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1
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Abbas K, Mubarak M. Expanding role of antibodies in kidney transplantation. World J Transplant 2025; 15:99220. [DOI: 10.5500/wjt.v15.i1.99220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 10/21/2024] [Accepted: 11/07/2024] [Indexed: 11/26/2024] Open
Abstract
The role of antibodies in kidney transplant (KT) has evolved significantly over the past few decades. This role of antibodies in KT is multifaceted, encompassing both the challenges they pose in terms of antibody-mediated rejection (AMR) and the opportunities for improving transplant outcomes through better detection, prevention, and treatment strategies. As our understanding of the immunological mechanisms continues to evolve, so too will the approaches to managing and harnessing the power of antibodies in KT, ultimately leading to improved patient and graft survival. This narrative review explores the multifaceted roles of antibodies in KT, including their involvement in rejection mechanisms, advancements in desensitization protocols, AMR treatments, and their potential role in monitoring and improving graft survival.
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Affiliation(s)
- Khawar Abbas
- Department of Transplant Immunology, Sindh Institute of Urology & Transplantation, Karachi 74200, Sindh, Pakistan
| | - Muhammed Mubarak
- Javed I. Kazi Department of Histopathology, Sindh Institute of Urology & Transplantation, Karachi 74200, Sindh, Pakistan
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San Segundo D, Comins-Boo A, López-Hoyos M. Anti-Human Leukocyte Antigen Antibody Detection from Terasaki's Humoral Theory to Delisting Strategies in 2024. Int J Mol Sci 2025; 26:630. [PMID: 39859344 PMCID: PMC11766285 DOI: 10.3390/ijms26020630] [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: 12/05/2024] [Revised: 01/03/2025] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
The human leukocyte antigen (HLA) system plays a critical role in transplant immunology, influencing outcomes through various immune-mediated rejection mechanisms. Hyperacute rejection is driven by preformed donor-specific antibodies (DSAs) targeting HLAs, leading to complement activation and graft loss within hours to days. Acute rejection typically occurs within six months post-transplantation, involving cellular and humoral responses, including the formation of de novo DSAs. Chronic rejection, a key factor in long-term graft failure, often involves class II DSAs and complex interactions between the innate and adaptive immune systems. Advancements in HLA antibody detection, particularly single antigen bead (SAB) assays, have improved the sensitivity and characterization of DSAs. However, these assays face challenges like false positives from denatured antigens and false negatives due to low antibody titers or complement competition. Furthermore, molecular mismatch (MM) analysis has emerged as a potential tool for refining donor-recipient compatibility but faces some issues such as a lack of standardization. Highly sensitized patients with calculated panel-reactive antibodies (cPRA) of 100% face barriers to transplantation. Strategies like serum dilution, novel therapies (e.g., Imlifidase), and delisting approaches could refine immunological risk assessment and delisting strategies are essential to expand transplant opportunities for these patients.
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Affiliation(s)
- David San Segundo
- Immunology Department, University Hospital Marqués de Valdecilla, 39008 Santander, Spain; (D.S.S.); (A.C.-B.)
- Institute for Research Marqués de Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Alejandra Comins-Boo
- Immunology Department, University Hospital Marqués de Valdecilla, 39008 Santander, Spain; (D.S.S.); (A.C.-B.)
- Institute for Research Marqués de Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Marcos López-Hoyos
- Immunology Department, University Hospital Marqués de Valdecilla, 39008 Santander, Spain; (D.S.S.); (A.C.-B.)
