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Altundaş N, Balkan E, Kizilkaya M, Aksungur N, Kara S, Demirci E, Korkut E, Öztürk G, Dursun H. Effects of de novo donor-specific Class I and II antibodies on graft outcomes after liver transplantation: A pilot cohort study. Open Life Sci 2025; 20:20251078. [PMID: 40129472 PMCID: PMC11931657 DOI: 10.1515/biol-2025-1078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 01/17/2025] [Accepted: 02/11/2025] [Indexed: 03/26/2025] Open
Abstract
This study investigates the role of donor-specific antibodies (DSAs) in liver transplantation outcomes, focusing on their effects on liver damage. Ninety-four patients who underwent liver transplantation between 2019 and 2024 at Atatürk University were included. DSA testing was performed using the Luminex QIAGEN LifeCodes method. Patient demographic data, laboratory results, clinical conditions, and biopsy findings were analyzed. Disease-specific analyses were conducted for Wilson's disease, autoimmune hepatitis, hepatocellular carcinoma (HCC), and hepatitis B virus (HBV). Due to the limited sample size, larger validation studies are needed, and the impact of the COVID-19 pandemic on the data collection process was considered. At the end of 1 year, persistent DSA had no significant effect on liver damage. However, early DSA positivity, particularly persistence and titration, requires further investigation. In Wilson's disease, two DSA-positive patients (mean fluorescence intensity [MFI] 1,000-1,500) showed no damage. Among autoimmune hepatitis patients, 5 of 19 were DSA positive (MFI 1,700-5,600), with no detected damage. Four HCC patients were DSA positive (MFI 1,300-2,200). Among HBV patients, 12 of 31 were DSA positive, and 5 experienced liver damage. Tacrolimus levels in the third month were statistically associated with bilirubin levels. Prospective studies are needed to further clarify the clinical significance of DSA.
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Affiliation(s)
- Necip Altundaş
- Department of General Surgery, Atatürk University, 25240, Erzurum, Turkey
| | - Eda Balkan
- Department of Medical Biology, Faculty of Medicine, Atatürk University, 21 Lalapaşa, 25240, Erzurum, Turkey
| | - Murat Kizilkaya
- Department of Medical Biology, Faculty of Medicine, Atatürk University, 21 Lalapaşa, 25240, Erzurum, Turkey
| | - Nurhak Aksungur
- Department of General Surgery, Atatürk University, 25240, Erzurum, Turkey
| | - Salih Kara
- Department of General Surgery, Atatürk University, 25240, Erzurum, Turkey
| | - Elif Demirci
- Department of Pathology, Atatürk University, 25240, Erzurum, Turkey
| | - Ercan Korkut
- Department of General Surgery, Atatürk University, 25240, Erzurum, Turkey
| | - Gürkan Öztürk
- Department of General Surgery, Atatürk University, 25240, Erzurum, Turkey
| | - Hakan Dursun
- Department of Internal Medicine, Atatürk University, 25240, Erzurum, Turkey
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Jang E, Youn J. Contribution of long-lived plasma cells to antibody-mediated allograft rejection. CLINICAL TRANSPLANTATION AND RESEARCH 2024; 38:341-353. [PMID: 39690904 PMCID: PMC11732765 DOI: 10.4285/ctr.24.0047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/15/2024] [Accepted: 11/15/2024] [Indexed: 12/19/2024]
Abstract
Persistent alloantigens derived from allograft tissues can be recognized by the host's alloreactive immune system. This process enables cognate B cells to differentiate into plasma cells, which secrete donor-specific antibodies that are key drivers of antibody-mediated allograft rejection. A subset of these plasma cells can survive for extended periods in a suitable survival niche and mature into long-lived plasma cells (LLPCs), which are a cellular component of humoral memory. The current understanding of LLPCs is limited due to their scarcity, heterogeneity, and absence of unique markers. However, accumulating evidence indicates that LLPCs, unlike conventional short-lived plasma cells, can respond to extrinsic signals from their survival niches and can resist cell death associated with intracellular stress through cell-intrinsic mechanisms. Notably, they are refractory to traditional immunosuppressants and B cell depletion therapies. This resistance, coupled with their longevity, may explain why current treatments targeting antibody-mediated rejection are often ineffective. This review offers insights into the biology of LLPCs and discusses ongoing therapeutic trials that target LLPCs in the context of antibody-mediated allograft rejection.
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Affiliation(s)
- Eunkyeong Jang
- Laboratory of Autoimmunology, Department of Anatomy and Cell Biology, Hanyang University College of Medicine, Seoul, Korea
| | - Jeehee Youn
- Laboratory of Autoimmunology, Department of Anatomy and Cell Biology, Hanyang University College of Medicine, Seoul, Korea
- Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
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Morris AB, Achram R, Cliff Sullivan H, Gebel HM, Bray RA. Hiding in plain sight: Misinterpretation of immunogenic DPB epitopes within G/P groups. Hum Immunol 2024; 85:111115. [PMID: 39277973 DOI: 10.1016/j.humimm.2024.111115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 07/18/2024] [Accepted: 09/07/2024] [Indexed: 09/17/2024]
Abstract
The clinical impact of HLA DP antibodies is poorly understood, resulting in variable clinical strategies for transplant candidates and recipients with donor-directed HLA-DP antibodies. Complicating matters further, the DPB naming convention is not based on allelic homology and requires sequence alignments to identify potential immunogenic epitopes. Historically, G and P codes, which consolidated alleles that were identical over Exon 2, were used to simplify the reporting of HLA Class II typing as differences outside of Exon 2 have not been considered immunogenic (i.e., able to induce an antibody response). Herein, we present four cases demonstrating that polymorphisms at codons 96R/K and 170I/T, in Exon 3 of DPB, are targets for alloantibody recognition. These regions "hide in plain sight" due to the current use of G/P code-level typing, potentially leading to incorrect compatibility assessments (i.e., virtual crossmatches) and misinterpreted antibody responses. The unintentional crossing of an HLA-DPB donor-specific antibody (DSA) in a solid organ or hematopoietic stem cell transplant may lead to unforeseen deleterious clinical outcomes. Our data underscore the complexities of DPB histocompatibility assessments and highlight the need for adaptable systems that align with evolving research and clinical outcomes.
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Affiliation(s)
- Anna B Morris
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
| | - Robert Achram
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
| | - H Cliff Sullivan
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
| | - Howard M Gebel
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
| | - Robert A Bray
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
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Melere MU, Feier FH, Neumann J, Kalil AN, Montagner JDM, Nader LS, da Silva CS, Junior MAF, Coral GP, Bobsin GP, Ferreira CT. Human leukocyte antigen compatibility and incidence of donor-specific antibodies in pediatric liver transplant recipients. World J Gastroenterol 2024; 30:3837-3845. [PMID: 39351427 PMCID: PMC11438625 DOI: 10.3748/wjg.v30.i33.3837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 08/01/2024] [Accepted: 08/20/2024] [Indexed: 09/02/2024] Open
Abstract
BACKGROUND Antibody-mediated rejection following liver transplantation (LT) has been increasingly recognized, particularly with respect to the emergence of de novo donor-specific antibodies (DSAs) and their impact on graft longevity. While substantial evidence for adult populations exists, research focusing on pediatric LT outcomes remains limited. AIM To investigate the prevalence of human leukocyte antigen (HLA) mismatches and DSA and evaluate their association with rejection episodes after pediatric LT. METHODS A cohort of pediatric LT recipients underwent HLA testing at Santa Casa de Porto Alegre, Brazil, between December 2013 and December 2023. Only patients who survived for > 30 days after LT with at least one DSA analysis were included. DSA classes I and II and cross-matches were analyzed. The presence of de novo DSA (dnDSA) was evaluated at least 3 months after LT using the Luminex® single antigen bead method, with a positive reaction threshold set at 1000 MFI. Rejection episodes were confirmed by liver biopsy. RESULTS Overall, 67 transplanted children were analyzed; 61 received grafts from living donors, 85% of whom were related to recipients. Pre-transplant DSA (class I or II) was detected in 28.3% of patients, and dnDSA was detected in 48.4%. The median time to DSA detection after LT was 19.7 [interquartile range (IQR): 4.3-35.6] months. Biopsy-proven rejection occurred in 13 patients at follow-up, with C4d positivity observed in 5/13 Liver biopsies. The median time to rejection was 7.8 (IQR: 5.7-12.8) months. The presence of dnDSA was significantly associated with rejection (36% vs 3%, P < 0.001). The rejection-free survival rates at 12 and 24 months were 76% vs 100% and 58% vs 95% for patients with dnDSA anti-DQ vs those without, respectively. CONCLUSION Our findings highlight the importance of incorporating DSA assessment into pre- and post-transplantation protocols for pediatric LT recipients. Future implications may include immunosuppression minimization strategies based on this analysis in pediatric LT recipients.
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Affiliation(s)
- Melina U Melere
- Department of Hepatology and Liver Transplantation, Santa Casa de Porto Alegre, Porto Alegre 90050170, Rio Grande do Sul, Brazil
| | - Flavia H Feier
- Department of Hepato-biliary-pancreatic Surgery and Liver Transplantation, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Rio Grande do Sul, Brazil
- Postgraduation Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Rio Grande do Sul, Brazil
| | - Jorge Neumann
- Laboratory of Transplantation Immunology, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Rio Grande do Sul, Brazil
| | - Antônio N Kalil
- Department of Hepato-biliary-pancreatic Surgery and Liver Transplantation, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Rio Grande do Sul, Brazil
- Postgraduation Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Rio Grande do Sul, Brazil
| | - Juliana de M Montagner
- Laboratory of Transplantation Immunology, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Rio Grande do Sul, Brazil
| | - Luiza S Nader
- Department of Hepatology and Liver Transplantation, Santa Casa de Porto Alegre, Porto Alegre 90050170, Rio Grande do Sul, Brazil
| | - Carolina S da Silva
- Department of Hepatology and Liver Transplantation, Santa Casa de Porto Alegre, Porto Alegre 90050170, Rio Grande do Sul, Brazil
| | - Marco Aurélio F Junior
- Department of Hepatology and Liver Transplantation, Santa Casa de Porto Alegre, Porto Alegre 90050170, Rio Grande do Sul, Brazil
| | - Gabriela P Coral
- Department of Hepatology and Liver Transplantation, Santa Casa de Porto Alegre, Porto Alegre 90050170, Rio Grande do Sul, Brazil
- Postgraduation Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Rio Grande do Sul, Brazil
| | - Guilherme P Bobsin
- Department of Hepatology and Liver Transplantation, Santa Casa de Porto Alegre, Porto Alegre 90050170, Rio Grande do Sul, Brazil
| | - Cristina T Ferreira
- Department of Hepatology and Liver Transplantation, Santa Casa de Porto Alegre, Porto Alegre 90050170, Rio Grande do Sul, Brazil
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Berg T, Aehling NF, Bruns T, Welker MW, Weismüller T, Trebicka J, Tacke F, Strnad P, Sterneck M, Settmacher U, Seehofer D, Schott E, Schnitzbauer AA, Schmidt HH, Schlitt HJ, Pratschke J, Pascher A, Neumann U, Manekeller S, Lammert F, Klein I, Kirchner G, Guba M, Glanemann M, Engelmann C, Canbay AE, Braun F, Berg CP, Bechstein WO, Becker T, Trautwein C. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1397-1573. [PMID: 39250961 DOI: 10.1055/a-2255-7246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Affiliation(s)
- Thomas Berg
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Niklas F Aehling
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Tony Bruns
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martin-Walter Welker
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin. Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Tobias Weismüller
- Klinik für Innere Medizin - Gastroenterologie und Hepatologie, Vivantes Humboldt-Klinikum, Berlin, Deutschland
| | - Jonel Trebicka
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Deutschland
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Pavel Strnad
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martina Sterneck
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - Utz Settmacher
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Jena, Deutschland
| | - Daniel Seehofer
- Klinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Eckart Schott
- Klinik für Innere Medizin II - Gastroenterologie, Hepatologie und Diabetolgie, Helios Klinikum Emil von Behring, Berlin, Deutschland
| | | | - Hartmut H Schmidt
- Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Essen, Essen, Deutschland
| | - Hans J Schlitt
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg, Regensburg, Deutschland
| | - Johann Pratschke
- Chirurgische Klinik, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - Andreas Pascher
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Münster, Münster, Deutschland
| | - Ulf Neumann
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Essen, Deutschland
| | - Steffen Manekeller
- Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Bonn, Bonn, Deutschland
| | - Frank Lammert
- Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - Ingo Klein
- Chirurgische Klinik I, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - Gabriele Kirchner
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg und Innere Medizin I, Caritaskrankenhaus St. Josef Regensburg, Regensburg, Deutschland
| | - Markus Guba
- Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Universitätsklinikum München, München, Deutschland
| | - Matthias Glanemann
- Klinik für Allgemeine, Viszeral-, Gefäß- und Kinderchirurgie, Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - Cornelius Engelmann
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Ali E Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - Felix Braun
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
| | - Christoph P Berg
- Innere Medizin I Gastroenterologie, Hepatologie, Infektiologie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Wolf O Bechstein
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Thomas Becker
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
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Norman DJ, Enestvedt CK, Naugler WE, Erhan R, Shaut CA. The fate of anti-HLA antibodies following liver transplantation. FRONTIERS IN NEPHROLOGY 2024; 4:1403096. [PMID: 38933742 PMCID: PMC11199851 DOI: 10.3389/fneph.2024.1403096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 05/13/2024] [Indexed: 06/28/2024]
Abstract
Introduction Liver transplant recipients may have pre-formed anti-HLA antibodies directed to mismatched HLA of the liver donor (donor specific antibodies, DSA) or not directed to the liver donor (non-donor specific, non-DSA). We observed the fate of these antibodies (DSA and non-DSA) at 12 months after transplant. Methods Patients transplanted between 4/2015 and 12/2018 (N = 216) who had anti-HLA antibody measurements at both transplant and 12 months posttransplant (N = 124) and with DSAs at transplant (N = 31) were considered informative for a paired analysis of the natural history of DSA and non-DSA following liver transplantation. Results Class I DSAs and non-DSAs decreased between transplant and 12 months; however, Class I DSAs essentially disappeared by 12 months while Class I non-DSAs did not. Anti-HLA Class II DSAs performed differently. While there was a significant drop in values between transplant and 12 months, these antibodies mostly persisted at a low level. Discussion Our study demonstrated a significant difference in the kinetics of DSA compared to non-DSA following liver transplantation, most profoundly for anti-HLA Class I antibodies. Class I DSAs were mostly absent at 12 months while Class II DSAs persisted, although at lower levels. The mechanisms of reduction in anti-HLA antibodies following liver transplantation are not completely understood and were not pursued as a part of this study. This detailed analysis of Class I and Class II DSAs and non-DSAs represents and important study to explore the change in antibodies at one year from liver transplantation.
