissected islets showed HLA from the best matched donor in all 23 microdissection samples, compared to 1/23 for the least matched donor. This case report demonstrates that allogeneic islets can survive over 13 years while maintaining insulin independence. Allogeneic islets had unique morphologic features and implanted in the liver regardless of their size. Finally, our results suggest that, in this case, rejection had been prevalent over autoimmunity, although this hypothesis warrants further investigation.
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Affiliation(s)
- Y D Muller
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.,Division of Clinical Immunology and Allergology, Department of Internal Medicine, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - S Gupta
- Centre for Infection and Inflammation Research, Faculty of Health, University of Copenhagen, Denmark
| | - P Morel
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - S Borot
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - F Bettens
- National Reference Laboratory for Histocompatibility, Department of Internal Medicine, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - M E Truchetet
- Division of Clinical Immunology and Allergology, Department of Internal Medicine, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - J Villard
- Division of Clinical Immunology and Allergology, Department of Internal Medicine, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - J D Seebach
- Division of Clinical Immunology and Allergology, Department of Internal Medicine, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - D Holmberg
- Centre for Infection and Inflammation Research, Faculty of Health, University of Copenhagen, Denmark
| | - C Toso
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - J A Lobrinus
- Department of Pathology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - D Bosco
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - T Berney
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
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Eikmans M, Claas FHJ. HLA-targeted cell sorting of microchimeric cells opens the way to phenotypical and functional characterization. CHIMERISM 2013; 2:114-6. [PMID: 22509428 DOI: 10.4161/chim.2.4.19133] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Microchimerism refers to the presence of less than 1% of non-host cells in a person. Our group developed a reliable method for separating viable microchimeric cells from the host environment. Optimal separation of microchimeric cells at proportions as low as 0.01% could be established with two monoclonal antibodies directed against different HLA antigens, one targeting the microchimeric cells and the other the host cells. Purity of separated cell populations was validated by HLA-allele-specific and Y-chromosome directed real-time qPCR assays. The methodology was used successfully to separate microchimeric maternal cells from child umbilical cord mononuclear cells after pregnancy. Cell sorting with HLA monoclonal antibodies targeting allelic differences enables reliable microchimeric cell detection and separation in blood specimens. With this approach, maximal enrichment of potentially viable microchimeric cells from a background cell population is reached, which opens the way to phenotypical and functional characterization of microchimeric cells.
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Affiliation(s)
- Michael Eikmans
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
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15
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Joo DJ, Ju MK, Huh KH, Kim MS, Choi GH, Choi JS, Jeon KO, Kim SI. Does lymphocyte cross-matching predict acute rejection and graft survival in liver transplantation? Transplant Proc 2012; 44:418-20. [PMID: 22410032 DOI: 10.1016/j.transproceed.2012.01.071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
INTRODUCTION The role of lymphocyte cross-matches (LCM) remains controversial in the liver transplant field. The aim of this study was to correlate the risk for acute rejection episodes and graft survival in liver transplantation with pretransplant LCM results. PATIENTS AND METHODS We enrolled 184 adult liver transplantation patients, excluding pediatric and second grafts. The 129 living donor and 55 deceased donor liver transplantations were divided into 2 groups: LCM (+); (n=20) and LCM (-); (n=164). RESULTS There were no differences in the demographic features, such as gender and recipient age, original disease, Model for End-Stage Liver Disease score, donor type, number of human leukocyte antigen mismatches, and cold ischemia times. There were no hyperacute rejection episodes in the LCM (+) group. Also, posttransplant complications such as acute rejection episode, biliary complication, or hepatic artery thrombosis were not different. Acute rejection episodes occurred in 5.0% of the LCM (+) group and 15.2% of the LCM (-) group (P=.317). Bile duct complications after transplantation arose in 20.0% of the LCM (+) group and in 32.9% of the LCM (-) group (P=.312). The 2 groups showed no difference in graft survival rate analyzed by the Kaplan-Meier method according to LCM results. CONCLUSION Pretransplant LCM results were not associated with overall graft survival or acute rejection episodes in this study.