- Institute for Research Marqués de Valdecilla (IDIVAL), 39011 Santander, Spain
- Departamento de Biología Molecular, Universidad de Cantabria, 39011 Santander, Spain
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Gil-Etayo FJ, Niño-Ramírez JE, Fonseca-Santos M, Arroyo-Sánchez D, Navarro-Bailón A, Vicente Parra A, Jiménez Hernaz I, Terradillos Sánchez P, Boix F, Alcoceba M, Marín L, Pérez-López E, Cabrero M, Martín-López AÁ, López M, Baile M, Avendaño A, Cabero A, García-Bacelar A, Vázquez L, Sánchez-Guijo F, García-Sanz R, López-Corral L, Tejeda Velarde A. Quantifying HLA Mismatches at Epitope Level in Haplo-HSCT: Impact in the Outcome in Strategies Using PTCy. HLA 2024; 104:e15738. [PMID: 39533852 DOI: 10.1111/tan.15738] [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: 04/16/2024] [Revised: 09/23/2024] [Accepted: 10/10/2024] [Indexed: 11/16/2024]
Abstract
Haploidentical haematopoietic stem cell transplantation (haplo-HSCT) is one of the most effective therapies for treating malignant haematological disorders. However, HLA disparities are significant barriers to the success of this process since they increase the risk of graft versus host disease (GvHD). HLA disparities quantification could help to anticipate the probability and degree of GvHD, but the best tool for such quantification remains a challenge. The aim of this study was to quantify the degree of HLA epitope incompatibilities using PIRCHE (Predicted Indirectly Recognisable HLA Epitopes) algorithm for immunogenicity prediction and their potential relationship with GvHD degree and clinical outcome. We studied 145 patients who underwent a haplo-HSCT with post-transplant cyclophosphamide (PTCy) from a related donor between 2013 and 2020 at our centre evaluating molecular HLA mismatches by PIRCHE-algorithm. Patients with PIRCHE Score (PS) I + II > 38 in GvH direction, developed acute GvHD grade II-IV earlier than their counterparts (HR: 1.71, 95% CI: 1.02-2.87, p = 0.032). In addition, PS-B > 1 in GvH direction was an independent risk factor for chronic GvHD, (HR: 2.51, 95% CI 1.17-5.36, p = 0.017). A higher incidence of relapse was found for patients with PS-II > 28 HvG (HR: 9.16, 95% CI: 2.47-33.92, p < 0.001) which also favoured a worse GvHD/relapse-free survival in patients with PS-II > 27 in HvG direction (HR: 1.88, 95% CI: 1.11-3.18, p = 0.017). These findings indicate that the alloreactivity inferred by epitope HLA disparities is associated with post-transplant outcomes. Thus, analysing PS could benefit the selection of the most suitable donors allowing patient stratification based on HLA mismatches in the context of haplo-HSCT with PTCy.
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Affiliation(s)
- Francisco Javier Gil-Etayo
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
- Centro de Investigación Contra el Cáncer (CIC), Salamanca, Spain
| | - Jairo Eduardo Niño-Ramírez
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
- Centro de Investigación Contra el Cáncer (CIC), Salamanca, Spain
| | - Marta Fonseca-Santos
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Contra el Cáncer (CIC), Salamanca, Spain
| | - Daniel Arroyo-Sánchez
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Contra el Cáncer (CIC), Salamanca, Spain
| | - Almudena Navarro-Bailón
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Contra el Cáncer (CIC), Salamanca, Spain
| | - Ariadna Vicente Parra
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
| | - Isabel Jiménez Hernaz
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
| | - Pilar Terradillos Sánchez
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
| | - Francisco Boix
- Transfusion Centre of Comunidad Valenciana, Valencia, Spain
| | - Miguel Alcoceba
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
- Centro de Investigación Contra el Cáncer (CIC), Salamanca, Spain
| | - Luis Marín
- Immunology Unit, Clinical Analysis Department, Albacete University Hospital Complex, Albacete, Spain
| | - Estefanía Pérez-López
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Contra el Cáncer (CIC), Salamanca, Spain
| | - Mónica Cabrero
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Contra el Cáncer (CIC), Salamanca, Spain
| | - Ana África Martín-López
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Contra el Cáncer (CIC), Salamanca, Spain
| | - Miriam López
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Contra el Cáncer (CIC), Salamanca, Spain
| | - Mónica Baile
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Contra el Cáncer (CIC), Salamanca, Spain
| | - Alejandro Avendaño
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Contra el Cáncer (CIC), Salamanca, Spain
| | - Almudena Cabero
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Contra el Cáncer (CIC), Salamanca, Spain
| | - Ana García-Bacelar
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Contra el Cáncer (CIC), Salamanca, Spain
| | - Lourdes Vázquez
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Contra el Cáncer (CIC), Salamanca, Spain
- Faculty of Medicine, University of Salamanca (USAL), Salamanca, Spain
| | - Fermín Sánchez-Guijo
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
- Centro de Investigación Contra el Cáncer (CIC), Salamanca, Spain