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Affiliation(s)
- Douglas J. Norman
- Laboratory of Immunogenetics and Transplantation, Oregon Health & Science University, Portland, OR, United States
- Section of Transplantation Medicine, Division of Nephrology, Department of Medicine, Oregon Health & Science University, Portland, OR, United States
| | - C. Kristian Enestvedt
- Division of Abdominal Organ Transplantation, Department of Surgery, Oregon Health & Science University, Portland, OR, United States
| | - Willscott E. Naugler
- Division of Gastroenterology and Hepatology, Department of Medicine, Oregon Health & Science University, Portland, OR, United States
| | - Rouella Erhan
- Laboratory of Immunogenetics and Transplantation, Oregon Health & Science University, Portland, OR, United States
| | - Carley A. Shaut
- Laboratory of Immunogenetics and Transplantation, Oregon Health & Science University, Portland, OR, United States
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Demir Z, Raynaud M, Aubert O, Debray D, Sebagh M, Duong Van Huyen JP, Del Bello A, Jolivet NC, Paradis V, Durand F, Muratot S, Lozach C, Chardot C, Francoz C, Kamar N, Sarnacki S, Coilly A, Samuel D, Vibert E, Féray C, Lefaucheur C, Loupy A. Identification of liver transplant biopsy phenotypes associated with distinct liver biological markers and allograft survival. Am J Transplant 2024; 24:954-966. [PMID: 38097016 DOI: 10.1016/j.ajt.2023.12.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 11/07/2023] [Accepted: 12/06/2023] [Indexed: 01/01/2024]
Abstract
The intricate association between histologic lesions and circulating antihuman leucocyte antigen donor-specific antibodies (DSA) in liver transplantation (LT) requires further clarification. We conducted a probabilistic, unsupervised approach in a comprehensively well-annotated LT cohort to identify clinically relevant archetypes. We evaluated 490 pairs of LT biopsies with DSA testing from 325 recipients transplanted between 2010 and 2020 across 3 French centers and an external cohort of 202 biopsies from 128 recipients. Unsupervised archetypal analysis integrated all clinico-immuno-histologic parameters of each biopsy to identify biopsy archetypes. The median time after LT was 1.17 (interquartile range, 0.38-2.38) years. We identified 7 archetypes distinguished by clinico-immuno-histologic parameters: archetype #1: severe T cell-mediated rejection (15.9%); #2: chronic rejection with ductopenia (1.8%); #3: architectural and microvascular damages (3.5%); #4: (sub)normal (55.9%); #5: mild T cell-mediated rejection (4.9%); #6: acute antibody-mediated rejection (6.5%); and #7: chronic rejection with DSA (11.4%). Cell infiltrates vary in the archetype. These archetypes were associated with distinct liver biological markers and allograft outcomes. These findings remained consistent when stratified using the patient's age or indications for LT, with good performance in the external cohort (mean highest probability assignment = 0.58, standard deviation ± 0.17). In conclusion, we have identified clinically meaningful archetypes, providing valuable insights into the intricate DSA-histology association, which may help standardize liver allograft pathology classification.
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Affiliation(s)
- Zeynep Demir
- Paris Translational Research Center for Organ Transplantation, Université de Paris Cité, INSERM, PARCC, Paris, France
| | - Marc Raynaud
- Paris Translational Research Center for Organ Transplantation, Université de Paris Cité, INSERM, PARCC, Paris, France
| | - Olivier Aubert
- Paris Translational Research Center for Organ Transplantation, Université de Paris Cité, INSERM, PARCC, Paris, France; Kidney Transplantation Department, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Dominique Debray
- Pediatric Hepatology and Liver Transplantation Unit, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Mylène Sebagh
- Pathology Department Paul-Brousse Hospital, Assistance Publique - Hôpitaux de Paris, Villejuif, France
| | - Jean-Paul Duong Van Huyen
- Pathology Department, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Arnaud Del Bello
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Nicolas Congy Jolivet
- Department of Immunology, Hôpital de Rangueil, CHU de Toulouse, Molecular Immunogenetics Laboratory, EA 3034, IFR150 (INSERM), Toulouse, France
| | - Valérie Paradis
- Pathology Department, Beaujon Hospital, Assistance Publique - Hôpitaux de Paris, Clichy, France
| | - François Durand
- Hepatology Department, Beaujon Hospital, Assistance Publique - Hôpitaux de Paris, Clichy, France
| | - Sophie Muratot
- Paris Translational Research Center for Organ Transplantation, Université de Paris Cité, INSERM, PARCC, Paris, France
| | - Cécile Lozach
- Department of Pediatric Radiology, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Christophe Chardot
- Department of Pediatric Surgery, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Claire Francoz
- Hepatology Department, Beaujon Hospital, Assistance Publique - Hôpitaux de Paris, Clichy, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Sabine Sarnacki
- Department of Pediatric Surgery, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Audrey Coilly
- Hepatobiliary Center, Paul-Brousse Hospital, Assistance Publique - Hôpitaux de Paris, Inserm Paris-Saclay Research Unit 1193, Paris-Saclay University, Villejuif, France
| | - Didier Samuel
- Hepatobiliary Center, Paul-Brousse Hospital, Assistance Publique - Hôpitaux de Paris, Inserm Paris-Saclay Research Unit 1193, Paris-Saclay University, Villejuif, France
| | - Eric Vibert
- Hepatobiliary Center, Paul-Brousse Hospital, Assistance Publique - Hôpitaux de Paris, Inserm Paris-Saclay Research Unit 1193, Paris-Saclay University, Villejuif, France
| | - Cyrille Féray
- Hepatobiliary Center, Paul-Brousse Hospital, Assistance Publique - Hôpitaux de Paris, Inserm Paris-Saclay Research Unit 1193, Paris-Saclay University, Villejuif, France
| | - Carmen Lefaucheur
- Paris Translational Research Center for Organ Transplantation, Université de Paris Cité, INSERM, PARCC, Paris, France; Department of Nephrology and Kidney Transplantation, Saint-Louis Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Alexandre Loupy
- Paris Translational Research Center for Organ Transplantation, Université de Paris Cité, INSERM, PARCC, Paris, France; Kidney Transplantation Department, Necker enfants malades Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France.
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8
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Ashokkumar C, Ningappa M, Raghu V, Mazariegos G, Higgs BW, Morgan P, Remaley L, Fazzolare Martin T, Holzer P, Trostle K, Xu Q, Zeevi A, Squires J, Soltys K, Horslen S, Khanna A, Ganoza A, Sindhi R. Enhanced Donor Antigen Presentation by B Cells Predicts Acute Cellular Rejection and Late Outcomes After Transplantation. Transplant Direct 2024; 10:e1589. [PMID: 38414976 PMCID: PMC10898653 DOI: 10.1097/txd.0000000000001589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 10/16/2023] [Accepted: 11/11/2023] [Indexed: 02/29/2024] Open
Abstract
Background Enhanced B-cell presentation of donor alloantigen relative to presentation of HLA-mismatched reference alloantigen is associated with acute cellular rejection (ACR), when expressed as a ratio called the antigen presenting index (API) in an exploratory cohort of liver and intestine transplant (LT and IT) recipients. Methods To test clinical performance, we measured the API using the previously described 6-h assay in 84 LT and 54 IT recipients with median age 3.3 y (0.05-23.96). Recipients experiencing ACR within 60 d after testing were termed rejectors. Results We first confirmed that B-cell uptake and presentation of alloantigen induced and thus reflected the alloresponse of T-helper cells, which were incubated without and with cytochalasin and primaquine to inhibit antigen uptake and presentation, respectively. Transplant recipients included 76 males and 62 females. Rejectors were tested at median 3.6 d before diagnosis. The API was higher among rejectors compared with nonrejectors (2.2 ± 0.2 versus 0.6 ± 0.04, P value = 1.7E-09). In logistic regression and receiver-operating-characteristic analysis, API ≥1.1 achieved sensitivity, specificity, and positive and negative predictive values for predicting ACR in 99 training set samples. Corresponding metrics ranged from 80% to 88% in 32 independent posttransplant samples, and 73% to 100% in 20 independent pretransplant samples. In time-to-event analysis, API ≥1.1 predicted higher incidence of late donor-specific anti-HLA antibodies after API measurements in LT recipients (P = 0.011) and graft loss in IT recipients (P = 0.008), compared with recipients with API <1.1, respectively. Conclusions Enhanced donor antigen presentation by circulating B cells predicts rejection after liver or intestine transplantation as well as higher incidence of DSA and graft loss late after transplantation.
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Affiliation(s)
- Chethan Ashokkumar
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Mylarappa Ningappa
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Vikram Raghu
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital Pittsburgh, PA
| | - George Mazariegos
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Brandon W. Higgs
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Paul Morgan
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Lisa Remaley
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Tamara Fazzolare Martin
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Pamela Holzer
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Kevin Trostle
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Qingyong Xu
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Adriana Zeevi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - James Squires
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital Pittsburgh, PA
| | - Kyle Soltys
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Simon Horslen
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital Pittsburgh, PA
| | - Ajai Khanna
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Armando Ganoza
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
| | - Rakesh Sindhi
- Department of Surgery, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, PA
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Peters AL, DePasquale EA, Begum G, Roskin KM, Woodle ES, Hildeman DA. Defining the T cell transcriptional landscape in pediatric liver transplant rejection at single cell resolution. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.26.582173. [PMID: 38464256 PMCID: PMC10925238 DOI: 10.1101/2024.02.26.582173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Acute cellular rejection (ACR) affects >80% of pediatric liver transplant recipients within 5 years, and late ACR is associated with graft failure. Traditional anti-rejection therapy for late ACR is ineffective and has remained unchanged for six decades. Although CD8+ T cells promote late ACR, little has been done to define their specificity and gene expression. Here, we used single-cell sequencing and immune repertoire profiling (10X Genomics) on 30 cryopreserved 16G liver biopsies from 14 patients (5 pre-transplant or with no ACR, 9 with ACR). We identified expanded intragraft CD8+ T cell clonotypes (CD8EXP) and their gene expression profiles in response to anti-rejection treatment. Notably, we found that expanded CD8+ clonotypes (CD8EXP) bore markers of effector and CD56hiCD161- 'NK-like' T cells, retaining their clonotype identity and phenotype in subsequent biopsies from the same patients despite histologic ACR resolution. CD8EXP clonotypes localized to portal infiltrates during active ACR, and persisted in the lobule after histologic ACR resolution. CellPhoneDB analysis revealed differential crosstalk between KC and CD8EXP during late ACR, with activation of the LTB-LTBR pathway and downregulation of TGFß signaling. Therefore, persistently-detected intragraft CD8EXP clones remain active despite ACR treatment and may contribute to long-term allograft fibrosis and failure of operational tolerance.
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Affiliation(s)
- Anna L. Peters
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Erica A.K. DePasquale
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Gousia Begum
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Krishna M. Roskin
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - E. Steve Woodle
- Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - David A. Hildeman
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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10
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Hartleif S, Hodson J, Lloyd C, Cousin VL, Czubkowski P, D'Antiga L, Debray D, Demetris A, Di Giorgio A, Evans HM, Fischler B, Gonzales E, Gouw ASH, Hübscher SG, Jacquemin E, Lacaille F, Malenicka S, McLin VA, Markiewicz-Kijewska M, Mazariegos GV, Rajanayagam JK, Scheenstra R, Singer S, Smets F, Sokal E, Squires JE, Sturm E, Verkade H, Kelly DA. Long-term Outcome of Asymptomatic Patients With Graft Fibrosis in Protocol Biopsies After Pediatric Liver Transplantation. Transplantation 2023; 107:2394-2405. [PMID: 37143195 DOI: 10.1097/tp.0000000000004603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
BACKGROUND The histological prevalence of allograft fibrosis in asymptomatic children after liver transplantation (LT) is well documented. However, long-term graft and patient survival remain unclear. This retrospective multicenter study aims to determine the prevalence of allograft fibrosis and analyze the long-term outcome for patients transplanted in childhood. METHODS We reviewed clinical data of children who had undergone 10-y protocol liver biopsies. We excluded patients with autoimmune hepatitis, primary sclerosing cholangitis, hepatitis B or C, and retransplantation. In total, 494 patients transplanted in childhood across 12 international transplant centers were included. We evaluated the development of fibrosis by comparing the results with biopsies obtained 5 and 15 y post-LT. Histological findings were correlated with graft and patient survival up to 20 y post-LT. RESULTS In the 10-y biopsies, periportal or pericentral fibrosis was observed in 253 patients (51%), 87 (18%) had bridging fibrosis, 30 (6%) had cirrhosis, and 124 (25%) had no fibrosis. The prevalence and stage of graft fibrosis significantly progressed from 5 to 10 y. At 10 y, the severity of fibrosis correlated significantly with inflammation. Patients with graft cirrhosis in the 10-y biopsy were more likely to die or require retransplantation subsequently ( P = 0.027). CONCLUSIONS At 10 y post-LT, most patients transplanted in childhood developed fibrosis, based on the protocol liver biopsies. Although mild-to-moderate graft fibrosis did not largely affect patient or graft survival up to 20 y post-LT, this progressive fibrosis finding has substantial implications for developing cirrhosis and portal hypertension in adult care.