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Affiliation(s)
- D J Joo
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Korea
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16
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HLA-targeted flow cytometric sorting of blood cells allows separation of pure and viable microchimeric cell populations. Blood 2011; 118:e149-55. [PMID: 21931111 DOI: 10.1182/blood-2011-06-362053] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Microchimerism is defined by the presence of low levels of nonhost cells in a person. We developed a reliable method for separating viable microchimeric cells from the host environment. For flow cytometric cell sorting, HLA antigens were targeted with human monoclonal HLA antibodies (mAbs). Optimal separation of microchimeric cells (present at a proportion as low as 0.01% in artificial mixtures) was obtained with 2 different HLA mAbs, one targeting the chimeric cells and the other the background cells. To verify purity of separated cell populations, flow-sorted fractions of 1000 cells were processed for DNA analysis by HLA-allele-specific and Y-chromosome-directed real-time quantitative PCR assays. After sorting, PCR signals of chimeric DNA markers in the positive fractions were significantly enhanced compared with those in the presort samples, and they were similar to those in 100% chimeric control samples. Next, we demonstrate applicability of HLA-targeted FACS sorting after pregnancy by separating chimeric maternal cells from child umbilical cord mononuclear cells. Targeting allelic differences with anti-HLA mAbs with FACS sorting allows maximal enrichment of viable microchimeric cells from a background cell population. The current methodology enables reliable microchimeric cell detection and separation in clinical specimens.
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17
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Truong DQ, Bourdeaux C, Wieërs G, Saussoy P, Latinne D, Reding R. The immunological monitoring of kidney and liver transplants in adult and pediatric recipients. Transpl Immunol 2009; 22:18-27. [PMID: 19800003 DOI: 10.1016/j.trim.2009.09.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2009] [Revised: 09/17/2009] [Accepted: 09/22/2009] [Indexed: 12/31/2022]
Abstract
Over the last half century, kidney and liver transplantation have been recognized as the treatment of choice for adult and children with end-stage renal or liver failure. Infants present a relative naïve immune system, but they are capable of mounting both cellular and humoral immune responses to the foreign antigens presented by the allograft. Immune monitoring is a way of measuring functional and molecular correlates of immune reactivity which may provide clinically useful information for identifying patients who have an increase risk of acute rejection prior to clinical symptoms or develop transplant tolerance. However, although numerous assays have been shown to predict rejection, to date no assays have been demonstrated to detect or predict transplantation tolerance. This is a summary of the published literature on promising antigen-specific and non-antigen-specific assays used for immunological monitoring in solid organ transplantation. This work also attempts to review their applicability to pediatric transplantation, specifically, pediatric kidney and liver recipients.
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Affiliation(s)
- Dinh Quang Truong
- Pediatric Surgery and Transplant Unit, Saint-Luc University Clinics, Université catholique de Louvain, Brussels, Belgium
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18
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Daniel V, Opelz G. Clinical Relevance of Immune Monitoring in Solid Organ Transplantation. Int Rev Immunol 2009; 28:155-84. [DOI: 10.1080/08830180902929404] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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19
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Ayala R, Grande S, Albizua E, Crooke A, Meneu JC, Moreno A, Pérez B, Gilsanz F, Moreno E, Martínez-Lopez J. Long-term follow-up of donor chimerism and tolerance after human liver transplantation. Liver Transpl 2009; 15:581-91. [PMID: 19479801 DOI: 10.1002/lt.21736] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
We aimed to quantify peripheral donor chimerism (DC) and to analyze its association with graft and recipient outcome. Forty-two liver transplant recipients and their respective donors were studied, providing a total of 148 posttransplantation serum samples. DC was assessed with real-time quantitative polymerase chain reaction (qPCR) to detect polymorphic markers. DC did not decrease with time post-transplantation and was higher in child recipients versus adults and in recipients of deceased donor liver transplants versus recipients of live donor liver transplants. Higher levels of DC were detected in Rh-positive blood group donors, in O blood group recipients versus A blood group recipients, and in recipients with hepatitis C virus versus recipients with alcoholic cirrhosis. High DC was associated with patients with organ damage due to recurrent disease and rejection. Stable, high levels of DC, in the absence of other major clinical events, may thus be a marker of transplantation tolerance, and this knowledge may help to tailor immunosuppressive treatment. In conclusion, qPCR is a useful technique for DC follow-up in liver transplantation, although the evolution of DC levels should be analyzed in accordance with the clinical outcome of the patient.
