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1
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Bellamy COC, O'Leary JG, Adeyi O, Baddour N, Batal I, Bucuvalas J, Del Bello A, El Hag M, El-Monayeri M, Farris AB, Feng S, Fiel MI, Fischer SE, Fung J, Grzyb K, Guimei M, Haga H, Hart J, Jackson AM, Jaeckel E, Khurram NA, Knechtle SJ, Lesniak D, Levitsky J, McCaughan G, McKenzie C, Mescoli C, Miquel R, Minervini MI, Nasser IA, Neil D, O'Neil MF, Pappo O, Randhawa P, Ruiz P, Fueyo AS, Schady D, Schiano T, Sebagh M, Smith M, Stevenson HL, Taner T, Taubert R, Thung S, Trunecka P, Wang HL, Wood-Trageser M, Yilmaz F, Zen Y, Zeevi A, Demetris AJ. Banff 2022 Liver Group Meeting report: Monitoring long-term allograft health. Am J Transplant 2024; 24:905-917. [PMID: 38461883 DOI: 10.1016/j.ajt.2024.03.008] [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: 09/12/2023] [Revised: 02/27/2024] [Accepted: 03/06/2024] [Indexed: 03/12/2024]
Abstract
The Banff Working Group on Liver Allograft Pathology met in September 2022. Participants included hepatologists, surgeons, pathologists, immunologists, and histocompatibility specialists. Presentations and discussions focused on the evaluation of long-term allograft health, including noninvasive and tissue monitoring, immunosuppression optimization, and long-term structural changes. Potential revision of the rejection classification scheme to better accommodate and communicate late T cell-mediated rejection patterns and related structural changes, such as nodular regenerative hyperplasia, were discussed. Improved stratification of long-term maintenance immunosuppression to match the heterogeneity of patient settings will be central to improving long-term patient survival. Such personalized therapeutics are in turn contingent on a better understanding and monitoring of allograft status within a rational decision-making approach, likely to be facilitated in implementation with emerging decision-support tools. Proposed revisions to rejection classification emerging from the meeting include the incorporation of interface hepatitis and fibrosis staging. These will be opened to online testing, modified accordingly, and subject to consensus discussion leading up to the next Banff conference.
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Affiliation(s)
- Christopher O C Bellamy
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland and Department of Pathology, Edinburgh Royal Infirmary, Edinburgh, Scotland.
| | - Jacqueline G O'Leary
- Dallas VA Medical Center & University of Texas, Southwestern, Department of Medicine, Dallas Texas, USA
| | - Oyedele Adeyi
- University of Minnesota Medical School, Department of Pathology, Minneapolis, Minnesota, USA
| | - Nahed Baddour
- Faculty of Medicine, University of Alexandria, Egypt
| | - Ibrahim Batal
- Pathology, Columbia University Irving Medical Center, New York, New York, USA
| | | | | | | | | | - Alton B Farris
- Pathology, Emory University Hospital, Atlanta, Georgia, USA
| | - Sandy Feng
- UCSF Health, Department of Surgery, San Francisco, California, USA
| | - Maria Isabel Fiel
- Pathology, Icahn School of Medicine, Mount Sinai, New York, New York, USA
| | | | - John Fung
- Uchicago Medicine, Department of Surgery, Chicago, Illinois, USA
| | | | - Maha Guimei
- Armed Forces College of Medicine, Cairo, Egypt
| | | | - John Hart
- Uchicago Medicine, Department of Pathology, Chicago, Illinois, USA
| | | | | | - Nigar A Khurram
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | | | - Drew Lesniak
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | | | | | | | | | - Rosa Miquel
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Marta I Minervini
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | - Imad Ahmad Nasser
- Beth Israel Deaconess Medical Center, Harvard, Boston, Massachusetts, USA
| | - Desley Neil
- University Hospitals Birmingham NHS Foundation Trust, United Kingdom
| | - Maura F O'Neil
- University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Orit Pappo
- Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Parmjeet Randhawa
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | - Phillip Ruiz
- University of Miami Hospital, Miami, Florida, USA
| | | | | | - Thomas Schiano
- Recanati/Miller Transplantation Institute, Mount Sinai Medical Center, New York, New York, USA
| | | | - Maxwell Smith
- Pathology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | | | - Timucin Taner
- Division of Transplantation Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Richard Taubert
- Dept. of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Swan Thung
- Pathology, Icahn School of Medicine, Mount Sinai, New York, New York, USA
| | - Pavel Trunecka
- Institute for Clinical and Experimental Medicine (IKEM), Prague, Czechia
| | - Hanlin L Wang
- Pathology, UCLA Health, Los Angeles, California, USA
| | - Michelle Wood-Trageser
- University of Pittsburgh Medical Center, Department of Pathology, Pittsburgh, Pennsylvania, USA
| | - Funda Yilmaz
- Pathology, University of Ege, Imir, Bornova, Turkey
| | - Yoh Zen
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Adriana Zeevi
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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2
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Liu W, Wang ZL, Kang ZY, Xiao YL, Liu C, Li DH. Liver graft injury caused by de novo donor-specific HLA antibodies in pediatric liver transplant recipients with low, moderate, and high immunologic risk. Am J Surg 2023; 225:275-281. [PMID: 36116972 DOI: 10.1016/j.amjsurg.2022.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 08/31/2022] [Accepted: 09/04/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND This study investigated the association between different risk levels of de novo donor-specific anti-human leukocyte antigen antibodies (dnDSAs) and liver graft injury after liver transplantation in pediatric patients. METHODS This retrospective cohort study enrolled 130 patients after liver transplantation. Subjects were divided into the following 4 groups according to the mean fluorescence intensity (MFI) of dnDSAs: high risk group(MFI ≥10,000), medium risk group(4000 ≤ MFI <10,000), low risk group(500 ≤ MFI <4000), and negative group(<500). Liver function indices were examined along with liver puncture biopsy，and the relationship between dnDSA risk level and liver injury after transplantation was assessed. RESULTS Pediatric liver transplant recipients showed significant differences in liver function (ALT, AST, GGT and Bilirubin) according to dnDSA risk level (P < 0.05), and no differences in cumulative incidences of rejection (P = 0.413) and liver fibrosis (P = 0.978) were observed among the number of dnDSAs group. There were differences in the cumulative incidences of antibody-mediated rejection (AMR) (P = 0.001) and T cell-mediated rejection （TCMR） (P = 0.003) across risk groups. The cumulative incidences of TCMR and liver fibrosis (P = 0.0001) were higher in the low-risk group than in the other 3 groups. There were no differences in graft survival rate (P = 0.846) across risk groups. CONCLUSION DnDSAs in pediatric liver transplant recipients are associated with liver transplant rejection and fibrosis. The level of dnDSAs in low risk group should not be disregarded. Routine detection of dnDSAs has clinical utility for noninvasive risk stratification in this population.