- Faculty of Medicine, University of Salamanca (USAL), Salamanca, Spain
| | - Ramón García-Sanz
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
- Centro de Investigación Contra el Cáncer (CIC), Salamanca, Spain
- Faculty of Medicine, University of Salamanca (USAL), Salamanca, Spain
| | - Lucía López-Corral
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
- Centro de Investigación Contra el Cáncer (CIC), Salamanca, Spain
- Faculty of Medicine, University of Salamanca (USAL), Salamanca, Spain
| | - Amalia Tejeda Velarde
- Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
- Centro de Investigación Contra el Cáncer (CIC), Salamanca, Spain
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Mattoo A, Jaffe IS, Keating B, Montgomery RA, Mangiola M. Improving long-term kidney allograft survival by rethinking HLA compatibility: from molecular matching to non-HLA genes. Front Genet 2024; 15:1442018. [PMID: 39415982 PMCID: PMC11480002 DOI: 10.3389/fgene.2024.1442018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 09/19/2024] [Indexed: 10/19/2024] Open
Abstract
Optimizing immunologic compatibility in organ transplantation extends beyond the conventional approach of Human Leukocyte Antigen (HLA) antigen matching, which exhibits significant limitations. A broader comprehension of the roles of classical and non-classical HLA genes in transplantation is imperative for enhancing long-term graft survival. High-resolution molecular HLA genotyping, despite its inherent challenges, has emerged as the cornerstone for precise patient-donor compatibility assessment. Leveraging understanding of eplet biology and indirect immune activation, eplet mismatch calculators and the PIRCHE-II algorithm surpass traditional methods in predicting allograft rejection. Understanding minor histocompatibility antigens may also present an opportunity to personalize the compatibility process. While the application of molecular matching in deceased donor organ allocation presents multiple technical, logistical, and conceptual barriers, rendering it premature for mainstream use, several other areas of donor-recipient matching and post-transplant management are ready to incorporate molecular matching. Provision of molecular mismatch scores to physicians during potential organ offer evaluations could potentially amplify long-term outcomes. The implementation of molecular matching in living organ donation and kidney paired exchange programs is similarly viable. This article will explore the current understanding of immunologic matching in transplantation and the potential applications of epitope and non-epitope molecular biology and genetics in clinical transplantation.
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Affiliation(s)
- Aprajita Mattoo
- *Correspondence: Aprajita Mattoo, ; Ian S. Jaffe, ; Massimo Mangiola,
| | - Ian S. Jaffe
- *Correspondence: Aprajita Mattoo, ; Ian S. Jaffe, ; Massimo Mangiola,
| | | | | | - Massimo Mangiola
- NYU Langone Transplant Institute, New York University Langone Health, New York, NY, United States
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Bezstarosti S, Erpicum P, Maggipinto G, Dreyer GJ, Reinders MEJ, Meziyerh S, Roelen DL, De Fijter JW, Kers J, Weekers L, Beguin Y, Jouret F, Heidt S. Allogeneic mesenchymal stromal cell therapy in kidney transplantation: should repeated human leukocyte antigen mismatches be avoided? Front Genet 2024; 15:1436194. [PMID: 39399215 PMCID: PMC11466828 DOI: 10.3389/fgene.2024.1436194] [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: 05/21/2024] [Accepted: 08/15/2024] [Indexed: 10/15/2024] Open
Abstract
Mesenchymal stromal cells (MSCs) have immunomodulatory properties and are therefore considered promising tools in kidney transplantation. Although most studies have been conducted with autologous MSCs, using allogeneic MSCs as an off-the-shelf product is more feasible in clinical settings. However, allogeneic MSCs could potentially induce an immune response, which might eventually be directed towards the kidney allograft because of shared human leukocyte antigen (HLA) epitope mismatches between the kidney and MSC donor. In this study, we performed in-depth analyses of two cohorts (n = 20) that received third-party MSC therapy after kidney transplantation. While the Neptune Study from Leiden University Medical Center specifically selected MSC to avoid repeated HLA antigen mismatches between kidney and MSC donors, the study from the University of Liège did not perform specific MSC selection. The comparative analyses of amino acid mismatches between these cohorts showed that MSC selection to avoid repeated HLA mismatches at the split antigen level was not sufficient to prevent repeated mismatches at the amino acid level. However, repeated amino acid mismatches were not associated with the occurrence of donor-specific antibodies (DSAs). Thus, the clinical relevance of repeated amino acid mismatches seems to be limited with regard to the risk of DSA formation. Since DSA formation was limited (3 of 20 patients) in this study, larger studies are required to investigate the relevance of preventing repeated HLA mismatches in allogeneic MSC therapy in kidney transplantation.