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Affiliation(s)
- Rosa Ayala
- Haematology Service, Hospital 12 de Octubre, Madrid, Spain
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20
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Araújo MB, Leonardi LS, Leonardi MI, Boin IFSF, Magna LA, Donadi EA, Kraemer MHS. Prospective analysis between the therapy of immunosuppressive medication and allogeneic microchimerism after liver transplantation. Transpl Immunol 2008; 20:195-8. [PMID: 18790055 DOI: 10.1016/j.trim.2008.08.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2008] [Revised: 08/02/2008] [Accepted: 08/06/2008] [Indexed: 01/09/2023]
Abstract
After liver transplantation, migration of donor-derived hematopoietic cells to recipient can be detected in peripheral blood. This state is termed microchimerism. The aim of this study was to investigate prospectively the presence of allogeneic microchimerism, the occurrence of acute cellular rejection and the level of immunosuppression in transplanted patients. Microchimerism occurrence between 10 days and 12 months after liver transplantation was analyzed in 47 patients aged between 15 and 65 by a two-stage nested PCR/SSP technique to detect donor MHC HLA-DR gene specifically. A pre-transplant blood sample was collected from each patient to serve as individual negative control. Microchimerism was demonstrated in 32 (68%) of the 47 patients; of these, only 10 patients (31.2%) presented rejection. Early microchimerism was observed in 25 patients (78.12%) and late microchimerism in 7 patients (21.8%). Among the patients with microchimerism, 14 were given CyA and 18 were given FK506. In the group without microchimerism, 12 patients were given CyA and 03 were given FK506. There was a significant association between the presence of microchimerism and the absence of rejection (p=0.02) and also between microchimerism and the type of immunosuppression used. Our data indicate that microchimerism and probably differentiation of donor-derived leukocytes can have relevant immunologic effects both in terms of sensitization of recipient and in terms of immunomodulation toward tolerance induction.
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Affiliation(s)
- M B Araújo
- Immunogenetic Transplant Laboratory, Department of Clinical Pathology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil.
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21
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Rosen HR. Transplantation immunology: what the clinician needs to know for immunotherapy. Gastroenterology 2008; 134:1789-801. [PMID: 18471555 DOI: 10.1053/j.gastro.2008.02.062] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2007] [Revised: 01/23/2008] [Accepted: 02/12/2008] [Indexed: 12/15/2022]
Abstract
The liver is unique among transplanted organs with respect to its interaction with the host immune system. There is evidence, both anecdotal and documented, that some liver recipients who cease taking immunosuppressive drugs maintain allograft function, suggesting robust tolerance is in place. Moreover, recipients of human liver allografts require less immunosuppression than do other organ recipients, and liver transplants confer protection on other organ grafts from the same donor. Hence, the liver shows features of immune privilege. Still, the liver can display destructive immunologic processes such as rejection in approximately one quarter of patients. The understanding of the cellular and molecular mechanisms operant in tolerance vs allograft rejection is important for developing new agents to improve long-term outcome, minimize infectious complications (including recurrence of hepatotropic viruses), and deliver immunosuppression without long-term toxicity. This review describes the unique aspects of the hepatic immune response, the pathways involved in T-cell activation and alloantigen recognition, effector cells and pathways mediating liver allograft rejection, the role of regulatory T cells, and targets of current and future immunosuppressive agents.
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Affiliation(s)
- Hugo R Rosen
- Division of Gastroenterology & Hepatology, Liver Transplantation, Hepatitis C Center, Department of Medicine, University of Colorado Health Sciences Center, Aurora, Colorado 80045, USA.
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Yoshizawa K, Shirakawa H, Ichijo T, Umemura T, Tanaka E, Kiyosawa K, Imagawa E, Matsuda K, Hidaka E, Sano K, Nakazawa Y, Ikegami T, Hashikura Y, Miyagawa S, Ota M, Nakano M. De novo autoimmune hepatitis following living-donor liver transplantation for primary biliary cirrhosis. Clin Transplant 2008; 22:385-90. [PMID: 18190552 DOI: 10.1111/j.1399-0012.2007.00787.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Since first being described in 1998, de novo autoimmune hepatitis (AIH) after liver transplantation has been reported in several cases suffering from non-autoimmune liver diseases and primary biliary cirrhosis (PBC). Glutathione S-transferase (GST) T1 genotype mismatches between donor and recipient have also been suggested to constitute a risk factor for de novo AIH. Here, we report a 33-yr-old woman who presented complaining of marked fatigue and jaundice four yr after living-donor liver transplantation for PBC. On examination, transaminase levels were highly elevated and ANA and antimitochondrial antibody M2 were positive. Histological findings showed zonal necrosis with lymphoplasmacytic infiltration closely resembling AIH. She had pretreatment AIH score of 16 and 19 points after relapse of de novo AIH. Two color fluorescence in situ hybridization with X and Y chromosome-specific probes clearly revealed that the hepatocytes were of donor origin and lymphocytes were of patient origin. The GSTT1 genotype of the patient and the donor were the same null type, suggesting that mechanisms other than GSTT1 mismatches may exist in de novo AIH development. In conclusion, recipient immune cells attacked the allogeneic transplanted liver of the patient via de novo AIH, although the exact participation of autoimmune mechanisms is unclear.