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Affiliation(s)
- Wei Liu
- Department of Blood Transfusion, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Zheng-Lu Wang
- Department of Pathology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Zhong-Yu Kang
- Department of Blood Transfusion, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Yan-Li Xiao
- Department of Blood Transfusion, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Chun Liu
- Department of Blood Transfusion, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Dai-Hong Li
- Department of Blood Transfusion, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China.
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Li Y, Zhou Y, Qiao W, Shi J, Qiu X, Dong N. Application of decellularized vascular matrix in small-diameter vascular grafts. Front Bioeng Biotechnol 2023; 10:1081233. [PMID: 36686240 PMCID: PMC9852870 DOI: 10.3389/fbioe.2022.1081233] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 12/13/2022] [Indexed: 01/09/2023] Open
Abstract
Coronary artery bypass grafting (CABG) remains the most common procedure used in cardiovascular surgery for the treatment of severe coronary atherosclerotic heart disease. In coronary artery bypass grafting, small-diameter vascular grafts can potentially replace the vessels of the patient. The complete retention of the extracellular matrix, superior biocompatibility, and non-immunogenicity of the decellularized vascular matrix are unique advantages of small-diameter tissue-engineered vascular grafts. However, after vascular implantation, the decellularized vascular matrix is also subject to thrombosis and neoplastic endothelial hyperplasia, the two major problems that hinder its clinical application. The keys to improving the long-term patency of the decellularized matrix as vascular grafts include facilitating early endothelialization and avoiding intravascular thrombosis. This review article sequentially introduces six aspects of the decellularized vascular matrix as follows: design criteria of vascular grafts, components of the decellularized vascular matrix, the changing sources of the decellularized vascular matrix, the advantages and shortcomings of decellularization technologies, modification methods and the commercialization progress as well as the application prospects in small-diameter vascular grafts.
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Affiliation(s)
| | | | | | | | - Xuefeng Qiu
- *Correspondence: Xuefeng Qiu, ; Nianguo Dong,
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4
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The Immunohistochemical Expression of the Von Willebrand Factor: A Potential Tool to Predict Kidney Allograft Outcomes. Appl Immunohistochem Mol Morphol 2022; 30:687-693. [PMID: 36251974 DOI: 10.1097/pai.0000000000001078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/15/2022] [Indexed: 11/26/2022]
Abstract
Few reports assessed endothelial activation biomarkers in kidney allograft biopsies using immunohistochemistry. This retrospective cohort study evaluated the association between posttransplant outcomes and the immunohistochemistry expression of Caveolin-1, Von Willebrand Factor (Vwf), and T-Cadherin in for-cause biopsies diagnosed as interstitial fibrosis and tubular atrophy of unknown etiology. Samples with antibody-mediated changes were excluded. The patients were followed for 3 years after the biopsy or until graft loss/death. Seventy-one (71) samples from 66 patients were included. Eighteen (25.4%) patients lost their grafts, mainly due to chronic rejection (33.3%). Caveolin-1 and T-Cadherin were not associated with graft loss. Vwf had good accuracy in predicting graft failure (AUC 0.637, 95% CI 0.486 to 0.788 P=0.101). The presence of more than 10% of Vwf positivity in the microvasculature (Vwf >10%) was associated with reduced death-censored graft survival (58.2% vs. 85.4% P=0.006), and this result was also observed in the subgroup presenting mild interstitial fibrosis (ci=1) (65.7% vs. 88.6% P=0.033). The multivariate analysis showed that Vwf >10% was an independent risk factor for graft loss (HR=2.88, 95% CI 1.03 to 8.02 P=0.043). In conclusion, Vwf might be an additional tool to predict allograft outcomes in kidney transplant recipients with interstitial fibrosis and tubular atrophy of unknown etiology, probably reflecting immune endothelial activation.
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5
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Lee BT, Ganjoo N, Fiel MI, Hechtman JF, Sarkar SA, Kim-Schluger L, Florman SS, Schiano TD. Recurrent Liver Allograft Injury in Patients With Donor-Derived Malignancy Treated With Immunosuppression Cessation and Retransplantation. Am J Clin Pathol 2022; 158:199-205. [PMID: 35285881 DOI: 10.1093/ajcp/aqac026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 01/28/2022] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVES Donor-derived malignancy of the liver allograft is a rare but serious condition in the setting of necessary immunosuppression. Retransplantation after abrupt immunosuppression cessation has been performed with durable cancer-free survival. METHODS We present 2 cases of patients with donor-derived malignancy who were treated with complete immunosuppression cessation, which induced rapidly progressive liver allograft rejection and failure, with a need for subsequent retransplantation. We reviewed all serial liver biopsies and explants from both patients and performed C4d immunostaining. RESULTS Initial explants of both patients showed severe allograft rejection, with unusual features of sinusoidal obstruction syndrome and C4d positivity. Malignant tumors in the explants were necrotic, related to rejection of donor-derived cancer cells and tissue. Follow-up of both patients has shown long-term cancer-free survival but issues with recurrent allograft failure requiring a third transplant. The reasons for retransplantation in both cases were related to allograft failure from antibody-mediated rejection. CONCLUSIONS Clinicians should be aware of a potentially increased risk of rejection and recurrent allograft failure when strategizing treatment of donor-derived malignancy with immunosuppression cessation and retransplantation.