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Affiliation(s)
- Steffen Hartleif
- Pediatric Gastroenterology and Hepatology, University Hospital Tübingen, Tübingen, Germany
| | - James Hodson
- Department of Health Informatics, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Institute of Translational Medicine, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Carla Lloyd
- Liver Unit, Birmingham Women's and Children's Hospital, Birmingham, United Kingdom
| | - Vladimir L Cousin
- Swiss Pediatric Liver Centre, Division of Pediatric Specialties, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals Geneva and University of Geneva, Geneva, Switzerland
| | - Piotr Czubkowski
- Department of Liver Disorders and Transplantation, The Children's Memorial Health Institute, Warsaw, Poland
| | - Lorenzo D'Antiga
- Pediatric Hepatology, Gastroenterology and Transplantation, ASST Ospedale Papa Giovanni XXIII, Bergamo, Italy
| | - Dominique Debray
- Pediatric Liver Unit, National Reference Centre for Rare Pediatric Liver Diseases (Biliary Atresia and Genetic Cholestasis), FILFOIE, Necker-Enfants Malades Hospital, University of Paris, Paris, France
| | - Anthony Demetris
- Division of Liver and Transplantation Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, PA
| | - Angelo Di Giorgio
- Pediatric Hepatology, Gastroenterology and Transplantation, ASST Ospedale Papa Giovanni XXIII, Bergamo, Italy
| | - Helen M Evans
- Department of Pediatric Gastroenterology, Starship Child Health, University of Auckland, Auckland, New Zealand
| | - Björn Fischler
- Pediatric Digestive Diseases, Astrid Lindgren Children's Hospital, Karolinska University Hospital, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Emmanuel Gonzales
- Hépatologie et Transplantation Hépatique Pédiatriques, Centre de référence de l'atrésie des voies biliaires et des cholestases génétiques, FSMR FILFOIE, Hôpital Bicêtre, AP-HP, Université Paris-Saclay, Kremlin-Bicêtre, France
| | - Annette S H Gouw
- Department of Pathology and Medical Biology, University Medical Centre Groningen, Groningen, The Netherlands
| | - Stefan G Hübscher
- Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Emmanuel Jacquemin
- Hépatologie et Transplantation Hépatique Pédiatriques, Centre de référence de l'atrésie des voies biliaires et des cholestases génétiques, FSMR FILFOIE, Hôpital Bicêtre, AP-HP, Université Paris-Saclay, Kremlin-Bicêtre, France
| | - Florence Lacaille
- Pediatric Liver Unit, National Reference Centre for Rare Pediatric Liver Diseases (Biliary Atresia and Genetic Cholestasis), FILFOIE, Necker-Enfants Malades Hospital, University of Paris, Paris, France
| | - Silvia Malenicka
- Pediatric Digestive Diseases, Astrid Lindgren Children's Hospital, Karolinska University Hospital, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Valerie A McLin
- Swiss Pediatric Liver Centre, Division of Pediatric Specialties, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals Geneva and University of Geneva, Geneva, Switzerland
| | | | - George V Mazariegos
- Department of Surgery, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - Jeremy K Rajanayagam
- Paediatric Gastroenterology, Hepatology and Nutrition, The Royal Children's Hospital, Melbourne, Australia
| | - René Scheenstra
- Pediatric Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Stephan Singer
- Institute of Pathology, University Hospital Tübingen, Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany
| | - Françoise Smets
- UClouvain, Clinical and Experimental Research Institute and Cliniques Universitaires Saint Luc, Service de Gastroentérologie Hépatologie Pédiatrique, Brussels, Belgium
| | - Etienne Sokal
- UClouvain, Clinical and Experimental Research Institute and Cliniques Universitaires Saint Luc, Service de Gastroentérologie Hépatologie Pédiatrique, Brussels, Belgium
| | - James E Squires
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - Ekkehard Sturm
- Pediatric Gastroenterology and Hepatology, University Hospital Tübingen, Tübingen, Germany
| | - Henkjan Verkade
- Pediatric Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Deirdre A Kelly
- Liver Unit, Birmingham Women's and Children's Hospital, Birmingham, United Kingdom
- University of Birmingham, Birmingham, United Kingdom
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11
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Al-Awadhi S, Raynaud M, Louis K, Bouquegneau A, Taupin JL, Aubert O, Loupy A, Lefaucheur C. Complement-activating donor-specific anti-HLA antibodies in solid organ transplantation: systematic review, meta-analysis, and critical appraisal. Front Immunol 2023; 14:1265796. [PMID: 37849755 PMCID: PMC10577173 DOI: 10.3389/fimmu.2023.1265796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 09/07/2023] [Indexed: 10/19/2023] Open
Abstract
Introduction Several studies have investigated the impact of circulating complement-activating anti-human leukocyte antigen donor-specific antibodies (anti-HLA DSAs) on organ transplant outcomes. However, a critical appraisal of these studies and a demonstration of the prognostic value of complement-activating status over anti-HLA DSA mean fluorescence intensity (MFI) level are lacking. Methods We conducted a systematic review, meta-analysis and critical appraisal evaluating the role of complement-activating anti-HLA DSAs on allograft outcomes in different solid organ transplants. We included studies through Medline, Cochrane, Scopus, and Embase since inception of databases till May 05, 2023. We evaluated allograft loss as the primary outcome, and allograft rejection as the secondary outcome. We used the Newcastle-Ottawa Scale and funnel plots to assess risk of bias and used bias adjustment methods when appropriate. We performed multiple subgroup analyses to account for sources of heterogeneity and studied the added value of complement assays over anti-HLA DSA MFI level. Results In total, 52 studies were included in the final meta-analysis (11,035 patients). Complement-activating anti-HLA DSAs were associated with an increased risk of allograft loss (HR 2.77; 95% CI 2.33-3.29, p<0.001; I²=46.2%), and allograft rejection (HR 4.98; 95% CI 2.96-8.36, p<0.01; I²=70.9%). These results remained significant after adjustment for potential sources of bias and across multiple subgroup analyses. After adjusting on pan-IgG anti-HLA DSA defined by the MFI levels, complement-activating anti-HLA DSAs were significantly and independently associated with an increased risk of allograft loss. Discussion We demonstrated in this systematic review, meta-analysis and critical appraisal the significant deleterious impact and the independent prognostic value of circulating complement-activating anti-HLA DSAs on solid organ transplant risk of allograft loss and rejection.
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Affiliation(s)
- Solaf Al-Awadhi
- Université de Paris Cité, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR)-S970, Paris Cardiovascular Research Center (PARCC), Paris Translational Research Centre for Organ Transplantation, Paris, France
| | - Marc Raynaud
- Université de Paris Cité, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR)-S970, Paris Cardiovascular Research Center (PARCC), Paris Translational Research Centre for Organ Transplantation, Paris, France
| | - Kevin Louis
- Université de Paris Cité, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR)-S970, Paris Cardiovascular Research Center (PARCC), Paris Translational Research Centre for Organ Transplantation, Paris, France
- Kidney Transplant Department, Saint-Louis Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Antoine Bouquegneau
- Université de Paris Cité, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR)-S970, Paris Cardiovascular Research Center (PARCC), Paris Translational Research Centre for Organ Transplantation, Paris, France
- Department of Nephrology, Dialysis and Transplantation, Centre Hospitalier Universitaire (CHU) de Liège, Liège, Belgium
| | - Jean-Luc Taupin
- Department of Immunology and Histocompatibility, Centre Hospitalier Universitaire (CHU) Paris–GH St–Louis Lariboisière, Paris, France
| | - Olivier Aubert
- Université de Paris Cité, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR)-S970, Paris Cardiovascular Research Center (PARCC), Paris Translational Research Centre for Organ Transplantation, Paris, France
- Kidney Transplant Department, Necker Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
| | - Alexandre Loupy
- Université de Paris Cité, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR)-S970, Paris Cardiovascular Research Center (PARCC), Paris Translational Research Centre for Organ Transplantation, Paris, France
- Kidney Transplant Department, Necker Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
| | - Carmen Lefaucheur
- Université de Paris Cité, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR)-S970, Paris Cardiovascular Research Center (PARCC), Paris Translational Research Centre for Organ Transplantation, Paris, France
- Kidney Transplant Department, Saint-Louis Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
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12
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Ravichandran R, Itabashi Y, Zhou F, Lin Y, Mohanakumar T, Chapman WC. Circulating exosomes from brain death and cardiac death donors have distinct molecular and immunologic properties: A pilot study. Clin Transplant 2023; 37:e15067. [PMID: 37428019 PMCID: PMC11019898 DOI: 10.1111/ctr.15067] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 05/15/2023] [Accepted: 06/19/2023] [Indexed: 07/11/2023]
Abstract
BACKGROUND AND AIMS Comparison of donation after brain death (DBD) and donation after cardiac death (DCD) lung tissue before transplantation have demonstrated activation of pro-inflammatory cytokine pathway in DBD donors. The molecular and immunological properties of circulating exosomes from DBD and DCD donors were not previously described. METHODS We collected plasma from 18 deceased donors (12 DBD and six DCD). Cytokines were analyzed by 30-Plex luminex Panels. Exosomes were analyzed for liver self-antigen (SAg), Transcription Factors and HLA class II (HLA-DR/DQ) using western blot. C57BL/6 animals were immunized with isolated exosomes to determine strength and magnitude of immune responses. Interferon (IFN)-γ and tumor necrosis factor-α producing cells were quantified by ELISPOT, specific antibodies to HLA class II antigens were measured by ELISA RESULTS: We demonstrate increased plasma levels of IFNγ, EGF, EOTAXIN, IP-10, MCP-1, RANTES, MIP-β, VEGF, and interleukins - 6/8 in DBD plasma versus DCD. MiRNA isolated from exosome of DBD donors demonstrated significant increase in miR-421, which has been reported to correlate with higher level of Interleukin-6. Higher levels of liver SAg Collagen III (p = .008), pro-inflammatory transcription factors (NF-κB, p < .05; HIF1α, p = .021), CIITA (p = .011), and HLA class II (HLA-DR, p = .0003 and HLA-DQ, p = .013) were detected in exosomes from DBD versus DCD plasma. The circulating exosomes isolated from DBD donors were immunogenic in mice and led to the development of Abs to HLA-DR/DQ. CONCLUSIONS This study provides potential new mechanisms by which DBD organs release exosomes that can activate immune pathways leading to cytokine release and allo-immune response.
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Affiliation(s)
| | - Yoshihiro Itabashi
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ
| | - Fangyu Zhou
- Division of General Surgery, Washington University School of Medicine, St. Louis, MO 63110
| | - Yiing Lin
- Division of General Surgery, Washington University School of Medicine, St. Louis, MO 63110
| | | | - William C. Chapman
- Division of General Surgery, Washington University School of Medicine, St. Louis, MO 63110
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13
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El Hag MI, Kaneku H, Jorgensen D, Zeevi A, Stevenson HL, Yadak N, Hassan M, Du X, Demetris AJ. Morphologic and immunophenotypic evaluation of liver allograft biopsies with contemporaneous serum DSA measurements. Clin Transplant 2023; 37:e14997. [PMID: 37096730 DOI: 10.1111/ctr.14997] [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: 02/02/2022] [Revised: 02/27/2023] [Accepted: 04/09/2023] [Indexed: 04/26/2023]
Abstract
BACKGROUND Acute antibody mediated rejection is increasingly identified in liver allografts as a unique form of alloimmune injury associated with donor specific antibodies (DSA). This manifests pathologically as microvascular injury and C4d uptake. Despite the liver allograft's relative resistance to alloimmune injury, liver allografts are not impervious to cellular and antibody-mediated rejection. METHODS In this blinded control study, we evaluated CD163 immunohistochemistry and applied the Banff 2016 criteria for diagnosis of acute AMR on a group of indication allograft liver biopsies from DSA positive patients and compared them to indication biopsies from DSA negative controls. RESULTS Most DSA positive patients were females (75%, p = .027), and underwent transplantation for HCV infection. Significant histopathological predictors of serum DSA positivity were Banff H-score (p = .01), moderate to severe cholestasis (p = .03), and CD163 score > 2 (p = .029). Other morphologic features that showed a trend with DSA positivity include Banff portal C4d-score (p = .06), bile ductular reaction (p = .07), and central perivenulitis (p = .07). The odds of DSA sMFI ≥5000 was 12.5 times higher in those with a C4d score >1 than those with a C4d score ≤ 1 (p = .04). Incidence of definite for aAMR in the DSA positive cohort was 25% (n = 5), and 0% in the DSA negative cohort. A group of 5 DSA positive cases were not classifiable by the current scheme. CONCLUSION Sinusoidal CD163, Banff H-score, and diffuse C4d are predictors of serum DSA, and facilitate recognition of histopathological features associated with serum DSA and tissue-antibody interaction.
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Affiliation(s)
- Mohamed I El Hag
- Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Hugo Kaneku
- Department of Surgery - Immunology and Histocompatibility Laboratory, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Dana Jorgensen
- Thomas E Starzl Transplantation Institute (STI), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Adriana Zeevi
- Thomas E Starzl Transplantation Institute (STI), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Division of Hepatic and Transplantation Pathology, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Heather L Stevenson
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Nour Yadak
- Department of Pathology, Methodist University Hospital, University of Tennessee, Memphis, Tennessee, USA
| | - Mohamed Hassan
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Xiaotang Du
- Department of Pathology, University of Chicago, Chicago, IL, USA
| | - Anthony J Demetris
- Thomas E Starzl Transplantation Institute (STI), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Division of Hepatic and Transplantation Pathology, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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14
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Peters AL, Rogers M, Begum G, Sun Q, Fei L, Leino D, Hildeman D, Woodle ES. T-cell infiltrate intensity is associated with delayed response to treatment in late acute cellular rejection in pediatric liver transplant recipients. Pediatr Transplant 2023; 27:e14475. [PMID: 36691289 PMCID: PMC10121906 DOI: 10.1111/petr.14475] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 11/21/2022] [Accepted: 01/09/2023] [Indexed: 01/25/2023]
Abstract
BACKGROUND Late acute cellular rejection (ACR) is associated with donor-specific antibodies (DSA) development, chronic rejection, and allograft loss. However, accurate predictors of late ACR treatment response are lacking. ACR is primarily T-cell mediated, yet B cells and plasma cells (PC) also infiltrate the portal areas during late ACR. To test the hypothesis that the inflammatory milieu is associated with delayed response (DR) to rejection therapy, we performed a single-center retrospective case-control study of pediatric late liver ACR using multiparameter immunofluorescence for CD4, CD8, CD68, CD20, and CD138 to identify immune cell subpopulations. METHODS Pediatric liver transplant recipients transplanted at <17 years of age and treated for biopsy-proven late ACR between January 2014 and 2019 were stratified into rapid response (RR) and DR based on alanine aminotransferase (ALT) normalization within 30 days of diagnosis. All patients received IV methylprednisolone as an initial rejection treatment. Immunofluorescence was performed on archived formalin-fixed paraffin embedded (FFPE) liver biopsy tissue. RESULTS Liver biopsies from 60 episodes of late ACR in 54 patients were included in the analysis, of which 33 were DR (55%). Anti-thymocyte globulin was only required in the DR group. The frequency of liver-infiltrating CD20+ and CD8+ lymphocytes and the prevalence of autoantibodies were higher in the DR group. In univariate logistic regression analysis, serum gamma-glutamyl transpeptidase (GGT) level at diagnosis, but not ALT, Banff score or presence of DSA, predicted DR. CONCLUSIONS Higher serum GGT level, presence of autoantibodies, and increased CD8+ T-cell infiltration portends DR in late ACR treatment in children.
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Affiliation(s)
- Anna L. Peters
- Department of Pediatrics, University of Cincinnati College of Medicine
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center
| | - Michael Rogers
- Department of Pediatrics, University of Cincinnati College of Medicine
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center
| | - Gousia Begum
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center
| | - Qin Sun
- Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center
| | - Lin Fei
- Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center
| | - Daniel Leino
- Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center
- Department of Pathology and Laboratory Medicine, University of Cincinnati
| | - David Hildeman
- Department of Pediatrics, University of Cincinnati College of Medicine
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - E. Steve Woodle
- Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH
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15
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Zhang Z, Zhao S, Si Z, Wang Z, Dong C, Sun C, Zheng W, Kai W, Zhang W, Song Z, Gao W, Shen Z. Incidence and risk factors of subclinical rejection after pediatric liver transplantation, and impact on allograft fibrosis. Clin Transplant 2023; 37:e14894. [PMID: 36581321 DOI: 10.1111/ctr.14894] [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: 09/29/2022] [Revised: 12/12/2022] [Accepted: 12/24/2022] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Subclinical rejection (SCR) is a common injury in protocol biopsy after pediatric liver transplantation (pLT), but its effect on the recipient is not clearly understood. We herein investigated the incidence and risk factors involved in SCR and analyzed the relationship between SCR and allograft fibrosis (AF). METHODS We retrospectively reviewed the biopsy results from 507 children between May 2013 and May 2019, and 352 patients underwent protocol biopsy 2 years after pLT, 203 underwent protocol biopsy 5 years after pLT, and 48 underwent protocol biopsy both 2 and 5 years after pLT. RESULTS The incidence of SCR in the 5-year group was higher than that in the 2-year group (20.2% vs.13.4%, respectively, p = .033). The number of patients with mild and moderate SCR in the 5-year group was also higher than that in the 2-year group (p = .039). Logistic regression analysis showed that acute rejection before liver biopsy and deceased donor liver transplantation (DDLT) were independent risk factors for SCR in the two groups, and that the incidence and severity of AF in protocol biopsies at both periods in the SCR group were higher than those in the non-SCR group (p < .05). CONCLUSIONS The incidence and severity of SCR increased with the prolongation of protocol biopsy time. We postulate that acute rejection and DDLT are independent risk factors for SCR after transplantation. As the occurrence of SCR also augmented the incidence and severity of AF.