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Affiliation(s)
- Kaname Yoshizawa
- Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
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Nikbin B, Bonab MM, Talebian F. Microchimerism and Stem Cell Transplantation in Multiple Sclerosis. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2007; 79:173-202. [PMID: 17531842 DOI: 10.1016/s0074-7742(07)79008-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/27/2023]
Abstract
Scientific advances have demonstrated that autoreactive cells are a component of the healthy immune repertoire. If we define autoimmunity as an active induction of autoreaction, the solution should be an active induction of self-tolerance, and may indicate the direction to explore the future therapies. Microchimerism (MC) refers to the presence of a limited number of nonhost cells in the body of an individual. These cells can enter via blood transfusion and organ transplantation or naturally through pregnancy. Chimeric cells engraft in the host body, develop, proliferate, and are accepted by the immune system as self. These include stem cells that enter the maternal body during fetal stages. These stem cells are also postulated to be helpful reservoirs in protecting the host body. MC has been considered a risk factor in autoimmune disease induction. However, today we know it is a natural phenomenon. MC can be considered a natural model of successful transplantation, the earliest engrafting cells being fetal mesenchymal stem cells (MSCs). MSCs have two notable features. They have an immunosuppressive quality when encountering the adoptive immune system and they display repair-inducing potential within damaged tissues. For the fetus, MC appears to be an effective factor in maternal tolerance induction toward the fetal graft and for the mother; these novel fetal cells might be useful in disease conditions occurring after pregnancy. Hematopoietic stem cell transplantation has become an accepted treatment option for both malignant and nonmalignant diseases and this unique procedure is now being investigated as a potential therapy for multiple sclerosis (MS). Due to the dichotomous properties of MSC, suppressing aggressive immune dysfunction while promoting damaged tissue repair, they may be appropriate therapy for MS.
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Affiliation(s)
- Behrouz Nikbin
- Immunogenetic Research Center, Department of Immunology, College of Medicine, Tehran University of Medical Sciences, Tehran 14155, Iran
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Schäppi MG, Belli DC, Rimensberger PC, Chardot C, Kaya G, Tiercy JM, Ozsahin H. Fatal GvHD as a complication of liver transplantation for undetermined fulminant hepatic failure and associated aplastic anemia. Liver Transpl 2006; 12:1693-7. [PMID: 17058230 DOI: 10.1002/lt.20916] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Fulminant hepatic failure of unknown origin is the most common cause of fulminant hepatitis with high incidence of aplastic anaemia. Furthermore, the association of liver failure and aplastic anaemia has an increased mortality rate. In this report we describe a 16-month-old boy who presented with aplastic anaemia preceding a non-A, non-B, non-C fulminant liver failure. He developed severe graft versus host disease (GvHD) after liver transplantation, proven by the presence of donor cells in the peripheral blood and in the skin biopsy. He received conventional therapy (steroids, mycophenolate, anti-IL-2 monoclonal antibodies, anti-thymocyte globulin) without success. In an attempt to obtain T cell depletion and reduce the GvHD, he was treated with Alemtuzumab, a first time use for this indication. Aplastic anaemia was extensively investigated, especially exploring the possibility of primary immunodeficiency and reticular dysgenesis which were excluded based on clinical history. However, another form of primary immunodeficiency could be the cause of the uncontrollable proliferation of the donor lymphocytes derived from the liver transplant. Despite aggressive treatment GvHD progressed and the patient died of multiorgan failure. The majority of authors mention aplastic anaemia as a secondary event post liver transplant, whereas in our view this might be a haematopoietic stem cell disorder preceding fulminant hepatic failure. These patients also need to be evaluated extensively in order to exclude a primary immunodeficiency. The underlying disease will determine the choice of immunosuppressive treatment, especially in case of development of GvHD caused by the transplanted lymphocytes inhabiting the donor liver.