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Affiliation(s)
- Brian T Lee
- Division of Gastroenterology and Transplantation Institute, Loma Linda University Health, Loma Linda, CA, USA
- Recanati/Miller Transplantation Institute, Division of Liver Diseases, Department of Medicine, New York, NY, USA
| | - Naveen Ganjoo
- Recanati/Miller Transplantation Institute, Division of Liver Diseases, Department of Medicine, New York, NY, USA
| | - M Isabel Fiel
- Department of Pathology, Molecular and Cell-Based Medicine, New York, NY, USA
| | | | - Suparna A Sarkar
- Department of Pathology, New York University School of Medicine, New York, NY, USA
| | - Leona Kim-Schluger
- Recanati/Miller Transplantation Institute, Division of Liver Diseases, Department of Medicine, New York, NY, USA
| | - Sander S Florman
- Recanati/Miller Transplantation Institute, Division of Abdominal Transplantation, Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Thomas D Schiano
- Recanati/Miller Transplantation Institute, Division of Liver Diseases, Department of Medicine, New York, NY, USA
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6
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Cross AR, Lion J, Poussin K, Glotz D, Mooney N. Inflammation Determines the Capacity of Allogenic Endothelial Cells to Regulate Human Treg Expansion. Front Immunol 2021; 12:666531. [PMID: 34305898 PMCID: PMC8299527 DOI: 10.3389/fimmu.2021.666531] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 06/23/2021] [Indexed: 11/25/2022] Open
Abstract
During allotransplantation, the endothelium acts as semi-professional antigen-presenting cells with the ability to activate proliferation and to promote differentiation of CD4+-T subsets. These abilities are dependent on the luminal expression of HLA class II antigens by microvascular endothelial cells, which is regulated by inflammatory cytokines. The upregulation of HLA-DR and HLA-DQ during rejection implies significant intragraft inflammation. Furthermore, the microvascular inflammation is an independent determinant for renal allograft failure. In this study, the potential of inflammation to modify endothelial regulation of peripheral CD4+ Treg cells was examined. Microvascular endothelial cells were exposed to pro-inflammatory cytokines for varying durations before co-culture with PBMC from non-HLA matched donors. Proliferation and expansion of CD4+Treg and soluble factor secretion was determined. Early interactions were detected by phosphorylation of Akt. Video microscopy was used to examine spatial and temporal endothelial-CD4+T interactions. Highly inflammatory conditions led to increased endothelial expression of HLA-DR, the adhesion molecule ICAM-1, the costimulatory molecule PD-L1 and de novo expression of HLA-DQ. Treg differentiation was impaired by exposure of endothelial cells to a high level of inflammation. Neither IL-6, IL-2 nor TGFβ were implicated in reducing Treg numbers. High PD-L1 expression interfered with early endothelial cell interactions with CD4+T lymphocytes and led to modified TCR signaling. Blocking endothelial PD-L1 resulted in a partial restoration of Treg. The allogenic endothelial cell-mediated expansion of Treg depends on a critical threshold of inflammation. Manipulation of the PD-L1/PD-1 pathway or endothelial activation post-transplantation may promote or interfere with this intrinsic mechanism of allospecific Treg expansion.
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Affiliation(s)
- Amy Rachael Cross
- Human Immunology, Pathophysiology and Immunotherapy, INSERM U976, Paris, France.,Université de Paris, INSERM U976, Paris, France
| | - Julien Lion
- Human Immunology, Pathophysiology and Immunotherapy, INSERM U976, Paris, France
| | - Karine Poussin
- Human Immunology, Pathophysiology and Immunotherapy, INSERM U976, Paris, France
| | - Denis Glotz
- Human Immunology, Pathophysiology and Immunotherapy, INSERM U976, Paris, France.,Université de Paris, INSERM U976, Paris, France.,Service de Néphrologie et Transplantation, Hôpital Saint Louis, Paris, France
| | - Nuala Mooney
- Human Immunology, Pathophysiology and Immunotherapy, INSERM U976, Paris, France.,Université de Paris, INSERM U976, Paris, France
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7
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Cross AR, Lion J, Poussin K, Assayag M, Taupin JL, Glotz D, Mooney N. HLA-DQ alloantibodies directly activate the endothelium and compromise differentiation of FoxP3 high regulatory T lymphocytes. Kidney Int 2019; 96:689-698. [PMID: 31307777 DOI: 10.1016/j.kint.2019.04.023] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 03/28/2019] [Accepted: 04/19/2019] [Indexed: 10/26/2022]
Abstract
Development of donor-specific antibodies is associated with reduced allograft survival in renal transplantation. Recent clinical studies highlight the prevalence of human leukocyte antigen (HLA)-DQ antibodies amongst de novo donor-specific antibodies (DSAs), yet the specific contribution of these DSAs to rejection has not been examined. Antibody-mediated rejection primarily targets the microvasculature, so this study explored how patient HLA-DQ alloantibodies can modulate endothelial activation and so immunoregulation. HLA-DQ antibodies phosphorylated Akt and S6 kinase in microvascular endothelial cells. This activation prior to culture with alloreactive lymphocytes increased IL-6 and RANTES secretion. The antibody-mediated upregulation of IL-6 was indeed Akt-dependent. The binding of HLA-DQ antibodies to endothelial cells selectively reduced T cell alloproliferation and FoxP3high Treg differentiation. In clinical studies, detection of HLA-DQ DSAs with other DSAs is associated with worse graft survival than either alone. Endothelial cells stimulated with HLA-DR and HLA-DQ antibodies showed a synergistic increase in pro-inflammatory cytokine secretion and a decrease in Treg expansion. HLA-DQ antibodies strongly promote pro-inflammatory responses in isolation and in combination with other HLA antibodies. Thus, our data give new insights into the pathogenicity of HLA-DQ DSAs.
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Affiliation(s)
- Amy R Cross
- Human Immunology and Immunopathology, Inserm UMR 976, Paris, France; Institut de Recherche Saint Louis, Sorbonne Paris Cité, Université Paris Diderot, Sorbonne Paris, Paris, France
| | - Julien Lion
- Human Immunology and Immunopathology, Inserm UMR 976, Paris, France; Institut de Recherche Saint Louis, Sorbonne Paris Cité, Université Paris Diderot, Sorbonne Paris, Paris, France
| | - Karine Poussin
- Human Immunology and Immunopathology, Inserm UMR 976, Paris, France
| | - Maureen Assayag
- Human Immunology and Immunopathology, Inserm UMR 976, Paris, France
| | - Jean-Luc Taupin
- Human Immunology and Immunopathology, Inserm UMR 976, Paris, France; Institut de Recherche Saint Louis, Sorbonne Paris Cité, Université Paris Diderot, Sorbonne Paris, Paris, France; Laboratoire d'Immunologie et Histocompatibilité, Hôpital Saint Louis, Paris, France; LabEx Transplantex, Université de Strasbourg, Strasbourg, France
| | - Denis Glotz
- Human Immunology and Immunopathology, Inserm UMR 976, Paris, France; Institut de Recherche Saint Louis, Sorbonne Paris Cité, Université Paris Diderot, Sorbonne Paris, Paris, France; LabEx Transplantex, Université de Strasbourg, Strasbourg, France; Service de Néphrologie et Transplantation, Hôpital Saint Louis, Paris, France
| | - Nuala Mooney
- Human Immunology and Immunopathology, Inserm UMR 976, Paris, France; Institut de Recherche Saint Louis, Sorbonne Paris Cité, Université Paris Diderot, Sorbonne Paris, Paris, France; LabEx Transplantex, Université de Strasbourg, Strasbourg, France.