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Affiliation(s)
- Zhixin Zhang
- First Central Clinic Institute, Tianjin Medical University, Tianjin, China
| | - Shengqiao Zhao
- First Central Clinic Institute, Tianjin Medical University, Tianjin, China
| | - Zhuyuan Si
- First Central Clinic Institute, Tianjin Medical University, Tianjin, China
| | - Zhenglu Wang
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Chong Dong
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Chao Sun
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Weiping Zheng
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Wang Kai
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Wei Zhang
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Zhuolun Song
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Wei Gao
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Zhongyang Shen
- Department of pediatric transplantation, Organ Transplantation Center, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
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16
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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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17
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Acute Antibody-Mediated Rejection in Liver Transplant Recipients with Autoimmune Liver Disease: A Clinical and Pathologic Study of 4 Cases. J Pers Med 2022; 13:jpm13010041. [PMID: 36675702 PMCID: PMC9865077 DOI: 10.3390/jpm13010041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/15/2022] [Accepted: 12/21/2022] [Indexed: 12/29/2022] Open
Abstract
Background: Acute antibody-mediated rejection (AMR) is an uncommon complication after ABO-compatible liver transplantation (LT). This case series investigated the clinicopathologic characteristics and outcomes of acute AMR in LT recipients with autoimmune liver disease (ALD). Patients and Methods: Among 809 patients who underwent LT from January 2014 to December 2020, four ALD patients developed AMR, which was confirmed based on clinical features, histopathology of liver biopsy, donor-specific antibodies (DSA) or panel reactive antibody (PRA) level. Therapies were individualized based on clinical manifestations. Results: The incidence of acute AMR was 0.49%, and the incidence of acute AMR with ALD and non-ALD recipients was 11.1% and 0%, respectively. Three patients had strongly positive HLA class II DSA, and one patient was with the PRA class I and II sensitivities, which were >80%; complement component 4d (C4d) staining was negative in all patients. The first patient underwent re-LT, and the other three patients had good prognoses with treatments. Conclusions: ALD patients are prone to acute AMR after LT, thus should be kept vigilant against the occurrence of acute AMR.
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18
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Harrington C, Krishnan S, Mack CL, Cravedi P, Assis DN, Levitsky J. Noninvasive biomarkers for the diagnosis and management of autoimmune hepatitis. Hepatology 2022; 76:1862-1879. [PMID: 35611859 PMCID: PMC9796683 DOI: 10.1002/hep.32591] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 01/07/2023]
Abstract
Autoimmune hepatitis (AIH) is a rare disease of unclear etiology characterized by loss of self-tolerance that can lead to liver injury, cirrhosis, and acute liver failure. First-line treatment consists of systemic corticosteroids, or budesonide, and azathioprine, to which most patients are initially responsive, although predictors of response are lacking. Relapses are very common, correlate with histological activity despite normal serum transaminases, and increase hepatic fibrosis. Furthermore, current regimens lead to adverse effects and reduced quality of life, whereas medication titration is imprecise. Biomarkers that can predict the clinical course of disease, identify patients at elevated risk for relapse, and improve monitoring and medication dosing beyond current practice would have high clinical value. Herein, we review novel candidate biomarkers in adult and pediatric AIH based on prespecified criteria, including gene expression profiles, proteins, metabolites, and immune cell phenotypes in different stages of AIH. We also discuss biomarkers relevant to AIH from other immune diseases. We conclude with proposed future directions in which biomarker implementation into clinical practice could lead to advances in personalized therapeutic management of AIH.
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Affiliation(s)
- Claire Harrington
- Division of Gastroenterology & HepatologyNorthwestern University Feinberg School of MedicineChicagoIllinoisUSA
| | - Swathi Krishnan
- Medicine DepartmentYale School of MedicineNew HavenConnecticutUSA
| | - Cara L. Mack
- Section of Pediatric Gastroenterology, Hepatology & Nutrition, Children's Hospital ColoradoUniversity of Colorado School of MedicineAuroraColoradoUSA
| | - Paolo Cravedi
- Division of NephrologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - David N. Assis
- Section of Digestive DiseasesYale School of MedicineNew HavenConnecticutUSA
| | - Josh Levitsky
- Division of Gastroenterology & HepatologyNorthwestern University Feinberg School of MedicineChicagoIllinoisUSA
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19
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The Role of Dynamic DNA Methylation in Liver Transplant Rejection in Children. Transplant Direct 2022; 8:e1394. [PMID: 36259078 PMCID: PMC9575761 DOI: 10.1097/txd.0000000000001394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 08/14/2022] [Indexed: 11/04/2022] Open
Abstract
Transcriptional regulation of liver transplant (LT) rejection may reveal novel predictive and therapeutic targets. The purpose of this article is to test the role of differential DNA methylation in children with biopsy-proven acute cellular rejection after LT.
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20
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Wozniak LJ, Venick RS, Naini BV, Scapa J, Hickey MJ, Rossetti M, Korin Y, Reed EF, Farmer DG, Busuttil RW, Vargas JH, McDiarmid SV. Operational tolerance is not always permanent: A 10-year prospective study in pediatric liver transplantation recipients. Liver Transpl 2022; 28:1640-1650. [PMID: 35395132 DOI: 10.1002/lt.26474] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/03/2022] [Accepted: 03/02/2022] [Indexed: 12/25/2022]
Abstract
Immunosuppression withdrawal can be safely performed in select liver transplantation recipients, but the long-term outcomes and sustainability of tolerance have not been well studied. We completed a 10-year prospective, observational study of 18 pediatric liver transplantation recipients with operational tolerance to (1) assess the sustainability of tolerance over time, (2) compare the clinical characteristics of patients who maintained versus lost tolerance, (3) characterize liver histopathology findings in surveillance liver biopsies; and (4) describe immunologic markers in patients with tolerance. Comparator patients from two clinical phenotype groups termed "stable" and "nontolerant" patients were used as controls. Of the 18 patients with operational tolerance, the majority of patients were males (n = 14, 78%) who were transplanted for cholestatic liver disease (n = 12, 67%). Median age at transplantation was 1.9 (range, 0.6-8) years. Median time after transplantation that immunosuppression had been discontinued was 13.1 (range, 2.9-22.1) years. As many as 11 (61%) maintained tolerance for a median of 10.4 (range, 1.9-22.1) years, whereas 7 (39%) lost tolerance after a median of 3.2 (range, 1.5-18.6) years. Populations of T regulatory cells (%CD4+ CD25hi CD127lo ) were significantly higher in patients with tolerance (p = 0.02). Our results emphasize that spontaneous operational tolerance is a dynamic and nonpermanent state. It is therefore essential for patients who are clinically stable off immunosuppression to undergo regular follow-up and laboratory monitoring, as well as surveillance biopsies to rule out subclinical rejection.
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Affiliation(s)
- Laura J Wozniak
- Pediatric Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Robert S Venick
- Pediatric Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.,Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Bita V Naini
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Jason Scapa
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Michelle J Hickey
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.,Immunogenetics Center, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - Maura Rossetti
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.,Immunogenetics Center, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - Yael Korin
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.,Immunogenetics Center, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - Elaine F Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.,Immunogenetics Center, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - Douglas G Farmer
- Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Ronald W Busuttil
- Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Jorge H Vargas
- Pediatric Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Sue V McDiarmid
- Pediatric Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.,Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
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21
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The New Challenge in Pediatric Liver Transplantation: Chronic Antibody-Mediated Rejection. J Clin Med 2022; 11:jcm11164834. [PMID: 36013073 PMCID: PMC9409831 DOI: 10.3390/jcm11164834] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 08/07/2022] [Accepted: 08/16/2022] [Indexed: 12/21/2022] Open
Abstract
Antibody-mediated rejection (AMR) of liver allograft transplantation was considered as anecdotal for many decades. However recently, AMR has gained clinical awareness as a potential cause of chronic liver injury, leading to liver allograft fibrosis and eventual graft failure. (1) Methods: Literature on chronic AMR (cAMR) in pediatric post-liver transplant patients was reviewed for epidemiologic data, physiopathology, diagnosis, and treatment approaches. (2) Results: Accurate incidence of cAMR in pediatric liver transplantation remains unknown. Diagnostic criteria of cAMR were suggested by the Banff Working Group in 2016 and are based on standardized histopathological findings, C4d staining pattern, associated with the presence of donor-specific antibodies (DSA). Physio-pathological mechanisms are not clear for the technically difficult-to-obtain animal models reproducing cAMR. Treatment protocols are not established, being limited to case reports and case series, based on experience in ABO incompatible transplantation and kidney transplantation. Immunosuppression compliance with adequate dose adjustment may prevent cAMR. Conversion of Cyclosporine to Tacrolimus may improve pathological findings if treated in early phase. The association of steroids, Mycophenolate Mofetil (MMF) and mTOR inhibitors have shown some synergistic effects. Second-line treatments such as intravenous immunoglobulin (IVIG) and plasma exchange may decrease antibody titers based on ABO incompatible transplant protocols. The use of anti-CD20 (Rituximab) and proteasome inhibitors (Bortezomib) is controversial due to the lack of qualified studies. Therefore, multicenter randomized trials are needed to establish the best therapeutic strategy. In refractory cases, re-transplantation is the only treatment for allograft failure. (3) Conclusions: This literature review collects recent clinical, histopathological, and therapeutical advances of cAMR in liver allograft transplantation of pediatric patients. There are many physio-pathological aspects of cAMR to be clarified. Further efforts with multicenter prospective protocols to manage patients with cAMR are needed to improve its outcome.
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22
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Shin S, Lee M, Dente E, Yazigi N, Khan KM, Kaufman SS, Ahn J, Timofeeva OA, Ekong UD. Mismatch epitope load predicts de novo-DSA-free survival in pediatric liver transplantation. Pediatr Transplant 2022; 26:e14251. [PMID: 35279919 DOI: 10.1111/petr.14251] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 01/28/2022] [Accepted: 02/03/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Our knowledge of de novo anti-HLA donor-specific antibodies (dnDSA) in liver transplantation continues to be defined. We hypothesized that differences of HLA-DR/DQ mismatches can improve precision in alloimmune risk categorization and be applied to tailor immunosuppression. METHODS A retrospective chart review of 244 pediatric patients consecutively transplanted at our center between 2003 and 2019 was performed to identify patients tested for dnDSA. Records were queried for: demographics, pre-transplant diagnosis, biopsy-proven T-cell-mediated rejection (TCMR), radiology proven biliary complications, tacrolimus trough levels, dnDSA characteristics, and HLA typing. The eplet mismatch analyses were performed using HLAMatchmaker™ 3.1. All statistical analyses were conducted using R software version 3.40. RESULTS There were 99 dnDSA-negative patients and 73 dnDSA-positive patients (n = 70 against class II and n = 3 against class I and II). ROC analysis identified optimal cutoff of eplet mismatch load for dnDSA and defined risk groups for an alloimmune outcome. Kaplan-Meier curves and log-rank tests showed high eplet mismatch load was associated with shorter dnDSA-free survival (log-rank p = .001). Multivariable Cox regression models showed that tacrolimus coefficient of variation and tacrolimus mean levels were significantly associated with dnDSA-free survival (p < .001 and p = .036). Fisher's exact test showed that dnDSA was associated with an increased likelihood of TCMR (OR 14.94; 95% CI 3.65 - 61.19; p < .001). Patients without TCMR were more likely to have dnDSA to HLA-DQ7 and less likely to have dnDSA to HLA-DQ2 (p = .03, p = .080). CONCLUSIONS Mismatched epitope load predicts dnDSA-free survival in pediatric liver transplant, while dnDSA specificity may determine alloimmune outcome.
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Affiliation(s)
- Stephanie Shin
- Georgetown University School of Medicine, Washington, District of Columbia, USA
| | - Margaret Lee
- Georgetown University School of Medicine, Washington, District of Columbia, USA
| | - Elizabeth Dente
- Georgetown University School of Medicine, Washington, District of Columbia, USA
| | - Nada Yazigi
- Georgetown University School of Medicine, Washington, District of Columbia, USA.,Medstar Georgetown Transplant Institute, Medstar Georgetown University Hospital, Washington, District of Columbia, USA
| | - Khalid M Khan
- Georgetown University School of Medicine, Washington, District of Columbia, USA.,Medstar Georgetown Transplant Institute, Medstar Georgetown University Hospital, Washington, District of Columbia, USA
| | - Stuart S Kaufman
- Georgetown University School of Medicine, Washington, District of Columbia, USA.,Medstar Georgetown Transplant Institute, Medstar Georgetown University Hospital, Washington, District of Columbia, USA
| | - Jaeil Ahn
- Department of Biostatistics, Bioinformatics, & Biomathematics, Georgetown University, Washington, District of Columbia, USA
| | - Olga A Timofeeva
- Georgetown University School of Medicine, Washington, District of Columbia, USA.,Histocompatibility Laboratory, Department of Pathology & Laboratory Medicine, Georgetown University, Washington, District of Columbia, USA
| | - Udeme D Ekong
- Georgetown University School of Medicine, Washington, District of Columbia, USA.,Medstar Georgetown Transplant Institute, Medstar Georgetown University Hospital, Washington, District of Columbia, USA
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23
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Meszaros M, Dubois V, Congy-Jolivet N, Hamada S, Thevenin C, Faure S, Boillot O, Kamar N, Pageaux GP, Del Bello A, Dumortier J. Impact of calcineurin inhibitor-free immunosuppression on de novo donor-specific antibody formation in liver transplant recipients. Liver Int 2022; 42:1132-1143. [PMID: 35184373 DOI: 10.1111/liv.15201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 12/14/2021] [Accepted: 01/12/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Low calcineurin inhibitor (CNI) levels expose liver transplant recipients to rejection episodes and potentially to antibody-mediated rejection. There are little data on the impact of CNI-free immunosuppression on de novo donor-specific HLA antibody (dnDSA) development. Here we evaluated the prevalence of dnDSA in liver transplant recipients on CNI-free maintenance regimens and their associations with histopathological abnormalities of allografts. METHODS Seven hundred and twenty-seven liver transplant recipients underwent a first liver transplant between 2000 and 2018 in three French transplant centres and had protocolized follow-up with dnDSA screening and allograft biopsy 1, 5 and 10 years after transplantation. RESULTS CNIs were withdrawn in 166 (22.8%) patients with or without conversion to mammalian target of rapamycin inhibitors and/or maintenance with mycophenolic acid. DSA were present after withdrawal in 30.1% (50/166) patients on CNI-free immunosuppression compared with 16% (90/561) on CNI maintenance therapy (p < 0.001). The cumulative incidence of dnDSA 10 years after transplant was 20% in the CNI group versus 28% in the CNI-free group (p < 0.01). dnDSAs were associated with histological graft abnormalities (significant allograft fibrosis or rejection) (HR 2.24, 95% CI 1.2-4.1; p = 0.01). In univariate Cox regression analysis, being on a CNI-free regimen did not impact graft histology. CONCLUSIONS Patients on a CNI-free IS regimen have a higher prevalence of dnDSA than patients on a standard IS regimen. dnDSAs but not CNI-free immunosuppression were associated with abnormal allograft histology.