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Affiliation(s)
- Michela G Schäppi
- Gastroenterology and Hepatology Unit, Department of Pediatrics, University Hospital of Geneva, Switzerland.
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25
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Wieërs G, Gras J, Bourdeaux C, Truong DQ, Latinne D, Reding R. Monitoring tolerance after human liver transplantation. Transpl Immunol 2006; 17:83-93. [PMID: 17306738 DOI: 10.1016/j.trim.2006.09.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2006] [Accepted: 09/13/2006] [Indexed: 01/25/2023]
Abstract
The validation of reliable, non-invasive immunological assays evaluating anti-donor responsiveness in allograft recipients would provide a clinically relevant tool for the early detection of ongoing rejection process as well as for the identification of operational tolerance in the long term. A sequential approach towards immunological monitoring of allografts is proposed in this review: (i) investigations exploring the initial donor-recipient alloresponses, including the analysis of the cytokine network; (ii) investigations regarding graft acceptance and operational tolerance in long-term transplant patients, consisting in the analysis of regulatory T cells and of circulating precursors of dendritic cells, in the measurement of T cell alloreactivity as well as in the study of T cell receptor repertoires. Beside the conventional in vivo and in vitro immunological techniques, the potential applications of molecular imaging in transplantation also deserve further exploration, with particular respect to allograft immune monitoring. Enforced collaboration between transplant clinicians and immunologists will be required to develop the translational research protocols required for the development of immunological monitoring, within an international multicentric network.
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Affiliation(s)
- Grégoire Wieërs
- Pediatric Liver Transplant Program, Saint-Luc University Clinics, Université catholique de Louvain, Brussels, Belgium
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Reding R, Gras J, Truong DQ, Wieërs G, Latinne D. The immunological monitoring of alloreactive responses in liver transplant recipients: a review. Liver Transpl 2006; 12:373-83. [PMID: 16498661 DOI: 10.1002/lt.20704] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The aim of this work is to review the current knowledge in the field of immunological monitoring of allogenic responsiveness in clinical liver transplantation. When compared to other solid-organ transplants, liver allografts are considered as immunologically privileged, and, accordingly, constitute a favorable setting to develop experimental as well as clinical strategies for minimization of immunosuppression and even induction of operational tolerance. The validation of simple, reliable, noninvasive assays exploring antidonor alloreactivity will constitute a crucial step toward implementing such approaches in the clinic. In contrast to research in rodents claiming the development of donor-specific tolerance in case of graft survivals of over 100 days without immunosuppression, it is impractical to confirm tolerance induction in this way in humans. Promising candidate assays include the detection of post-transplant immune deviation, of circulating precursors of dendritic cells subtypes, and of regulatory T cells. A conceptual framework for the development of tolerance assays in clinical liver transplantation is also proposed.
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Affiliation(s)
- Raymond Reding
- Pediatric Liver Transplant Program, Saint-Luc University Clinics, Université Catholique de Louvain, Brussels, Belgium.
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Klein I, Crispe IN. Complete differentiation of CD8+ T cells activated locally within the transplanted liver. ACTA ACUST UNITED AC 2006; 203:437-47. [PMID: 16476766 PMCID: PMC2118211 DOI: 10.1084/jem.20051775] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The transplanted liver elicits systemic tolerance, and the underlying mechanism may also account for the persistence of liver infections, such as malaria and viral hepatitis. These phenomena have led to the hypothesis that antigen presentation within the liver is abortive, leading to T cell tolerance or apoptosis. Here we test this hypothesis in an optimized orthotopic liver transplantation model. In direct contradiction to this model, the liver itself induces full CD8+ T cell activation and differentiation. The effects of microchimerism were neutralized by bone marrow transplantation in the liver donor, and the lack of liver-derived antigen-presenting cells was documented by eight-color flow cytometry and by sensitive functional assays. We conclude that local antigen presentation cannot explain liver tolerance. On the contrary, the liver may be an excellent priming site for naive CD8+ T cells.
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Affiliation(s)
- Ingo Klein
- David H. Smith Center for Vaccine Biology and Immunology, Aab Institute for Biomedical Research, University of Rochester, Rochester, NY 14642, USA.
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