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8
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Cross AR, Glotz D, Mooney N. The Role of the Endothelium during Antibody-Mediated Rejection: From Victim to Accomplice. Front Immunol 2018; 9:106. [PMID: 29434607 PMCID: PMC5796908 DOI: 10.3389/fimmu.2018.00106] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 01/12/2018] [Indexed: 12/14/2022] Open
Abstract
Antibody-mediated rejection (AMR) of solid organ transplants is characterized by the activation and injury of the allograft endothelium. Histological and transcriptomic studies have associated microvascular inflammation and endothelial lesions with the severity of rejection and poor graft outcomes. The allograft endothelium forms the physical barrier between the donor organ and the recipient; this position directly exposes the endothelium to alloimmune responses. However, endothelial cells are not just victims and can actively participate in the pathogenesis of rejection. In healthy tissues, the endothelium plays a major role in vascular and immune homeostasis. Organ transplantation, however, subjects the endothelium to an environment of inflammation, alloreactive lymphocytes, donor-specific antibodies, and potentially complement activation. As a result, endothelial cells become activated and have modified interactions with the cellular effectors of allograft damage: lymphocytes, natural killer, and myeloid cells. Activated endothelial cells participate in leukocyte adhesion and recruitment, lymphocyte activation and differentiation, as well as the secretion of cytokines and chemokines. Ultimately, highly activated endothelial cells promote pro-inflammatory alloresponses and become accomplices to AMR.
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Affiliation(s)
- Amy Rachael Cross
- INSERM U1160, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Denis Glotz
- INSERM U1160, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Paris, France.,AP-HP, Hôpital Saint Louis, Département de Néphrologie, Paris, France.,LabEx Transplantex, Université de Strasbourg, Strasbourg, France
| | - Nuala Mooney
- INSERM U1160, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Paris, France.,LabEx Transplantex, Université de Strasbourg, Strasbourg, France
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9
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Emond JC, Griesemer AD. Tolerance in clinical liver transplantation: The long road ahead. Hepatology 2017; 65:411-413. [PMID: 27718261 DOI: 10.1002/hep.28862] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 09/27/2016] [Accepted: 09/29/2016] [Indexed: 12/15/2022]
Affiliation(s)
- Jean C Emond
- Department of Surgery, Columbia University, New York, NY
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10
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Demetris AJ, Bellamy C, Hübscher SG, O'Leary J, Randhawa PS, Feng S, Neil D, Colvin RB, McCaughan G, Fung JJ, Del Bello A, Reinholt FP, Haga H, Adeyi O, Czaja AJ, Schiano T, Fiel MI, Smith ML, Sebagh M, Tanigawa RY, Yilmaz F, Alexander G, Baiocchi L, Balasubramanian M, Batal I, Bhan AK, Bucuvalas J, Cerski CTS, Charlotte F, de Vera ME, ElMonayeri M, Fontes P, Furth EE, Gouw ASH, Hafezi-Bakhtiari S, Hart J, Honsova E, Ismail W, Itoh T, Jhala NC, Khettry U, Klintmalm GB, Knechtle S, Koshiba T, Kozlowski T, Lassman CR, Lerut J, Levitsky J, Licini L, Liotta R, Mazariegos G, Minervini MI, Misdraji J, Mohanakumar T, Mölne J, Nasser I, Neuberger J, O'Neil M, Pappo O, Petrovic L, Ruiz P, Sağol Ö, Sanchez Fueyo A, Sasatomi E, Shaked A, Shiller M, Shimizu T, Sis B, Sonzogni A, Stevenson HL, Thung SN, Tisone G, Tsamandas AC, Wernerson A, Wu T, Zeevi A, Zen Y. 2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection. Am J Transplant 2016; 16:2816-2835. [PMID: 27273869 DOI: 10.1111/ajt.13909] [Citation(s) in RCA: 414] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 06/01/2016] [Accepted: 05/25/2016] [Indexed: 02/06/2023]
Abstract
The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.
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Affiliation(s)
- A J Demetris
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - C Bellamy
- The University of Edinburgh, Edinburgh, Scotland
| | | | - J O'Leary
- Baylor University Medical Center, Dallas, TX
| | - P S Randhawa
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - S Feng
- University of California San Francisco Medical Center, San Francisco, CA
| | - D Neil
- Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | - R B Colvin
- Massachusetts General Hospital, Boston, MA
| | - G McCaughan
- Royal Prince Alfred Hospital, Sydney, Australia
| | | | | | - F P Reinholt
- Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - H Haga
- Kyoto University Hospital, Kyoto, Japan
| | - O Adeyi
- University Health Network and University of Toronto, Toronto, Canada
| | - A J Czaja
- Mayo Clinic College of Medicine, Rochester, MN
| | - T Schiano
- Mount Sinai Medical Center, New York, NY
| | - M I Fiel
- Icahn School of Medicine at Mount Sinai, New York, NY
| | - M L Smith
- Mayo Clinic Health System, Scottsdale, AZ
| | - M Sebagh
- AP-HP Hôpital Paul-Brousse, Paris, France
| | - R Y Tanigawa
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - F Yilmaz
- University of Ege, Faculty of Medicine, Izmir, Turkey
| | | | - L Baiocchi
- Policlinico Universitario Tor Vergata, Rome, Italy
| | | | - I Batal
- Columbia University College of Physicians and Surgeons, New York, NY
| | - A K Bhan
- Massachusetts General Hospital, Boston, MA
| | - J Bucuvalas
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - C T S Cerski
- Universidade Federal do Rio Grande do Sul, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
| | | | | | - M ElMonayeri
- Ain Shams University, Wady El-Neel Hospital, Cairo, Egypt
| | - P Fontes
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - E E Furth
- Hospital of the University of Pennsylvania, Philadelphia, PA
| | - A S H Gouw
- University Medical Center Groningen, Groningen, the Netherlands
| | | | - J Hart
- University of Chicago Hospitals, Chicago, IL
| | - E Honsova
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - W Ismail
- Beni-Suef University, Beni-Suef, Egypt
| | - T Itoh
- Kobe University Hospital, Kobe, Japan
| | | | - U Khettry
- Lahey Hospital and Medical Center, Burlington, MA
| | | | - S Knechtle
- Duke University Health System, Durham, NC
| | - T Koshiba
- Soma Central Hospital, Soma, Fukushima, Japan
| | - T Kozlowski
- University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - C R Lassman
- David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - J Lerut
- Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - J Levitsky
- Northwestern University Feinberg School of Medicine, Chicago, IL
| | - L Licini
- Pope John XXIII Hospital, Bergamo, Italy
| | - R Liotta
- Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, University of Pittsburgh Medical Center, Palermo, Italy
| | - G Mazariegos
- Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA
| | - M I Minervini
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - J Misdraji
- Massachusetts General Hospital, Boston, MA
| | - T Mohanakumar
- St. Joseph's Hospital and Medical Center, Norton Thoracic Institute, Phoenix, AZ
| | - J Mölne
- University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - I Nasser
- Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA
| | - J Neuberger
- Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | - M O'Neil
- University of Kansas Medical Center, Kansas City, KS
| | - O Pappo
- Hadassah Medical Center, Jerusalem, Israel
| | - L Petrovic
- University of Southern California, Los Angeles, CA
| | - P Ruiz
- University of Miami, Miami, FL
| | - Ö Sağol
- School of Medicine, Dokuz Eylul University, Izmir, Turkey
| | | | - E Sasatomi
- University of North Carolina School of Medicine, Chapel Hill, NC
| | - A Shaked
- University of Pennsylvania Health System, Philadelphia, PA
| | - M Shiller
- Baylor University Medical Center, Dallas, TX
| | - T Shimizu
- Toda Chuo General Hospital, Saitama, Japan
| | - B Sis
- University of Alberta Hospital, Edmonton, Canada
| | - A Sonzogni
- Pope John XXIII Hospital, Bergamo, Italy
| | | | - S N Thung
- Icahn School of Medicine at Mount Sinai, New York, NY
| | - G Tisone
- University of Rome-Tor Vergata, Rome, Italy
| | | | - A Wernerson
- Karolinska University Hospital, Stockholm, Sweden
| | - T Wu
- Tulane University School of Medicine, New Orleans, LA
| | - A Zeevi
- University of Pittsburgh, Pittsburgh, PA
| | - Y Zen
- Kobe University Hospital, Kobe, Japan
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11
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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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12
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Hickey MJ, Valenzuela NM, Reed EF. Alloantibody Generation and Effector Function Following Sensitization to Human Leukocyte Antigen. Front Immunol 2016; 7:30. [PMID: 26870045 PMCID: PMC4740371 DOI: 10.3389/fimmu.2016.00030] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 01/20/2016] [Indexed: 02/06/2023] Open
Abstract
Allorecognition is the activation of the adaptive immune system to foreign human leukocyte antigen (HLA) resulting in the generation of alloantibodies. Due to a high polymorphism, foreign HLA is recognized by the immune system following transplant, transfusion, or pregnancy resulting in the formation of the germinal center and the generation of long-lived alloantibody-producing memory B cells. Alloantibodies recognize antigenic epitopes displayed by the HLA molecule on the transplanted allograft and contribute to graft damage through multiple mechanisms, including (1) activation of the complement cascade resulting in the formation of the MAC complex and inflammatory anaphylatoxins, (2) transduction of intracellular signals leading to cytoskeletal rearrangement, growth, and proliferation of graft vasculature, and (3) immune cell infiltration into the allograft via FcγR interactions with the FC portion of the antibody. This review focuses on the generation of HLA alloantibody, routes of sensitization, alloantibody specificity, and mechanisms of antibody-mediated graft damage.
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Affiliation(s)
- Michelle J Hickey
- Department of Pathology and Laboratory Medicine, UCLA Immunogenetics Center, University of California Los Angeles , Los Angeles, CA , USA
| | - Nicole M Valenzuela
- Department of Pathology and Laboratory Medicine, UCLA Immunogenetics Center, University of California Los Angeles , Los Angeles, CA , USA
| | - Elaine F Reed
- Department of Pathology and Laboratory Medicine, UCLA Immunogenetics Center, University of California Los Angeles , Los Angeles, CA , USA
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13
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Cuadrado A, San Segundo D, López-Hoyos M, Crespo J, Fábrega E. Clinical significance of donor-specific human leukocyte antigen antibodies in liver transplantation. World J Gastroenterol 2015; 21:11016-11026. [PMID: 26494958 PMCID: PMC4607901 DOI: 10.3748/wjg.v21.i39.11016] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2015] [Revised: 06/29/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Antibody-mediated rejection (AMR) caused by donor-specific anti-human leukocyte antigen antibodies (DSA) is widely accepted to be a risk factor for decreased graft survival after kidney transplantation. This entity also plays a pathogenic role in other solid organ transplants as it appears to be an increasingly common cause of heart graft dysfunction and an emerging issue in lung transplantation. In contrast, the liver appears relatively resistant to DSA-mediated injury. This “immune-tolerance” liver property has been sustained by a low rate of liver graft loss in patients with preformed DSA and by the intrinsic liver characteristics that favor the absorption and elimination of DSA; however, alloantibody-mediated adverse consequences are increasingly being recognized, and several cases of acute AMR after ABO-compatible liver transplant (LT) have been reported. Furthermore, the availability of new solid-phase assays, allowing the detection of low titers of DSA and the refinement of objective diagnostic criteria for AMR in solid organ transplants and particularly in LT, have improved the recognition and management of this entity. A cost-effective strategy of DSA monitoring, avoidance of class II human leukocyte antigen mismatching, judicious immunosuppression attached to a higher level of clinical suspicion of AMR, particularly in cases unresponsive to conventional anti-rejection therapy, can allow a rational approach to this threat.
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Abstract
PURPOSE OF REVIEW Liver allograft antibody-mediated rejection (AMR) studies have lagged behind parallel efforts in kidney and heart because of a comparative inherent hepatic resistance to AMR. Three developments, however, have increased interest: first, solid phase antibody testing enabled more precise antibody characterization; second, increased expectations for long-term, morbidity-free survival; and third, immunosuppression minimization trials. RECENT FINDINGS Two overlapping liver allograft AMR phenotypic expressions are beginning to emerge: acute and chronic AMR. Acute AMR usually occurs within the several weeks after transplantation and characterized clinically by donor-specific antibodies (DSA) persistence, allograft dysfunction, thrombocytopenia, and hypocomplementemia. Acute AMR appears histopathologically similar to acute AMR in other organs: diffuse microvascular endothelial cell hypertrophy, C4d deposits, neutrophilic, eosinophilic, and macrophag-mediated microvasculitis/capillaritis, along with liver-specific ductular reaction, centrilobular hepatocyte swelling, and hepatocanalicular cholestasis often combined with T-cell-mediated rejection (TCMR). Chronic AMR is less well defined, but strongly linked to serum class II DSA and associated with late-onset acute TCMR, fibrosis, chronic rejection, and decreased survival. Unlike acute AMR, chronic AMR is a slowly evolving insult with a number of potential manifestations, but most commonly appears as low-grade lymphoplasmacytic portal and perivenular inflammation accompanied by unusual fibrosis patterns and variable microvascular C4d deposition; capillaritis can be more difficult to identify than in acute AMR. SUMMARY More precise DSA characterization, increasing expectations for long-term survival, and immunosuppression weaning precipitated a re-emergence of liver allograft AMR interest. Pathophysiological similarities exist between heart, kidney, and liver allografts, but liver-specific considerations may prove critical to our ultimate understanding of all solid organ AMR.