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Affiliation(s)
- Magdalena Meszaros
- Département d'hépatologie et transplantation hépatique, CHU Saint Eloi, Montpellier, France
| | - Valérie Dubois
- Etablissement Français du Sang, Laboratoire d'Histocompatibilité, Lyon, France
| | | | - Sarah Hamada
- Etablissement Français du Sang, Laboratoire d'Histocompatibilité, Lyon, France
| | - Céline Thevenin
- Département d'Immunologie, CHU Montpellier, Montpellier, France
| | - Stephanie Faure
- Département d'hépatologie et transplantation hépatique, CHU Saint Eloi, Montpellier, France
| | - Olivier Boillot
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Unité de Transplantation hépatique, Lyon, France
| | - Nassim Kamar
- Département de Néphrologie et Transplantation d'Organes, CHU, Toulouse, France
| | | | - Arnaud Del Bello
- Département de Néphrologie et Transplantation d'Organes, CHU, Toulouse, France
| | - Jérôme Dumortier
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Unité de Transplantation hépatique, Lyon, France
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24
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Barbetta A, Meeberg G, Rocque B, Barhouma S, Weaver C, Gilmour S, Faytrouni F, Guttman O, Zielsdorf S, Etesami K, Kwon Y, Yanni G, Campbell P, Shapiro J, Emamaullee J. Immunologic benefits of maternal living donor allografts in pediatric liver transplantation: fewer rejection episodes and no evidence of de novo allosensitization. Pediatr Transplant 2022; 26:e14197. [PMID: 34806273 PMCID: PMC9053650 DOI: 10.1111/petr.14197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 10/23/2021] [Accepted: 11/10/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Pediatric liver transplant (LT) recipients of maternal living liver donor (LLD) grafts have been reported to experience fewer rejection episodes. However, it is unclear whether this benefit translates to reduction in developing donor-specific antibody (DSA) among maternal-LLD recipients. The aim of this study was to compare immunologic outcomes among maternal-LLD, non-maternal-LLD, and deceased donor liver transplant (DDLT) recipients. METHODS Children (≤18 years) who underwent LT between 1/1998 and 12/2019 at two high-volume LT centers in North America were evaluated. Patients were divided into three groups by type of graft received (maternal-LLD, non-maternal LLD, and DDLT). Clinical variables and outcomes were compared according to each graft type. RESULTS A total of 450 pediatric primary LT were analyzed: 275 (61.1%) DDLT, 73 (16.2%) maternal-LLD, and 102 (22.6%) non-maternal-LLD. Children receiving LLD grafts were less likely to develop rejection when compared to the DDLT group (DDLT 46.9% vs. maternal-LLD 31.5% vs. non-maternal-LLD 28.4%, p = 0.001). There was no difference in rejection rates between maternal and non-maternal-LLD recipients. A higher percentage of maternal-LLD recipients were on immunosuppression monotherapy compared to non-maternal-LLD and DDLT recipients (6.7% vs. 1.2 vs. 2.4%, respectively). A subgroup of 68 patients were tested for DSA post-LT. Maternal-LLD recipients were less likely to develop de novo DSA (maternal-LLD 11.8% vs. non-maternal-LLD 19.3% vs. DDLT 43%, p = 0.018). None of the maternal-LLD recipients developed antibody-mediated rejection. CONCLUSIONS These data support the concept of immunologic benefit of maternal-LLD in pediatric LT, with lower rates of rejection and allosensitization post-LT when compared to DDLT recipients.
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Affiliation(s)
- Arianna Barbetta
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, Los Angeles, CA, USA
| | | | - Brittany Rocque
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, Los Angeles, CA, USA
| | | | - Carly Weaver
- Division of Hepatobiliary and Abdominal Organ Transplantation Surgery, Children’s Hospital-Los Angeles, Los Angeles, CA USA
| | | | - Farah Faytrouni
- Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
| | - Orlee Guttman
- Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
| | - Shannon Zielsdorf
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, Los Angeles, CA, USA,University of Southern California, Los Angeles, CA, USA,Division of Hepatobiliary and Abdominal Organ Transplantation Surgery, Children’s Hospital-Los Angeles, Los Angeles, CA USA
| | - Kambiz Etesami
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, Los Angeles, CA, USA,University of Southern California, Los Angeles, CA, USA,Division of Hepatobiliary and Abdominal Organ Transplantation Surgery, Children’s Hospital-Los Angeles, Los Angeles, CA USA
| | - Yong Kwon
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, Los Angeles, CA, USA,University of Southern California, Los Angeles, CA, USA,Division of Hepatobiliary and Abdominal Organ Transplantation Surgery, Children’s Hospital-Los Angeles, Los Angeles, CA USA
| | - George Yanni
- University of Southern California, Los Angeles, CA, USA,Department of Pediatrics, Children’s Hospital-Los Angeles, Los Angeles, CA USA
| | - Patricia Campbell
- Alberta Transplant Institute, Edmonton, AB, Canada,Departemtent of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | | | - Juliet Emamaullee
- Department of Surgery, Division of Abdominal Organ Transplant, University of Southern California, Los Angeles, CA, USA,University of Southern California, Los Angeles, CA, USA,Division of Hepatobiliary and Abdominal Organ Transplantation Surgery, Children’s Hospital-Los Angeles, Los Angeles, CA USA
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25
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Mangiola M, Marrari M, Xu Q, Sanchez PG, Zeevi A. Approaching the sensitized lung patient: risk assessment for donor acceptance. J Thorac Dis 2022; 13:6725-6736. [PMID: 34992848 PMCID: PMC8662510 DOI: 10.21037/jtd-2021-21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 05/14/2021] [Indexed: 12/16/2022]
Abstract
The presence of HLA antibodies is widely recognized as a barrier to solid organ transplantation, and for lung transplant candidates, it has a significant negative impact on both waiting time and waiting list mortality. Although HLA antibodies have been associated with a broad spectrum of allograft damage, precise characterization of these antibodies in allosensitized candidates may enhance their accessibility to transplant. The introduction of Luminex-based single antigen bead (SAB) assays has significantly improved antibody detection sensitivity and specificity, but SAB alone is not sufficient for risk-stratification. Functional characterization of donor-specific antibodies (DSA) is paramount to increase donor accessibility for allosensitized lung candidates. We describe here our approach to evaluate sensitized lung transplant candidates. By employing state-of-the-art technologies to assess histocompatibility and determine physiological properties of circulating HLA antibodies, we can provide our Clinical Team a better risk assessment for lung transplant candidates and facilitate a "road map" to transplant. The cases presented in this paper illustrate the "individualized steps" taken to determine calculated panel reactive antibodies (cPRA), titer and complement-fixing properties of each HLA antibody present in circulation. When a donor is considered, we can better predict the risk associated with potentially crossing HLA antibodies, thereby allowing the Clinical Team to approach allosensitized lung patients with an individualized medicine approach. To facilitate safe access of sensitized lung transplant candidates to potential donors, a synergy between the histocompatibility laboratory and the Clinical Team is essential. Ultimately, donor acceptance is a decision based on several parameters, leading to a risk-stratification unique for each patient.
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Affiliation(s)
| | - Marilyn Marrari
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Qingyong Xu
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Pablo G Sanchez
- Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Adriana Zeevi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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26
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Si Z, Dong C, Sun C, Wang K, Zhang W, Zheng W, Wei X, Gao W, Shen Z. Nomograms for Predicting the Incidence of Late-Onset Acute Cellular Rejection in Patients After Pediatric Liver Transplantation. Front Pediatr 2022; 10:915795. [PMID: 35722503 PMCID: PMC9203720 DOI: 10.3389/fped.2022.915795] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 05/16/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Late-onset acute cellular rejection (LACR) is a special type of acute rejection (AR) only rarely studied after pediatric liver transplantation (pLT). Our study aimed to explore the influencing factors of LACR after pLT and establish a nomogram to provide an individualized prediction of LACR after pLT. MATERIALS AND METHODS Data from 640 children who underwent pLT at Tianjin First Central Hospital from January 2016 to December 2019 were collected as part of this retrospective study. The nomogram was then established through the results of the multivariable analysis. RESULTS Forty-one patients experienced LACR > 1 ≤ 2 years after pLT. Cold ischemia time, donor-specific antibodies (DSAs), and tacrolimus concentration were independent influencing factors, and a nomogram was established with an AUC value of 0.834 (95% confidence interval, 0.755-0.912). Ten-fold cross-validation showed that the accuracy of the nomogram was about 76%. Sixty-three patients experienced LACR > 2 years after pLT. Child-Pugh grade, cold ischemic time, DSAs, early acute cellular rejection, and tacrolimus concentration were independent influencing factors, and a nomogram was established with an AUC value of 0.827 (95% confidence interval, 0.774-0.881). Ten-fold cross-validation showed that the accuracy of the nomogram was about 80.9%. CONCLUSION We established nomograms to predict the incidence of LACR > 1 ≤ 2 and > 2 years after pLT, respectively. The verification results showed that nomograms had good accuracy and clinical practicability.
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Affiliation(s)
- Zhuyuan Si
- First Central Clinic Institute, Tianjin Medical University, Tianjin, China
| | - Chong Dong
- Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Chao Sun
- Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Kai Wang
- Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Wei Zhang
- Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Weiping Zheng
- Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Xinzhe Wei
- Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China
| | - Wei Gao
- Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China.,Key Laboratory of Transplantation, Chinese Academy of Medical Sciences, Tianjin First Central Hospital, Tianjin, China.,Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
| | - Zhongyang Shen
- Organ Transplantation Center, Tianjin First Central Hospital, Tianjin, China.,Key Laboratory of Transplantation, Chinese Academy of Medical Sciences, Tianjin First Central Hospital, Tianjin, China.,Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, China
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27
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Protocol liver biopsies in stable long-term pediatric liver transplant recipients: risk or benefit? Eur J Gastroenterol Hepatol 2021; 33:e223-e232. [PMID: 33405423 DOI: 10.1097/meg.0000000000002006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Follow-up after pediatric liver transplantation (LTX) is challenging and needs to be refined to extend graft survival as well as general functional health and patients´ quality of life. Strategies towards individual immunosuppressive therapy seem to play a key role. Our aim was to evaluate protocol liver biopsies (PLB) as a tool in personalized follow up after pediatric LTX. PATIENTS AND METHODS Our retrospective analysis evaluates 92 PLB in clinically asymptomatic pediatric patients after LTX between 2009 and 2019. Histological findings were characterized using the Desmet scoring system. In addition to PLB, other follow-up tools like laboratory parameters, ultrasound imaging and transient elastography were evaluated. Risk factors for development of fibrosis or inflammation were analyzed. RESULTS PLB revealed a high prevalence of graft fibrosis (67.4%) and graft inflammation (47.8%). Graft inflammation was significantly (P = 0.0353*) more frequent within the first 5 years after transplantation compared to later time points. Besides conventional ultrasound, the measurement of liver stiffness using transient elastography correlate with stage of fibrosis (r = 0.567, P = <0.0001***). Presence of donor-specific anti-human leukocyte antigen antibodies in blood correlates with grade of inflammation in PLB (r = 0.6040, P = 0.0018 **). None of the patients who underwent PLB suffered from intervention-related complications. Histopathological results had an impact on clinical decision making in one-third of all patients after PLB. CONCLUSION PLB are a safe and useful tool to detect silent immune-mediated allograft injuries in the context of normal liver parameters.
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28
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Lee BT, Fiel MI, Schiano TD. Antibody-mediated rejection of the liver allograft: An update and a clinico-pathological perspective. J Hepatol 2021; 75:1203-1216. [PMID: 34343613 DOI: 10.1016/j.jhep.2021.07.027] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 07/06/2021] [Accepted: 07/14/2021] [Indexed: 12/16/2022]
Abstract
Antibody-mediated rejection after liver transplantation is an under-recognised cause of allograft injury. While definitions of acute and chronic antibody-mediated rejection have increased clinical awareness, timely identification and management of antibody-mediated rejection remain difficult because of complexities in diagnosis and histopathology, lack of treatment protocols, and unclear long-term outcomes. While recent cohort studies assessing the importance of donor-specific antibodies have aided in its diagnosis, literature on the treatment of antibody-mediated rejection in liver transplantation remain limited to case reports and small series. Further increasing the awareness and timely recognition of antibody-mediated rejection post-liver transplantation is crucial in order to stimulate future research and the development of protocols for its diagnosis and treatment. This review will summarise recent advances in the clinical diagnosis and treatment of antibody-mediated rejection in liver transplantation, as well as some of the histopathologic features (on liver biopsy tissue) of acute and chronic antibody-mediated rejection.
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Affiliation(s)
- Brian T Lee
- Division of Gastroenterology and Transplant Institute, Loma Linda University Health, Loma Linda, CA, USA.
| | - M Isabel Fiel
- Department of Pathology, Molecular and Cell-Based Medicine, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Thomas D Schiano
- Division of Liver Diseases, Department of Medicine, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
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29
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Zhou S, Mitsinikos T, Emamaullee J, Weaver C, Wang L, Shillingford N, Warren M, Bawab JH, Tiwari N, Genyk Y, Thomas D, Parham DM. Clinicopathologic Characteristics of Late Acute Antibody-mediated Rejection in Pediatric Liver Transplantation. Transplantation 2021; 105:2045-2053. [PMID: 33031223 DOI: 10.1097/tp.0000000000003469] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND An early and accurate diagnosis of liver antibody-mediated rejection (AMR) followed by timely intervention is important for clinical management but remains challenging. The aim of this study was to assess the clinicopathologic characteristics and outcomes of late acute AMR in pediatric liver transplantation recipients. METHODS We performed a retrospective review of 739 ABO-identical/compatible allograft liver biopsies from 199 pediatric transplantation recipients. RESULTS Based on Banff 2016 AMR criteria, 3 recipients fulfilled the criteria for definite for late acute AMR, 2 met the criteria for suspicious for AMR, and 2 were indeterminate for AMR. We further assessed the clinicopathologic characteristics of these 7 patients. All 7 patients had at least 1 biopsy with a histopathologic pattern compatible with acute AMR. Additionally, we observed accompanied moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury in all 7 patients; periportal/perivenular hepatocyte necrosis was seen in 6 of 7 patients; and arteritis was seen in 3 of 7 patients. In each case, microvascular C4d deposition was present in at least 1 biopsy. Posttransplant donor specific anti-HLA antibodies were detected in 5 patients. Two of 7 patients were retransplanted, and 2 died after developing refractory AMR. The remaining 5 patients were alive with stable graft function at a median follow-up of 4.1 years. CONCLUSIONS Our data suggest that acute AMR in pediatric liver grafts is rare, can develop late, and may be associated with graft loss or patient death. The recurrent histopathologic findings of moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury are features that appear unique to pediatric acute AMR of liver grafts.