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Affiliation(s)
- Suzanne Bezstarosti
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, Netherlands
| | - Pauline Erpicum
- Laboratory of Translational Research in Nephrology (LTRN), Interdisciplinary Cluster for Applied Genoproteomics (GIGA) - Cardiovascular Sciences, University of Liège, Liège, Belgium
- Division of Nephrology, CHU Liège, University of Liège, Liège, Belgium
| | - Gianni Maggipinto
- Division of Immuno-Hematology, CHU Liège, University of Liège, Liège, Belgium
| | - Geertje J. Dreyer
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, Netherlands
| | - Marlies E. J. Reinders
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, Netherlands
| | - Soufian Meziyerh
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, Netherlands
| | - Dave L. Roelen
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
| | - Johan W. De Fijter
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, Netherlands
| | - Jesper Kers
- Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
| | - Laurent Weekers
- Division of Nephrology, CHU Liège, University of Liège, Liège, Belgium
| | - Yves Beguin
- Division of Hematology, CHU Liège, University of Liège, Liège, Belgium
| | - François Jouret
- Laboratory of Translational Research in Nephrology (LTRN), Interdisciplinary Cluster for Applied Genoproteomics (GIGA) - Cardiovascular Sciences, University of Liège, Liège, Belgium
- Division of Nephrology, CHU Liège, University of Liège, Liège, Belgium
| | - Sebastiaan Heidt
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
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Gramkow AM, Baatrup JH, Gramkow ET, Thiesson HC, Koefoed-Nielsen P. Association of HLA B- and T-cell molecular mismatches with HLA antibodies, rejection, and graft survival in pediatric kidney transplantation. Pediatr Transplant 2024; 28:e14773. [PMID: 38808702 DOI: 10.1111/petr.14773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 04/01/2024] [Accepted: 04/18/2024] [Indexed: 05/30/2024]
Abstract
BACKGROUND Optimizing graft survival and diminishing human leukocyte antigen (HLA) sensitization are essential for pediatric kidney transplant recipients. More precise HLA matching predicting epitope mismatches could reduce alloreactivity. We investigated the association of predicted HLA B- and T-cell molecular mismatches with the formation of de novo donor-specific antibodies, HLA antibodies, rejection, and graft survival. METHODS Forty-nine pediatric kidney transplant recipients transplanted from 2009 to 2020 were retrospectively studied. Donors and recipients were high-resolution HLA typed, and recipients were screened for HLA antibodies posttransplant. HLA-EMMA (HLA Epitope MisMatch Algorithm) and PIRCHE-II (Predicted Indirectly ReCognizable HLA Epitopes) predicted the molecular mismatches. The association of molecular mismatches and the end-points was explored with logistic regression. RESULTS Five recipients (11%) developed de novo donor-specific antibodies. All five had de novo donor-specific antibodies against HLA class II, with four having HLA-DQ antibodies. We found no associations between PIRCHE-II or HLA-EMMA with de novo donor-specific antibodies, HLA sensitization, graft loss, or rejection. However, we did see a tendency towards an increased odds ratio in PIRCHE-II predicting de novo donor-specific antibodies formation, with an odds ratio of 1.12 (95% CI: 0.99; 1.28) on HLA class II. CONCLUSION While the study revealed no significant associations between the number of molecular mismatches and outcomes, a notable trend was observed - indicating a reduced risk of dnDSA formation with improved molecular match. It is important to acknowledge, however, that the modest population size and limited observed outcomes preclude us from making definitive conclusions.
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Affiliation(s)
- Ann-Maria Gramkow
- Department of Nephrology, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Johanne H Baatrup
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
| | - Emilie T Gramkow
- Department of Nephrology, Odense University Hospital, Odense, Denmark
- Department of Molecular Medicine - Cancer and Inflammation, University of Southern Denmark, Odense, Denmark
| | - Helle C Thiesson
- Department of Nephrology, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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Jucaud V. Allogeneic HLA Humoral Immunogenicity and the Prediction of Donor-Specific HLA Antibody Development. Antibodies (Basel) 2024; 13:61. [PMID: 39189232 PMCID: PMC11348167 DOI: 10.3390/antib13030061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 07/17/2024] [Accepted: 07/22/2024] [Indexed: 08/28/2024] Open
Abstract
The development of de novo donor-specific HLA antibodies (dnDSAs) following solid organ transplantation is considered a major risk factor for poor long-term allograft outcomes. The prediction of dnDSA development is a boon to transplant recipients, yet the assessment of allo-HLA immunogenicity remains imprecise. Despite the recent technological advances, a comprehensive evaluation of allo-HLA immunogenicity, which includes both B and T cell allorecognition, is still warranted. Recent studies have proposed using mismatched HLA epitopes (antibody and T cell) as a prognostic biomarker for humoral alloimmunity. However, the identification of immunogenic HLA mismatches has not progressed despite significant improvements in the identification of permissible mismatches. Certainly, the prediction of dnDSA development may benefit permissible HLA mismatched organ transplantations, personalized immunosuppression, and clinical trial design. However, characteristics that go beyond the listing of mismatched HLA antibody epitopes and T cell epitopes, such as the generation of HLA T cell epitope repertoires, recipient's HLA class II phenotype, and immunosuppressive regiments, are required for the precise assessment of allo-HLA immunogenicity.