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15
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Sana G, Lombard C, Vosters O, Jazouli N, Andre F, Stephenne X, Smets F, Najimi M, Sokal EM. Adult human hepatocytes promote CD4(+) T-cell hyporesponsiveness via interleukin-10-producing allogeneic dendritic cells. Cell Transplant 2015; 23:1127-42. [PMID: 23582182 DOI: 10.3727/096368913x666421] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
The success of liver cell therapy remains closely dependent on how well the infused cells can be accepted after transplantation and is directly related to their degree of immunogenicity. In this study, we investigated the in vitro immunogenic properties of isolated human hepatocytes (hHeps) and adult-derived human liver progenitor cells (ADHLPCs), an alternative cell candidate for liver cell transplantation (LCT). The constitutive expression of immune markers was first analyzed on these liver-derived cells by flow cytometry. Human liver-derived cells were then cocultured with allogeneic human adult peripheral blood mononuclear cells (PBMCs), and the resulting activation and proliferation of PBMCs was evaluated, as well as the cytokine levels in the coculture supernatant. The effect of liver-derived cells on monocyte-derived dendritic cell (MoDC) properties was further analyzed in a secondary coculture with naive CD4(+) T-cells. We report that hHeps and ADHLPCs expressed human leukocyte antigen (HLA) class I and Fas but did not express HLA-DR, Fas ligand, and costimulatory molecules. hHeps and ADHLPCs did not induce T-cell activation or proliferation. Moreover, hHeps induced a cell contact-dependent production of interleukin (IL)-10 that was not observed with ADHLPCs. The IL-10 was produced by a myeloid DC subset characterized by an incomplete mature state. Furthermore, hHep-primed MoDCs induced an antigen-independent hyporesponsiveness of naive CD4(+) T lymphocytes that was partially reversed by blocking IL-10, whereas nonprimed MoDCs (i.e., those cultured alone) did not. hHeps and ADHLPCs present a low immunogenic phenotype in vitro. Allogeneic hHeps, but not ADHLPCs, promote a cell contact-dependent production of IL-10 by myeloid DCs, which induces naive CD4(+) T-cells antigen-independent hyporesponsiveness.
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Affiliation(s)
- Gwenaëlle Sana
- Université Catholique de Louvain and Cliniques Universitaires Saint-Luc, Laboratory of Pediatric Hepatology and Cell Therapy, Brussels, Belgium
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16
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Association of Anti-Human Leukocyte Antigen and Anti-Angiotensin II Type 1 Receptor Antibodies With Liver Allograft Fibrosis After Immunosuppression Withdrawal. Transplantation 2014; 98:1105-11. [DOI: 10.1097/tp.0000000000000185] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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17
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Urahashi T, Mizuta K, Ihara Y, Sanada Y, Wakiya T, Yamada N, Okada N. Impact of post-transplant flow cytometric panel-reactive antibodies on late-onset hepatic venous outflow obstruction following pediatric living donor liver transplantation. Transpl Int 2014; 27:322-9. [DOI: 10.1111/tri.12255] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Revised: 04/30/2013] [Accepted: 11/28/2013] [Indexed: 12/22/2022]
Affiliation(s)
- Taizen Urahashi
- Department of Transplant Surgery; Jichi Medical University; Shimotsuke-shi Japan
| | - Koichi Mizuta
- Department of Transplant Surgery; Jichi Medical University; Shimotsuke-shi Japan
| | - Yoshiyuki Ihara
- Department of Transplant Surgery; Jichi Medical University; Shimotsuke-shi Japan
| | - Yukihiro Sanada
- Department of Transplant Surgery; Jichi Medical University; Shimotsuke-shi Japan
| | - Taiichi Wakiya
- Department of Transplant Surgery; Jichi Medical University; Shimotsuke-shi Japan
| | - Naoya Yamada
- Department of Transplant Surgery; Jichi Medical University; Shimotsuke-shi Japan
| | - Noriki Okada
- Department of Transplant Surgery; Jichi Medical University; Shimotsuke-shi Japan
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18
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Kaneku H, O'Leary JG, Banuelos N, Jennings LW, Susskind BM, Klintmalm GB, Terasaki PI. De novo donor-specific HLA antibodies decrease patient and graft survival in liver transplant recipients. Am J Transplant 2013. [PMID: 23721554 DOI: 10.1111/ajt.12212] [Citation(s) in RCA: 196] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The role of de novo donor-specific HLA antibodies (DSA) in liver transplantation remains unknown as most of the previous studies have only focused on preformed HLA antibodies. To understand the significance of de novo DSA, we designed a retrospective cohort study of 749 adult liver transplant recipients with pre- and posttransplant serum samples that were analyzed for DSA. We found that 8.1% of patients developed de novo DSA 1 year after transplant; almost all de novo DSAs were against HLA class II antigens, and the majority were against DQ antigens. In multivariable modeling, the use of cyclosporine (as opposed to tacrolimus) and low calcineurin inhibitor levels increased the risk of de novo DSA formation, while a calculated MELD score >15 at transplant and recipient age >60 years old reduced the risk. Multivariable analysis also demonstrated that patients with de novo DSA at 1-year had significantly lower patient and graft survival. In conclusion, we demonstrate that de novo DSA development after liver transplantation is an independent risk factor for patient death and graft loss.
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Affiliation(s)
- H Kaneku
- University of California, Los Angeles, Los Angeles, CA, USA.
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19
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Kaneku H, O’Leary JG, Banuelos N, Jennings LW, Susskind BM, Klintmalm GB, Terasaki PI. De novo donor-specific HLA antibodies decrease patient and graft survival in liver transplant recipients. Am J Transplant 2013; 13:1541-8. [PMID: 23721554 PMCID: PMC4408873 DOI: 10.1002/ajt.12212] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Revised: 01/16/2013] [Accepted: 02/04/2013] [Indexed: 01/25/2023]
Abstract
The role of de novo donor-specific HLA antibodies (DSA) in liver transplantation remains unknown as most of the previous studies have only focused on preformed HLA antibodies. To understand the significance of de novo DSA, we designed a retrospective cohort study of 749 adult liver transplant recipients with pre- and posttransplant serum samples that were analyzed for DSA. We found that 8.1% of patients developed de novo DSA 1 year after transplant; almost all de novo DSAs were against HLA class II antigens, and the majority were against DQ antigens. In multivariable modeling, the use of cyclosporine (as opposed to tacrolimus) and low calcineurin inhibitor levels increased the risk of de novo DSA formation, while a calculated MELD score >15 at transplant and recipient age >60 years old reduced the risk. Multivariable analysis also demonstrated that patients with de novo DSA at 1-year had significantly lower patient and graft survival. In conclusion, we demonstrate that de novo DSA development after liver transplantation is an independent risk factor for patient death and graft loss.