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Affiliation(s)
- Shengmei Zhou
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA
- Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Tania Mitsinikos
- Keck School of Medicine, University of Southern California, Los Angeles, CA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA
| | - Juliet Emamaullee
- Keck School of Medicine, University of Southern California, Los Angeles, CA
- Department of Surgery, Children's Hospital Los Angeles, Los Angeles, CA
| | - Carly Weaver
- Department of Surgery, Children's Hospital Los Angeles, Los Angeles, CA
| | - Larry Wang
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA
- Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Nick Shillingford
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA
- Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Mikako Warren
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA
- Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Julie Huss Bawab
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA
| | - Nishant Tiwari
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA
| | - Yuri Genyk
- Keck School of Medicine, University of Southern California, Los Angeles, CA
- Department of Surgery, Children's Hospital Los Angeles, Los Angeles, CA
| | - Danny Thomas
- Keck School of Medicine, University of Southern California, Los Angeles, CA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA
| | - David M Parham
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA
- Keck School of Medicine, University of Southern California, Los Angeles, CA
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30
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Vo HD, Radio SJ, Reyes-Santiago EM, Mauch TJ. Post-transplant hepatic fibrosis in pediatric liver-small bowel transplant recipients: A single-center, retrospective, observational study. Pediatr Transplant 2021; 25:e13965. [PMID: 33378567 DOI: 10.1111/petr.13965] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 12/02/2020] [Accepted: 12/15/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND Little is known about the prevalence of hepatic graft fibrosis in combined LSBT children. We aimed to determine the prevalence of and identify potential predictors for hepatic graft fibrosis in LSBT children and to compare them with those in LT children. METHODS We retrospectively included children younger than 19 years who had received a primary LT/LSBT between 2000 and 2018 and had a liver biopsy performed at least 6 months post-transplant. A Cox proportional hazards regression model was used to determine predictors associated with significant hepatic graft fibrosis (≥F2) in LSBT vs LT children. RESULTS Ninety-six children (47 LSBT, 54 females) were included. The median post-transplant follow-up (years) was 12.8 in LT vs 10.5 in LSBT patients (P = .06). Hepatic graft fibrosis was found in 81.6% of LT vs 70.2% of LSBT children (P = .19), after a median time of 2.5 years and 2.6 years, respectively. On multivariate analyses, having post-transplant biliary complications was found to be associated with significant graft fibrosis in LT children, whereas AST/ALT ratio was found to predict significant hepatic graft fibrosis in LSBT children. The use of parenteral nutrition after transplant was not associated with significant hepatic graft fibrosis. CONCLUSIONS The prevalence of hepatic graft fibrosis in LSBT children did not significantly differ from that in LT children, but the predictors may differ. Future studies should investigate the role of post-transplant autoimmune antibodies and donor-specific antibodies in the development and progression of hepatic graft fibrosis in LSBT children.
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Affiliation(s)
- Hanh D Vo
- Pediatric Gastroenterology, Hepatology, and Nutrition, University of Nebraska Medical Center, Omaha, NE, USA
| | - Stanley J Radio
- Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Emille M Reyes-Santiago
- Pediatric Gastroenterology, Hepatology, and Nutrition, University of Nebraska Medical Center, Omaha, NE, USA
| | - Teri J Mauch
- Pediatric Nephrology, University of Nebraska Medical Center, Omaha, NE, USA
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31
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Tambur AR, Kosmoliaptsis V, Claas FHJ, Mannon RB, Nickerson P, Naesens M. Significance of HLA-DQ in kidney transplantation: time to reevaluate human leukocyte antigen matching priorities to improve transplant outcomes? An expert review and recommendations. Kidney Int 2021; 100:1012-1022. [PMID: 34246656 DOI: 10.1016/j.kint.2021.06.026] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/01/2021] [Accepted: 06/07/2021] [Indexed: 12/14/2022]
Abstract
The weight of human leukocyte antigen (HLA) matching in kidney allocation algorithms, especially in the United States, has been devalued in a stepwise manner, supported by the introduction of modern immunosuppression. The intent was further to reduce the observed ethnic/racial disparity, as data emerged associating HLA matching with decreased access to transplantation for African American patients. In recent years, it has been increasingly recognized that a leading cause of graft loss is chronic antibody-mediated rejection, attributed to the development of de novo antibodies against mismatched donor HLA expressed on the graft. These antibodies are most frequently against donor HLA-DQ molecules. Beyond their impact on graft survival, generation of de novo donor-specific HLA antibodies also leads to increased sensitization, as measured by panel-reactive antibody metrics. Consequently, access to transplantation for patients returning to the waitlist in need of a second transplant is compromised. Herein, we address the implications of reduced HLA matching policies in kidney allocation. We highlight the observed diminished outcome data, the significant financial burden, the long-term health consequences, and, more important, the unintended consequences. We further provide recommendations to examine the impact of donor-recipient HLA class II and specifically HLA-DQα1β1 mismatching, focusing on collection of appropriate data, application of creative simulation approaches, and reconsideration of best practices to reduce inequalities while optimizing patient outcomes.
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Affiliation(s)
- Anat R Tambur
- Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA.
| | - Vasilis Kosmoliaptsis
- Department of Surgery, University of Cambridge, Cambridge, UK; NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation and NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
| | - Frans H J Claas
- Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands
| | - Roslyn B Mannon
- Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Peter Nickerson
- Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
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32
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Schotters FL, Beime J, Briem-Richter A, Binder T, Herden U, Grabhorn EF. Impact of donor-specific antibodies on long-term graft survival with pediatric liver transplantation. World J Hepatol 2021; 13:673-685. [PMID: 34239702 PMCID: PMC8239487 DOI: 10.4254/wjh.v13.i6.673] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/12/2021] [Accepted: 05/21/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In a previous paper, we reported a high prevalence of donor-specific antibody (DSA) in pediatric patients with chronic rejection and expressed the need for confirmation of these findings in a larger cohort.
AIM To clarify the importance of DSAs on long-term graft survival in a larger cohort of pediatric patients.
METHODS We performed a retrospective analysis of 123 pediatric liver transplantation (LT) recipients who participated in yearly follow-ups including Luminex testing for DSA at our center. The cohort was split into two groups according to the DSA status (DSA-positive n = 54, DSA-negative n = 69). Groups were compared with regard to liver function, biopsy findings, graft survival, need for re-LT and immunosuppressive medication.
RESULTS DSA-positive pediatric patients showed a higher prevalence of chronic rejection (P = 0.01), fibrosis (P < 0.001) and re-transplantation (P = 0.018) than DSA-negative patients. Class II DSAs particularly influenced graft survival. Alleles DQ2, DQ7, DQ8 and DQ9 might serve as indicators for the risk of chronic rejection and/or allograft fibrosis. Mean fluorescence intensity levels and DSA number did not impact graft survival. Previous episodes of chronic rejection might lead to DSA development.
CONCLUSION DSA prevalence significantly affected long-term liver allograft performance and liver allograft survival in our cohort of pediatric LT. Screening for class II DSAs in combination with assessment of protocol liver biopsies for chronic antibody-mediated rejection improved early identification of patients at risk of graft loss.
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Affiliation(s)
- Felicitas Leonie Schotters
- Department of Pediatric Hepatology and Liver Transplantation, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Jan Beime
- Department of Pediatric Hepatology and Liver Transplantation, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Andrea Briem-Richter
- Department of Pediatric Hepatology and Liver Transplantation, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Thomas Binder
- Department of Transfusion Medicine, Human Leucocyte Antigen Laboratory, University Medicine Rostock, Rostock 18057, Germany
| | - Uta Herden
- Department of Hepatobiliary & Transplant Surgery, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Enke Freya Grabhorn
- Department of Pediatric Hepatology and Liver Transplantation, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany
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33
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Liu W, Wang K, Xiao YL, Liu C, Gao W, Li DH. Clinical relevance of donor-specific human leukocyte antigen antibodies after pediatric liver transplantation. Exp Ther Med 2021; 22:867. [PMID: 34194545 PMCID: PMC8237393 DOI: 10.3892/etm.2021.10299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 09/30/2020] [Indexed: 11/06/2022] Open
Abstract
Donor-specific human leukocyte antigen (HLA) antibodies (DSAs) have a significant role in graft survival after pediatric liver transplantation. To understand the significance of DSAs, a retrospective cohort study of 48 pediatric liver transplant recipients with posttransplant serum samples that were analyzed for DSAs was performed. According to their test results, the recipients were divided into a DSA-positive group and a DSA-negative group. Postoperative liver transplantation biopsies were performed in patients with abnormal liver function. The liver condition and prognosis of the recipients were recorded, and their association was analyzed. A total of 48 recipients were followed up for 2.7±0.8 years. DSA positivity was detected in 10 cases (20.8%). One case was positive for HLA class I and HLA class II antibodies, whereas 9 cases were positive for HLA class II antibodies, and the gene loci were HLA-DR and/or DQ. Antibody-mediated rejection (AMR) occurred in four of 10 patients in the DSA-positive group. Liver function was abnormal in 3 of 38 cases in the DSA-negative group. Multivariate analysis revealed that DSA positivity was an independent risk factor for liver insufficiency and long-term survival of recipients. In addition, Kaplan-Meier survival analysis demonstrated that there were significant differences in the survival of graft recipients between the DSA-positive group and the DSA-negative group (P<0.05). The positivity of DSAs after pediatric liver transplantation was closely related to the occurrence of AMR. These results suggested that DSAs should be routinely monitored post-operatively, and that DSA-positive recipients should be screened as soon as possible and given appropriate treatment.
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Affiliation(s)
- Wei Liu
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Kai Wang
- Department of Transplantation Surgery, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Yan-Li Xiao
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Chun Liu
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Wei Gao
- Department of Transplantation Surgery, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Dai-Hong Li
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin 300192, P.R. China
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34
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Götz JK, Kiene H, Goldschmidt I, Junge N, Pfister ED, Leiskau C, Brown RM, Immenschuh S, Baumann U. Current Evidence on the Clinical Relevance of Donor-specific Antibodies in Paediatric Liver Transplantation. J Pediatr Gastroenterol Nutr 2021; 72:788-793. [PMID: 33908737 DOI: 10.1097/mpg.0000000000003127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
ABSTRACT The clinical impact of donor-specific antibodies (DSA) occurring before or after liver transplantation (LT) against donor-human leucocyte antigen (HLA) on graft outcome is still unclear. We aim to present the current consensus based on recent paediatric LT case series. Compared to kidney transplantation, the liver seems to be less susceptible to antibody-mediated graft damage, which is likely due to protective Kupffer cell activity. The incidence of DSA after liver transplantation is higher in children than in adults. DSA directed against HLA class II molecules, mainly DQ, occur more often. The presence of such anti-class II DSA (DQ/DR), especially of the complement-binding IgG3 subclass, may be associated with endothelial injury, T-cell-mediated rejection (TCMR), inflammation, and fibrosis. Regular DSA-posttransplant monitoring cannot as yet be recommended in routine practice but may be useful in selected cases.
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Affiliation(s)
- Juliane K Götz
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases
| | - Hella Kiene
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases
| | - Imeke Goldschmidt
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases
| | - Norman Junge
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases
| | - Eva-Doreen Pfister
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases
| | - Christoph Leiskau
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases
| | - Rachel M Brown
- Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham
- Department of Histopathology, Birmingham Children's Hospital
| | - Stephan Immenschuh
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Ulrich Baumann
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases
- Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
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35
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Sultani B, Marget M, Briem-Richter A, Herrmann J, Meisner S, Grabhorn EF, Ozga AK, Weidemann S, Herden U, Fischer L, Sterneck M. Presence of donor specific HLA class 2 antibodies (DSA class 2) is associated with development of graft fibrosis more than 10 years after liver transplantation-a retrospective single center study. Clin Transplant 2021; 35:e14336. [PMID: 33949011 DOI: 10.1111/ctr.14336] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 04/13/2021] [Accepted: 04/26/2021] [Indexed: 02/06/2023]
Abstract
Here the impact of donor specific human leukocyte antigen (HLA) class 2 antibodies (DSA cl 2) on long term outcome after liver transplantation (LT) was investigated. Altogether 156 (44 pediatric and 112 adult) LT recipients were included in the study. Graft fibrosis was assessed by liver elastography and biopsy. DSA cl 2 were determined by Luminex technology. 46% of LT recipients were positive for DSA cl 2 after a median follow-up of 15 years. In the multivariate analysis DSA cl 2 were significantly associated with immunosuppressive monotherapy (OR 5.42; 95% CI: 1.02-28.90; p = .048). Compared to DSA cl 2 negative patients, positive recipients had significantly more graft fibrosis based on the liver stiffness (mean 9.4 ± 9.0 kPa vs. 6.5 ± 6.3 kPa; p < .002) and fibrosis stages determined by liver elastography (p = .016) and the performed liver biopsies (p = .002). Also, a significantly higher incidence of chronic rejections (11% vs. 2%; p = .045) and graft losses (6% vs. 0%; p = .043) were found. In the multivariate regression analysis DSA cl 2 were significantly associated with graft fibrosis (OR 4.57; 95% CI 1.59-13.10; p = .005). So, these data suggest that development of DSA cl 2 occurs more often with immunosuppressive monotherapy and may ultimately result in chronic rejection and graft fibrosis.
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Affiliation(s)
- Bejan Sultani
- Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Matthias Marget
- Institute of Transfusion Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Andrea Briem-Richter
- Department of Pediatric Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Jochen Herrmann
- Department of Pediatric Radiology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Sebastian Meisner
- Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Enke Freya Grabhorn
- Department of Pediatric Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Ann-Kathrin Ozga
- Insitute of Medical Biometry, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Sören Weidemann
- Department of Pathology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Uta Herden
- Department of Visceral Transplantation, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Lutz Fischer
- Department of Visceral Transplantation, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Martina Sterneck
- Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany
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Feng S, Bucuvalas JC, Mazariegos GV, Magee JC, Sanchez-Fueyo A, Spain KM, Lesniak A, Kanaparthi S, Perito E, Venkat VL, Burrell BE, Alonso EM, Bridges ND, Doo E, Gupta NA, Himes RW, Ikle D, Jackson AM, Lobritto SJ, Lozano JJ, Martinez M, Ng VL, Rand EB, Sherker AH, Sundaram SS, Turmelle YP, Wood-Trageser M, Demetris AJ. Efficacy and Safety of Immunosuppression Withdrawal in Pediatric Liver Transplant Recipients: Moving Toward Personalized Management. Hepatology 2021; 73:1985-2004. [PMID: 32786149 PMCID: PMC12105584 DOI: 10.1002/hep.31520] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/13/2020] [Accepted: 07/26/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Tolerance is transplantation's holy grail, as it denotes allograft health without immunosuppression and its toxicities. Our aim was to determine, among stable long-term pediatric liver transplant recipients, the efficacy and safety of immunosuppression withdrawal to identify operational tolerance. APPROACH AND RESULTS We conducted a multicenter, single-arm trial of immunosuppression withdrawal over 36-48 weeks. Liver tests were monitored biweekly (year 1), monthly (year 2), and bimonthly (years 3-4). For-cause biopsies were done at investigators' discretion but mandated when alanine aminotransferase or gamma glutamyltransferase exceeded 100 U/L. All subjects underwent final liver biopsy at trial end. The primary efficacy endpoint was operational tolerance, defined by strict biochemical and histological criteria 1 year after stopping immunosuppression. Among 88 subjects (median age 11 years; 39 boys; 57 deceased donor grafts), 33 (37.5%; 95% confidence interval [CI] 27.4%, 48.5%) were operationally tolerant, 16 were nontolerant by histology (met biochemical but failed histological criteria), and 39 were nontolerant by rejection. Rejection, predicted by subtle liver inflammation in trial entry biopsies, typically (n = 32) occurred at ≤32% of the trial-entry immunosuppression dose and was treated with corticosteroids (n = 32) and/or tacrolimus (n = 38) with resolution (liver tests within 1.5 times the baseline) for all but 1 subject. No death, graft loss, or chronic, severe, or refractory rejection occurred. Neither fibrosis stage nor the expression level of a rejection gene set increased over 4 years for either tolerant or nontolerant subjects. CONCLUSIONS Immunosuppression withdrawal showed that 37.5% of selected pediatric liver-transplant recipients were operationally tolerant. Allograft histology did not deteriorate for either tolerant or nontolerant subjects. The timing and reversibility of failed withdrawal justifies future trials exploring the efficacy, safety, and potential benefits of immunosuppression minimization.
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Affiliation(s)
- Sandy Feng
- Division of Transplantation, Department of Surgery, University of California San Francisco, San Francisco, CA
| | - John C. Bucuvalas
- Mount Sinai Kravis Children’s Hospital and Recanati/Miller Transplantation Institute, Mount Sinai Health System, New York, NY
| | - George V. Mazariegos
- Hillman Center for Pediatric Transplantation, Children’s Hospital of Pittsburgh, Pittsburgh, PA
| | - John C. Magee
- Section of Transplant Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI
| | | | | | - Andrew Lesniak
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA
| | | | - Emily Perito
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of California San Francisco, San Francisco, CA
| | - Veena L. Venkat
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Pittsburgh Medical Center, Children’s Hospital of Pittsburgh, Pittsburgh PA
| | | | - Estella M. Alonso
- Siragusa Transplantation Center, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL
| | - Nancy D. Bridges
- Transplantation Branch, Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, Rockville, MD
| | - Edward Doo
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
| | - Nitika A. Gupta
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
| | - Ryan W. Himes
- Section of Gastroenterology, Hepatology, and Nutrition, Texas Children’s Hospital, Houston, TX
| | | | | | - Steven J. Lobritto
- Center for Liver Diseases and Transplantation, Department of Surgery, Columbia University Irving Medical Center, New York, NY
| | - Juan Jose Lozano
- Bioinformatic Platform, Biomedical Research Center in Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, Barcelona, Spain
| | - Mercedes Martinez
- Center for Liver Diseases and Transplantation, Department of Surgery, Columbia University Irving Medical Center, New York, NY
| | - Vicky L. Ng
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Transplant and Regenerative Medicine Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Elizabeth B. Rand
- Liver Transplant Program, The Children’s Hospital of Pennsylvania, Philadelphia, PA
| | - Averell H. Sherker
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
| | - Shikha S. Sundaram
- Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO
| | - Yumirle P. Turmelle
- Division of Gastroenterology, Hepatology, and Nutrition, Washington University School of Medicine, St. Louis, MO
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Autoantibodies and Donor-specific Antibodies are Associated With Graft Dysfunction in Pediatric Liver Transplantation. J Pediatr Gastroenterol Nutr 2021; 72:661-666. [PMID: 32810036 DOI: 10.1097/mpg.0000000000002913] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVES Autoantibodies (AAb) and donor-specific HLA antibodies (DSA) are frequently present in pediatric liver transplant (LT) recipients. Their clinical significance remains incompletely understood. We aimed to investigate the prevalence of serum AAb and DSA in pediatric LT recipients and its correlation with patient characteristics and histological and biochemical parameters. METHODS We retrospectively reviewed the data from 62 pediatric LT patients in follow-up at Ghent University Hospital between January 2007 and February 2018. Blood samples with AAb measurement were taken systematically, liver biopsies (LB) were performed on clinical indication. RESULTS AAb were detected in 27 (43.3%) patients, with antinuclear antibodies (ANA) being the most frequently (24%) encountered AAb. There was an association between AAb positivity and female gender (P = 0,032) and deceased donor LT (P = 0,006). Patients with positive AAb underwent a higher number of LB during their follow-up (P < 0,001), and an association was found with the presence of nonspecific histologic alterations (P = 0,032) in the absence of de novo autoimmune hepatitis. Positive AAb were also associated with higher alkaline phosphatase (P < 0,001), ALT (P < 0,001), AST (P < 0,001), γ-GT (P = 0,001), IgG (P = 0,011) and lower albumin (P = 0,029). Fourteen out of 50 (28%) patients were DSA-positive, mostly anti-HLA class II. DSA positivity was associated with T-cell-mediated rejection (P = 0,019), higher total (P = 0,033), and direct (P = 0,012) bilirubin and γ-GT (P < 0,001). CONCLUSIONS The presence of AAb and DSA is associated with histological and biochemical parameters of graft dysfunction. Larger prospective studies are warranted to investigate the causal relationships between AAb and DSA development and outcome parameters post pediatric LT.
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Angiotensin II Type-1 Receptor Antibodies Are Associated With Active Allograft Dysfunction Following Pediatric Liver Transplantation. Transplantation 2021; 104:2547-2556. [PMID: 32101982 DOI: 10.1097/tp.0000000000003206] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Angiotensin II type-1 receptor (AT1R) antibodies have been associated with rejection and allograft loss in solid organ transplantation and may act synergistically with HLA donor-specific antibodies (DSA). Our aims were to assess the prevalence of AT1R antibodies and determine if they were associated with allograft dysfunction in pediatric liver transplant recipients. METHODS We performed a retrospective, cross-sectional study of HLA DSA and AT1R antibodies in 2 cohorts of pediatric liver transplant recipients: a stable control cohort with normal allograft function (n = 70) who consented to have serum samples collected for research purposes during a routine clinic visit and a cohort with active allograft dysfunction (n = 9) whose serum samples were collected as part of clinical care. RESULTS AT1R antibodies >17 U/mL were detected in 29% of stable control patients and 89% of patients with active allograft dysfunction (P = 0.001). In stable control patients, AT1R antibodies were associated with younger age at transplant (P = 0.010), younger age at time of sample collection (P < 0.001), shorter interval since transplant (P = 0.090), and presence of HLA DSA (P = 0.003). AT1R antibodies in stable control patients were not associated with rejection or allograft loss. However, AT1R antibodies combined with HLA DSA in patients with active allograft dysfunction were associated with rejection and allograft loss. CONCLUSIONS Our results suggest that AT1R antibodies are more common in patients with active allograft dysfunction and may be a risk factor for worse outcomes. Further research is needed to longitudinally assess the clinical impact of HLA DSA and AT1R antibodies.
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Evaluation of Graft Fibrosis, Inflammation and Donor-specific Antibodies at Protocol Liver Biopsies in Pediatric Liver Transplant Patients: a Single Center Experience. Transplantation 2021; 106:85-95. [PMID: 33496554 DOI: 10.1097/tp.0000000000003649] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND The impact of graft fibrosis and inflammation on the natural history of pediatric liver transplants (LT) is still debated. Our objectives were to evaluate the evolution of posttransplant fibrosis and inflammation over time at protocol liver biopsies (PLBs), risk factors for fibrosis, presence of donor-specific antibodies (DSAs) and/or their correlation with graft and recipient factors. METHODS A single-center, retrospective (2000-2019) cross-sectional study on pediatric LT recipients who had at least one PLB, followed by a longitudinal evaluation in those who had at least two PLBs, was conducted. Fibrosis was assessed by the Liver Allograft Fibrosis Semiquantitative score, inflammation by the Rejection Activity Index, DSAs by Luminex®. RESULTS A total of 134 PLBs from 94 patients were included. Fibrosis was detected in 87% (30% mild, 45% moderate, 12% severe), 80% in the portal tracts. There was an increase in fibrosis between the 1-3 and the 4-6 year group (p=0.01), then it was stable. Inflammation was observed in 44% (30% mild, 13% moderate, 1% severe), 90% in the portal tracts. Anti-HLA II (IgG) DSAs were detected in 14/40 (35%). Portal fibrosis was associated with portal inflammation in the 1-3 year group (p=0.04). Low immunosuppression levels were correlated with sinusoidal fibrosis (p=0.04) and DSA positivity (p-value=0.006). There was no statistically significant correlation between DSA positivity and the presence of graft fibrosis or inflammation. CONCLUSIONS This study corroborates the concept of an early evolution of silent graft fibrosis. Suboptimal immunosuppression may play a role in the development of fibrosis and DSAs.
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40
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Thomson AW, Vionnet J, Sanchez-Fueyo A. Understanding, predicting and achieving liver transplant tolerance: from bench to bedside. Nat Rev Gastroenterol Hepatol 2020; 17:719-739. [PMID: 32759983 DOI: 10.1038/s41575-020-0334-4] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/11/2020] [Indexed: 02/07/2023]
Abstract
In the past 40 years, liver transplantation has evolved from a high-risk procedure to one that offers high success rates for reversal of liver dysfunction and excellent patient and graft survival. The liver is the most tolerogenic of transplanted organs; indeed, immunosuppressive therapy can be completely withdrawn without rejection of the graft in carefully selected, stable long-term liver recipients. However, in other recipients, chronic allograft injury, late graft failure and the adverse effects of anti-rejection therapy remain important obstacles to improved success. The liver has a unique composition of parenchymal and immune cells that regulate innate and adaptive immunity and that can promote antigen-specific tolerance. Although the mechanisms underlying liver transplant tolerance are not well understood, important insights have been gained into how the local microenvironment, hepatic immune cells and specific molecular pathways can promote donor-specific tolerance. These insights provide a basis for the identification of potential clinical biomarkers that might correlate with tolerance or rejection and for the development of novel therapeutic targets. Innovative approaches aimed at promoting immunosuppressive drug minimization or withdrawal include the adoptive transfer of donor-derived or recipient-derived regulatory immune cells to promote liver transplant tolerance. In this Review, we summarize and discuss these developments and their implications for liver transplantation.
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Affiliation(s)
- Angus W Thomson
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. .,Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| | - Julien Vionnet
- Institute of Liver Studies, Medical Research Council (MRC) Centre for Transplantation, School of Immunology and Infectious Diseases, King's College London University, King's College Hospital, London, UK.,Transplantation Center, University Hospital of Lausanne, Lausanne, Switzerland.,Service of Gastroenterology and Hepatology, University Hospital of Lausanne, Lausanne, Switzerland
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, Medical Research Council (MRC) Centre for Transplantation, School of Immunology and Infectious Diseases, King's College London University, King's College Hospital, London, UK
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Kovandova B, Slavcev A, Honsova E, Erhartova D, Skibova J, Viklicky O, Trunecka P. De novo HLA Class II antibodies are associated with the development of chronic but not acute antibody-mediated rejection after liver transplantation - a retrospective study. Transpl Int 2020; 33:1799-1806. [PMID: 33020979 DOI: 10.1111/tri.13763] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/04/2020] [Accepted: 09/28/2020] [Indexed: 02/02/2023]
Abstract
Donor-specific antibodies (DSA) cause antibody-mediated rejection (AMR); however, their pathogenic role has not yet been adequately investigated after liver transplantation. The aim of our study was to analyse the clinical significance of DSA and complement-binding DSA for the prediction of AMR after liver transplantation. Our cohort included 120 liver recipients with assessed protocol biopsies one year post-transplant. All patients had defined HLA-specific and complement-binding (C1q + and C3d+) antibodies before and in regular intervals after transplantation. The incidence of DSA was evaluated in relation with clinical and histopathological data in the liver allografts. A higher occurrence of acute AMR was observed in recipients with preformed complement-binding DSA to HLA Class I antigens. Patients who developed chronic AMR had more frequently de novo-produced antibodies against HLA Class II antigens (P = 0.0002). A correlation was also found between de novo-formed C1q + and C3d+-binding antibodies to HLA Class II antigens and the development of chronic AMR (P = 0.043). Our study implies that preformed complement-binding DSA to HLA Class I antigens are related to increased risk of acute antibody-mediated rejection, while chronic AMR is more frequent in patients with de novo-produced antibodies to HLA Class II antigens after liver transplantation.
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Affiliation(s)
| | | | - Eva Honsova
- Department of Clinical & Transplantation Pathology, IKEM, Prague, Czech Republic
| | - Denisa Erhartova
- Department of Hepatogastroenterology, IKEM, Prague, Czech Republic
| | - Jelena Skibova
- Department of Medical Statistics, IKEM, Prague, Czech Republic
| | | | - Pavel Trunecka
- Department of Hepatogastroenterology, IKEM, Prague, Czech Republic
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Donor-specific antibodies in liver transplantation: challenges in diagnosis and determining clinical impact. Curr Opin Organ Transplant 2020; 25:549-554. [PMID: 33105198 DOI: 10.1097/mot.0000000000000825] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW Our understanding of the clinical impact of donor-specific antibodies in liver transplant recipients has evolved in recent years as outcomes for liver allografts have improved and advances in diagnostic testing have made recognition of antibody mediated rejection in transplant patients more sensitive. RECENT FINDINGS Two main types of donor-specific antibodies - preformed and de novo - have been reported in the literature to have a negative impact on graft survival, and researchers have been able to further identify subclasses of class II donor-specific antibodies as being the most clinically impactful. Furthermore, there is evidence that donor-specific antibody formation can augment cellular rejection in liver grafts and lead to worsened clinical outcomes. Recent data have shown a higher prevalence of donor-specific antibody formation than previously reported. SUMMARY This review explores the most recent literature regarding the clinical impact of both preformed and de-novo donor-specific antibodies and potential management guidelines for patients undergoing liver transplantation. The best practice guidelines for undergoing monitoring for donor-specific antibody formation and protocol biopsies in sensitized patients will depend on further multiinstitutional studies.