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Affiliation(s)
- H. Kaneku
- University of California, Los Angeles, Los Angeles, CA,Corresponding author: Hugo Kaneku,
| | - J. G. O’Leary
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX
| | - N. Banuelos
- Terasaki Foundation Laboratory, Los Angeles, CA
| | - L. W. Jennings
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX
| | - B. M. Susskind
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX
| | - G. B. Klintmalm
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX
| | - P. I. Terasaki
- University of California, Los Angeles, Los Angeles, CA,Terasaki Foundation Laboratory, Los Angeles, CA
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20
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Acute cellular rejection in intra-abdominal solid organ allografts – immunology under the light microscope. ACTA ACUST UNITED AC 2012. [DOI: 10.1016/j.mpdhp.2012.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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21
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Dar W, Agarwal A, Watkins C, Gebel HM, Bray RA, Kokko KE, Pearson TC, Knechtle SJ. Donor-directed MHC class I antibody is preferentially cleared from sensitized recipients of combined liver/kidney transplants. Am J Transplant 2011; 11:841-7. [PMID: 21446981 DOI: 10.1111/j.1600-6143.2011.03467.x] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
For patients with chronic renal and liver diseases, simultaneous liver and kidney transplantation (SLKT) is the best therapeutic option. The role of a pretransplant donor-specific antibody (DSA) in SLKT is unclear. We report the results of a retrospective review from 7/08 to 10/09 of SLKT at our institution. Monitoring of DSA was performed using single antigen bead assay. Between 7/08 and 10/09, there were six SLKT who had preformed DSA and positive XM (four class I and II DSA, one class I DSA only, one class II only). One-year patient and renal graft survival was 83%. Death-censored liver allograft survival was 100%. Acute humoral rejection (AHR) of the kidney occurred in 66% (three with both class I and II DSA and one with only class II DSA) of patients. In those with AHR, class I antibodies were rapidly cleared (p < 0.01) while class II antibodies persisted (p = 0.25). All patients who had humoral rejection of their kidney had preformed anticlass II antibodies. Liver allografts may not be fully protective of the renal allograft, especially with pre-existing MHC class II DSA. Long-term and careful follow-up will be critical to determine the impact of DSA on both allografts.
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Affiliation(s)
- W Dar
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
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22
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Musat A, Agni R, Wai P, Pirsch J, Lorentzen D, Powell A, Leverson G, Bellingham J, Fernandez L, Foley D, Mezrich J, D'Alessandro A, Lucey M. The significance of donor-specific HLA antibodies in rejection and ductopenia development in ABO compatible liver transplantation. Am J Transplant 2011; 11:500-10. [PMID: 21342448 PMCID: PMC3357120 DOI: 10.1111/j.1600-6143.2010.03414.x] [Citation(s) in RCA: 142] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The role of humoral alloreactivity in ABO-compatible liver transplantation remains unclear. To understand the significance of donor-specific HLA alloantibodies (DSA) in liver rejection, we applied the currently used strategy for detection of antibody-mediated rejection of other solid allografts. For this purpose we reviewed the data on 43 recipients of ABO identical/compatible donor livers who had indication liver biopsy stained for complement element C4d and contemporaneous circulating DSA determination. Seventeen (40%) patients had significant circulating DSA in association with diffuse portal C4d deposition (DSA+/diffuse C4d+). These DSA+/diffuse C4d+ subjects had higher frequency of acute cellular rejection (ACR) 15/17 versus 13/26 (88% vs. 50%), p = 0.02, and steroid resistant rejection 7/17 versus 5/26 (41% vs. 19%), p = 0.03. Based on detection of the combination DSA+/diffuse C4d+, 53.6% of cases of ACR had evidence of concurrent humoral alloreactivity. Six of the 10 patients with ductopenic rejection had circulating DSA and diffuse portal C4d, three of whom (2 early and 1 late posttransplantation) developed unrelenting cholestasis, necessitating specific antibody-depleting therapy to salvage the allografts. Thus, in ABO-compatible liver transplantation humoral alloreactivity mediated by antibodies against donor HLA molecules appears to be frequently intertwined with cellular mechanisms of rejection, and to play a role in ductopenia development.
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Affiliation(s)
- A.I. Musat
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI,Corresponding author: Alexandru I. Musat,
| | - R.M. Agni
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - P.Y. Wai
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - J.D. Pirsch
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - D.F. Lorentzen
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - A. Powell
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - G.E. Leverson
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - J.M. Bellingham
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - L.A. Fernandez
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - D.P. Foley
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - J.D. Mezrich
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - A.M. D'Alessandro
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - M.R. Lucey
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
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23
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Kim MJ, Romero R, Kim CJ, Tarca AL, Chhauy S, LaJeunesse C, Lee DC, Draghici S, Gotsch F, Kusanovic JP, Hassan SS, Kim JS. Villitis of unknown etiology is associated with a distinct pattern of chemokine up-regulation in the feto-maternal and placental compartments: implications for conjoint maternal allograft rejection and maternal anti-fetal graft-versus-host disease. THE JOURNAL OF IMMUNOLOGY 2009; 182:3919-27. [PMID: 19265171 DOI: 10.4049/jimmunol.0803834] [Citation(s) in RCA: 151] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The co-presence of histoincompatible fetal and maternal cells is a characteristic of human placental inflammation. Villitis of unknown etiology (VUE), a destructive inflammatory lesion of villous placenta, is characterized by participation of Hofbauer cells (placental macrophages) and maternal T cells. In contrast to acute chorioamnionitis of infection-related origin, the fundamental immunopathology of VUE is unknown. This study was performed to investigate the placental transcriptome of VUE and to determine whether VUE is associated with systemic maternal and/or fetal inflammatory response(s). Comparison of the transcriptome between term placentas without and with VUE revealed differential expression of 206 genes associated with pathways related to immune response. The mRNA expression of a subset of chemokines and their receptors (CXCL9, CXCL10, CXCL11, CXCL13, CCL4, CCL5, CXCR3, CCR5) was higher in VUE placentas than in normal placentas (p < 0.05). Analysis of blood cell mRNA showed a higher expression of CXCL9 and CXCL13 in the mother, and CXCL11 and CXCL13 in the fetus of VUE cases (p < 0.05). The median concentrations of CXCL9, CXCL10, and CXCL11 in maternal and fetal plasma were higher in VUE (p < 0.05). Comparison of preterm cases without and with acute chorioamnionitis revealed elevated CXCL9, CXCL10, CXCL11, and CXCL13 concentrations in fetal plasma (p < 0.05), but not in maternal plasma with chorioamnionitis. We report for the first time the placental transcriptome of VUE. A systemic derangement of CXC chemokines in maternal and fetal circulation distinguishes VUE from acute chorioamnionitis. We propose that VUE be a unique state combining maternal allograft rejection and maternal antifetal graft-vs-host disease mechanisms.