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DSA Are Associated With More Graft Injury, More Fibrosis, and Upregulation of Rejection-associated Transcripts in Subclinical Rejection. Transplantation 2020; 104:551-561. [PMID: 31651790 DOI: 10.1097/tp.0000000000003034] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND Subclinical T cell-mediated rejection (subTCMR) is commonly found after liver transplantation and has a good short-term prognosis, even when it is left untreated. Donor-specific antibodies (DSA) are putatively associated with a worse prognosis for recipient and graft after liver transplantation. METHODS To assess the immune regulation in subTCMR grafts, gene expression of 93 transcripts for graft injury, tolerance, and immune regulation was analyzed in 77 biopsies with "no histologic rejection" (NHR; n = 25), "clinical TCMR" (cTMCR; n = 16), and subTCMR (n = 36). In addition, all available subTCMR biopsies (n = 71) were tested for DSA with bead assays. RESULTS SubTCMR showed heterogeneous and intermediate expression profiles of transcripts that were upregulated in cTCMR. Graft gene expression suggested a lower activation of effector lymphocytes and a higher activation of regulatory T cells in grafts with subTCMR compared to cTCMR. DSA positivity in subTCMR was associated with histological evidence of more severe graft inflammation and fibrosis. This more severe DSA+ associated graft injury in subTCMR was converged with an upregulation of cTCMR-associated transcripts. In nonsupervised analysis, DSA positive subTCMR mostly clustered together with cTCMR, while DSA negative subTCMR clustered together with NHR. CONCLUSIONS T cell-mediated rejection seems to form a continuum of alloimmune activation. Although subTCMR exhibited less expression of TCMR-associated transcript, DSA positivity in subTCMR was associated with an upregulation of rejection-associated transcripts. The identification of DSA positive subclinical rejection might help to define patients with more inflammation in the graft and development of fibrosis.
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Tokodai K, Miyagi S, Nakanishi W, Fujio A, Kashiwadate T, Goto M, Unno M, Kamei T. Effects of re-augmenting maintenance immunosuppression on post-transplant donor-specific HLA antibodies in liver transplantation. Transpl Immunol 2020; 63:101334. [PMID: 32919028 DOI: 10.1016/j.trim.2020.101334] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 09/05/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Donor-specific antibodies (DSAs) have various negative short- and long-term effects after organ transplantation. DSAs are prevalent in patients with insufficient immunosuppression; thus, even patients with stable conditions after liver transplantation should be under optimized immunosuppression. However, the effect of re-augmenting immunosuppression therapy for patients with insufficient immunosuppression remains unclear. In this study, we investigated the long-term changes and the effects of immunosuppression (IS) re-augmentation on the DSA status. METHODS Two DSA screenings were performed in 67 patients during long-term follow-up after liver transplantation. After the first screening, IS re-augmentation was performed in patients with consent. The effects of IS re-augmentation on the DSA status were analyzed using data of the serial DSA screenings. Negative conversion was defined as DSA positivity with MFI > 1000 converted to MFI < 1000. Improvement of DSA status was defined as either a 50% reduction of MFI or negative conversion. RESULTS The median interval between the first and second DSA screening was 50 months. Among 67 patients, 43 were positive for DSAs on the first screening. Among these 43 patients, 30 had minimal to no IS therapy at the time of the first screening. Among the 30 patients, IS re-augmentation was conducted in 19. A comparison between the patients with a re-augmented IS and those with a sustained minimized IS showed that the DSA levels significantly decreased in the former (63% (12/19) vs. 18% (2/11), p = 0.02). CONCLUSIONS The results of this study indicate that post-liver transplant IS re-augmentation had suppressive effects on the DSA status. However, the clinical significance of DSA-negative conversion and/or mean fluorescence intensity reduction needs to be further investigated through histological evaluation and/or graft survival during longer follow-up periods.
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Affiliation(s)
- Kazuaki Tokodai
- Department of Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan.
| | - Shigehito Miyagi
- Department of Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan
| | - Wataru Nakanishi
- Department of Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan
| | - Atsushi Fujio
- Department of Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan
| | - Toshiaki Kashiwadate
- Department of Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan
| | - Masafumi Goto
- Department of Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan; Division of Transplantation and Regenerative Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan
| | - Takashi Kamei
- Department of Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan
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Höfer A, Jonigk D, Hartleben B, Verboom M, Hallensleben M, Manns MP, Jaeckel E, Taubert R. Non-invasive screening for subclinical liver graft injury in adults via donor-specific anti-HLA antibodies. Sci Rep 2020; 10:14242. [PMID: 32859929 PMCID: PMC7455737 DOI: 10.1038/s41598-020-70938-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 07/02/2020] [Indexed: 02/06/2023] Open
Abstract
The majority of liver grafts exhibit abnormal histological findings late after transplantation, even when liver enzymes are normal. Such subclinical graft injuries were associated with rejection and fibrosis progression in recent studies. The identification of non-invasive biomarkers for subclinical graft injury might help to individualize immunosuppression. Therefore, graft injury was assessed in 133 liver biopsies with normal/near normal liver enzymes from a prospective liver biopsy program. Cytokeratin-18 cell death marker (M65) and donor specific anti-HLA antibodies (DSA) were measured as non-invasive markers in paired plasma samples in addition to routine parameters. M65 was associated with subclinical graft injury but this association was too weak for reasonable clinical application. DSA positivity was associated with more graft inflammation (OR = 5.4) and more fibrosis (OR = 4.2). Absence of DSA excluded fibrosis in 87–89%, while presence of DSA excluded histological criteria for immunosuppression minimization attempts in 92–97%. While CK18 cell death marker had no diagnostic value for the detection of subclinical liver graft injury, DSA testing can help to preselect patients for immunosuppression reduction in case of DSA negativity, while DSA positivity should prompt elastography or liver biopsy for the assessment of subclinical graft injury.
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Affiliation(s)
- Anne Höfer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.,European Reference Network On Hepatological Diseases (ERN RARE-LIVER), Hannover, Germany
| | - Danny Jonigk
- Institute for Pathology, Hannover Medical School, Hannover, Germany
| | - Björn Hartleben
- Institute for Pathology, Hannover Medical School, Hannover, Germany
| | - Murielle Verboom
- Institute for Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Michael Hallensleben
- Institute for Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,European Reference Network On Hepatological Diseases (ERN RARE-LIVER), Hannover, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.,European Reference Network On Hepatological Diseases (ERN RARE-LIVER), Hannover, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. .,Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany. .,European Reference Network On Hepatological Diseases (ERN RARE-LIVER), Hannover, Germany.
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Willuweit K, Frey A, Bieniek L, Heinold A, Büchter M, Horn PA, Wedemeyer H, Herzer K. HLA class II donor specific antibodies are associated with graft cirrhosis after liver transplant independent of the mean fluorescence intensity level. BMC Gastroenterol 2020; 20:288. [PMID: 32854625 PMCID: PMC7457295 DOI: 10.1186/s12876-020-01427-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 08/16/2020] [Indexed: 11/18/2022] Open
Abstract
Background The importance of donor-specific antibodies (DSA) after liver transplantation (LT) for graft and patient survival is an ongoing controversy. So far it has not been elucidated when and in how far DSA are harmful for graft and patient survival. Therefore, we had the aim to investigate the association of DSA with complications after LT. Methods Data of 430 LT recipients were collected and statistically analyzed. Detection of HLA antibodies (Ab) was performed by Luminex assay. Results DSA were detected in 81 patients (18.8%). These were mainly HLA class II Ab (81.5%). HLA class II Ab show a higher MFI (median: 5.300) compared to HLA class I Ab (median: 2.300). There is no association between MFI levels and development of complications after LT. However, cirrhosis occurred significantly more often in DSA positive patients (18%) than in patients without detectable DSA (9%, P = 0.027). All DSA positive patients with cirrhosis of the graft showed HLA class II antibodies (OR: 3.028; 95% CI: 1.51–6.075; P = 0.002). Conclusion Occurrence of HLA class II DSA after LT is associated with graft cirrhosis and may indicate a higher risk to develop graft damage independent on MFI and requires an individualized risk management.
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Affiliation(s)
- Katharina Willuweit
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.
| | - Alexandra Frey
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany
| | - Lisa Bieniek
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany
| | - Andreas Heinold
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Matthias Büchter
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.,Department of Internal Medicine, St. Nikolaus Stiftshospital, Andernach Teaching Hospital, University of Bonn, Andernach, Germany
| | - Peter A Horn
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany
| | - Kerstin Herzer
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany
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Cousin VL, Rougemont AL, Rubbia-Brandt L, Wildhaber BE, Villard J, Ferrari-Lacraz S, McLin VA. Peripheral Donor-specific Antibodies Are Associated With Histology and Cellular Subtypes in Protocol Liver Biopsies of Pediatric Recipients. Transplantation 2020; 104:1633-1643. [PMID: 32732841 DOI: 10.1097/tp.0000000000003099] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The cellular infiltrate in protocol liver biopsies (PB) following pediatric liver transplantation remains mostly uncharacterized, yet there is increasing concern about the role of inflammation and fibrosis in long-term liver allografts. We aimed to define cell types in PB and to analyze their relationship with donor-specific antibodies (DSA) and histological phenotype. METHODS PB were performed at least 1 year after transplantation. We identified 4 phenotypes: normal, fibrosis, inflammation, inflammation with fibrosis. Cell types were counted after immunostaining for CD3, CD4, CD8, CD68, CD20, MUM1, and FoxP3. RESULTS Forty-four patients underwent 1 PB between 2000 and 2015. Eleven percent (5/44) of PB displayed normal histology, 13.6% (6/44) fibrosis, 34.1% (15/44) inflammation, and 40.9% (18/44) inflammation and fibrosis. The main cell types in the portal tracts and lobules were CD3+ and CD68+ cells. Frequency of de novo DSA was 63% (27/44). The presence of CD8+ cells in the lobules was associated with fibrosis. Inflammation and fibrosis in PB were associated with the presence of circulating de novo DSA, number of de novo DSA, and C1q binding activity when compared to other phenotypes. CONCLUSIONS T cells (CD3+) and macrophages (CD68+) were the most prevalent cell-types in PB. In the presence of inflammation, portal tracts were enriched in CD3+, CD20+ but displayed fewer CD68+. This coincided with the presence and number of de novo DSA. How these cellular and humoral actors interact is unclear, but peripheral DSA may be a marker of immune cellular activity in the seemingly quiescent allograft.
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Affiliation(s)
- Vladimir L Cousin
- Swiss Pediatric Liver Center, Geneva University Hospitals, Department of Pediatrics, Gynecology, and Obstetrics, University of Geneva, Geneva, Switzerland
| | - Anne-Laure Rougemont
- Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Laura Rubbia-Brandt
- Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Barbara E Wildhaber
- Swiss Pediatric Liver Center, Geneva University Hospitals, Department of Pediatrics, Gynecology, and Obstetrics, University of Geneva, Geneva, Switzerland
- Department of Pediatrics, Gynecology, and Obstetrics, University of Geneva, Geneva, Switzerland
| | - Jean Villard
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
- Transplantation Immunology Unit and National Reference Laboratory for Histocompatibility, Geneva University Hospital and Medical School, Geneva, Switzerland
| | - Sylvie Ferrari-Lacraz
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
- Transplantation Immunology Unit and National Reference Laboratory for Histocompatibility, Geneva University Hospital and Medical School, Geneva, Switzerland
| | - Valérie A McLin
- Swiss Pediatric Liver Center, Geneva University Hospitals, Department of Pediatrics, Gynecology, and Obstetrics, University of Geneva, Geneva, Switzerland
- Department of Pediatrics, Gynecology, and Obstetrics, University of Geneva, Geneva, Switzerland
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Phase I/II Trial of Liver-derived Mesenchymal Stem Cells in Pediatric Liver-based Metabolic Disorders: A Prospective, Open Label, Multicenter, Partially Randomized, Safety Study of One Cycle of Heterologous Human Adult Liver-derived Progenitor Cells (HepaStem) in Urea Cycle Disorders and Crigler-Najjar Syndrome Patients. Transplantation 2020; 103:1903-1915. [PMID: 30801523 DOI: 10.1097/tp.0000000000002605] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Regenerative medicine using stem cell technology is an emerging field that is currently tested for inborn and acquired liver diseases. OBJECTIVE This phase I/II prospective, open label, multicenter, randomized trial aimed primarily at evaluating the safety of Heterologous Human Adult Liver-derived Progenitor Cells (HepaStem) in pediatric patients with urea cycle disorders (UCDs) or Crigler-Najjar (CN) syndrome 6 months posttransplantation. The secondary objective included the assessment of safety up to 12 months postinfusion and of preliminary efficacy. METHODS Fourteen patients with UCDs and 6 with CN syndrome were divided into 3 cohorts by body weight and intraportally infused with 3 doses of HepaStem. Clinical status, portal vein hemodynamics, morphology of the liver, de novo detection of circulating anti-human leukocyte antigen antibodies, and clinically significant adverse events (AEs) and serious adverse events to infusion were evaluated by using an intent-to-treat analysis. RESULTS The overall safety of HepaStem was confirmed. For the entire study period, patient-month incidence rate was 1.76 for the AEs and 0.21 for the serious adverse events, of which 38% occurred within 1 month postinfusion. There was a trend of higher events in UCD as compared with CN patients. Segmental left portal vein thrombosis occurred in 1 patient and intraluminal local transient thrombus in a second patient. The other AEs were in line with expectations for catheter placement, cell infusion, concomitant medications, age, and underlying diseases. CONCLUSIONS This study led to European clinical trial authorization for a phase II study in a homogeneous patient cohort, with repeated infusions and intermediate doses.
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Tolerance studies in liver transplantation: are we fooling ourselves? Curr Opin Organ Transplant 2020; 25:151-157. [DOI: 10.1097/mot.0000000000000738] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Influence of Preformed Antibodies in Liver Transplantation. J Clin Med 2020; 9:jcm9030708. [PMID: 32151032 PMCID: PMC7141359 DOI: 10.3390/jcm9030708] [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: 02/14/2020] [Accepted: 03/02/2020] [Indexed: 12/12/2022] Open
Abstract
The significance of human leukocyte antigen (HLA) matching and preformed donor-specific antibodies (DSAs) in liver transplantation remains unclear. The aim of this study was to analyze the presence of DSAs in a large cohort of 810 liver recipients undergoing liver transplant to determine the influence on acute (AR) or chronic liver rejection (CR), graft loss and allograft survival. DSAs were identified using complement dependent cytotoxicity crossmatch (CDC-CM) and multiplexed solid-phase-based flow cytometry assay (Luminex). CDC-CM showed that a 3.2% of liver transplants were positive (+CDC-CM) with an AR frequency of 19.2% which was not different from that observed in negative patients (-CDC-CM, 22.3%). Only two patients transplanted with +CDC-CM (7.6%) developed CR and suffered re-transplant. +CDC-CM patients showed a significantly lower survival rate compared to -CDC-CM patients (23.1% vs. 59.1%, p = 0.0003), developing allograft failure within the first three months (p < 0.00001). In conclusion, we have demonstrated a relationship between the presence of preformed DSAs and the low graft liver survival, indicating the important role and the potential interest of performing this analysis before liver transplantation. Our results could help to detect patients with an increased risk of graft loss, a better choice of liver receptors as well as the establishment of individualized immunosuppressive regimens.
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