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Affiliation(s)
- Mi Jeong Kim
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892 and Detroit, MI 48201, USA
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24
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Sakashita H, Haga H, Ashihara E, Wen MC, Tsuji H, Miyagawa-Hayashino A, Egawa H, Takada Y, Maekawa T, Uemoto S, Manabe T. Significance of C4d staining in ABO-identical/compatible liver transplantation. Mod Pathol 2007; 20:676-84. [PMID: 17431411 DOI: 10.1038/modpathol.3800784] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Complement degradation product C4d has become an important marker of humoral or antibody-mediated rejection in renal and heart allograft biopsies. Although there have been several reports on the detection of C4d in liver allografts, the significance of C4d in liver transplantation and its relationship with humoral rejection are still not clear. We investigated the frequency and pattern of C4d staining in liver allograft biopsies with reference to preoperative lymphocyte crossmatch tests, which detect donor-reactive lymphocyte antibody. Survival rates at 5 years were 77% for crossmatch-negative patients and 53% for crossmatch-positive patients (P=0.009). In crossmatch-negative patients, reproducible positive staining was obtained in 28 of 86 (33%) biopsies taken within 90 days after transplantation and 33 of 96 (34%) biopsies 90 days or after transplantation. Most C4d staining was observed in the portal areas, and no clear correlation was observed between C4d positivity and histological diagnosis. In crossmatch-positive patients, 9 of 11 (82%) biopsies showed positivity for C4d. C4d stained perivenular areas as well as portal areas. Histology of crossmatch-positive patients included acute rejection and cholangitis, but did not include periportal changes that were seen in humoral rejection in ABO-incompatible liver transplantation. In summary, focal C4d deposition was seen in various types of liver allograft injury and had little clinical impact on crossmatch-negative patients, but extensive C4d staining in crossmatch-positive patients may be associated with humoral rejection and poor graft survival.
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Affiliation(s)
- Hiromi Sakashita
- Laboratory of Diagnostic Pathology, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan
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25
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Affiliation(s)
- S G Hübscher
- Department of Pathology, University of Birmingham, UK.
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Abstract
Although it has been known for many years that the liver receives a nerve supply, it is only with the advent of immunohistochemistry that this innervation has been analysed in depth. It is now appreciated not only that many different nerve types are present, but also that there are significant differences between species, especially in the degree of parenchymal innervation. This has stimulated more detailed investigation of the innervation of the human liver in both health and disease. At the same time, functional studies have been underlining the important roles that these nerves play in processes as diverse as osmoreception and liver regeneration. This article briefly reviews current understanding of the morphology and functions of the hepatic nerve supply.
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Affiliation(s)
- D G Tiniakos
- Department of Pathology, University of Patras, Greece
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Adams DH, Hubscher S, Fear J, Johnston J, Shaw S, Afford S. Hepatic expression of macrophage inflammatory protein-1 alpha and macrophage inflammatory protein-1 beta after liver transplantation. Transplantation 1996; 61:817-25. [PMID: 8607189 DOI: 10.1097/00007890-199603150-00024] [Citation(s) in RCA: 76] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Two local events that are crucial for T cell emigration into tissue are (1) activation of T cell integrins to permit binding to endothelial counter-receptors and (2) directed migration through the endothelium and into tissue in response to chemotactic factors. Because the chemokines macrophage inflammatory protein-1 alpha (MIP-1 alpha) and MIP-1 beta can activate adhesion and induce migration of T cells in vitro, we investigated their expression in human liver allografts to determine whether they might be involved in regulating the recruitment of T cells to allografts in vivo. Both chemokines were expressed strongly by infiltrating leukocytes during rejection and could be detected immunohistochemically on biliary epithelium, an important target for T cell mediated graft damage. Both chemokines, but particularly MIP-1 beta, were detected on the vascular and sinusoidal endothelium of rejecting liver allografts, where they were coexpressed with the T cell beta 1-integrin receptor vascular cell adhesion molecule-1. In situ hybridization with complementary ribonucleic acid probes showed no MIP-1 alpha or MIP-1 beta mRNA in normal liver but dramatic expression of both chemokines in infiltrating leukocytes and graft endothelium during rejection. Expression was reduced after successful corticosteroid treatment of rejection but persisted in patients progressing to chronic rejection. Increased MIP-1 alpha and MIP-1 beta mRNA expression was already found in biopsies taken at the end of the transplant operation, suggesting that early induction of chemokines, possibly in response to graft reperfusion, might promote the subsequent development of graft rejection. These data demonstrate for the first time that MIP-1 alpha and MIP-1 beta are (1) expressed in human liver allografts, (2) produced by endothelial cells in vivo, and (3) induced early after transplantation. They suggest that MIP-1 alpha and MIP-1 beta produced by graft infiltrating leukocytes and graft endothelium might play a crucial role in regulating T cell recruitment to liver allografts in vivo.
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Affiliation(s)
- D H Adams
- The Liver Unit Research Laboratories, Queen Elizabeth Hospital, Birmingham, United Kingdom
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Boon AP, Hubscher SG, Lee JA, Hines JE, Burt AD. Hepatic reinnervation following orthotopic liver transplantation in man. J Pathol 1992; 167:217-22. [PMID: 1386107 DOI: 10.1002/path.1711670210] [Citation(s) in RCA: 31] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
We have studied changes in the pattern of intrinsic hepatic innervation in sequential liver biopsies from 16 patients who underwent orthotopic liver transplantation. Seventy-one needle biopsies were used, including specimens obtained at the time of transplantation (time zero) and up to 4 years post-transplantation; five transplant hepatectomy tissue blocks removed 3-32 months after transplantation were also assessed. Paraffin sections were immunostained with anti-PGP 9.5 and anti-S-100 to identify nerve fibres. All 'time zero' biopsies contained portal nerves and all but two showed staining of parenchymal fibres. After 1 week, no subsequent biopsies contained parenchymal fibres. The disappearance of portal fibres was less rapid and showed greater variability between patients, but they had all disappeared by 6 weeks and there was no positive staining between 6 and 60 weeks. Thereafter, a minority of biopsies showed innervation of a few small portal tracts. Samples from the porta hepatis, hepatectomy specimens, and needle biopsies containing large tracts showed persistence of major nerve trunks at all stages. Abnormally large nerve bundles were seen in some of these areas. The pattern of nerve staining showed no obvious relationship to the intensity of rejection changes. Our results suggest that there is a limited, delayed capacity for regeneration of portal, but not parenchymal, fibres in the transplanted human liver. The physiological significance of this long-term parenchymal denervation in transplanted livers remains to be determined.
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Affiliation(s)
- A P Boon
- Department of Histopathology, St Jame's University Hospital, Leeds, U.K
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Hubscher SG. Histological findings in liver allograft rejection--new insights into the pathogenesis of hepatocellular damage in liver allografts. Histopathology 1991; 18:377-83. [PMID: 2071098 DOI: 10.1111/j.1365-2559.1991.tb00865.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- S G Hubscher
- Department of Pathology, University of Birmingham Medical School, UK
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