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Affiliation(s)
- Vadim Jucaud
- Terasaki Institute for Biomedical Innovation, Los Angeles, CA 91367, USA
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Jabbour R, Heinzel A, Reindl-Schwaighofer R, Gregorich MG, Regele H, Kozakowski N, Kläger J, Fischer G, Kainz A, Becker JU, Wiebe C, Oberbauer R. Early progression of chronic histologic lesions in kidney transplant biopsies is not associated with HLA histocompatibility. Nephrol Dial Transplant 2024; 39:808-817. [PMID: 37960919 PMCID: PMC11181859 DOI: 10.1093/ndt/gfad246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND Early progression of chronic histologic lesions in kidney allografts represents the main finding in graft attrition. The objective of this retrospective cohort study was to elucidate whether HLA histocompatibility is associated with progression of chronic histologic lesions in the first year post-transplant. Established associations of de novo donor-specific antibody (dnDSA) formation with HLA mismatch and microvascular inflammation (MVI) were calculated to allow for comparability with other study cohorts. METHODS We included 117 adult kidney transplant recipients, transplanted between 2016 and 2020 from predominantly deceased donors, who had surveillance biopsies at 3 and 12 months. Histologic lesion scores were assessed according to the Banff classification. HLA mismatch scores [i.e. eplet, predicted indirectly recognizable HLA-epitopes algorithm (PIRCHE-II), HLA epitope mismatch algorithm (HLA-EMMA), HLA whole antigen A/B/DR] were calculated for all transplant pairs. Formation of dnDSAs was quantified by single antigen beads. RESULTS More than one-third of patients exhibited a progression of chronic lesion scores by at least one Banff grade in tubular atrophy (ct), interstitial fibrosis (ci), arteriolar hyalinosis (ah) and inflammation in the area of interstitial fibrosis and tubular atrophy (i-IFTA) from the 3- to the 12-month biopsy. Multivariable proportional odds logistic regression models revealed no association of HLA mismatch scores with progression of histologic lesions, except for ah and especially HLA-EMMA DRB1 [odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.03-1.18]. Furthermore, the established associations of dnDSA formation with HLA mismatch and MVI (OR = 5.31, 95% CI 1.19-22.57) could be confirmed in our cohort. CONCLUSIONS These data support the association of HLA mismatch and alloimmune response, while suggesting that other factors contribute to early progression of chronic histologic lesions.
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Affiliation(s)
- Rhea Jabbour
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Andreas Heinzel
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Roman Reindl-Schwaighofer
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Mariella G Gregorich
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Section for Clinical Biometrics, Center for Medical Statistics, Informatics and Intelligent Systems (CeMSIIS), Medical University of Vienna, Vienna, Austria
| | - Heinz Regele
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | | | - Johannes Kläger
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Gottfried Fischer
- Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
| | - Alexander Kainz
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Jan U Becker
- Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Chris Wiebe
- Department of Medicine, University of Manitoba, Winnipeg, Canada; Shared Health Services Manitoba, Canada; Department of Immunology, University of Manitoba, Winnipeg, Canada
| | - Rainer Oberbauer
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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Meneghini M, Tambur AR. HLA (emphasis on DQ) compatibility for longer allograft survival in pediatric transplantation: Modern evidence and challenges. Pediatr Transplant 2024; 28:e14606. [PMID: 37716000 DOI: 10.1111/petr.14606] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 08/08/2023] [Accepted: 08/28/2023] [Indexed: 09/18/2023]
Abstract
Kidney transplantation is the treatment of choice for children with end-stage kidney failure, yet suboptimal outcomes, the need for long-term immunosuppression, and the dependency on consecutive transplants pose significant barriers to success. Providing better HLA-matched organs to pediatric patients seems to be the most logical approach to improve graft and patient outcomes and to reduce risk of anti-HLA sensitization after graft failure. We here review recent literature on HLA matching in pediatric kidney transplantation. We further review newer approaches attempting to improve matching by using molecular mismatch load analysis. Our main focus is on the role of HLA-DQ compatibility between recipient and donor. We further emphasize the need to develop creative approaches that will support HLA (and DQ) matching utilization in organ allocation schemes, at least in those geared specifically for pediatric patients.
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Affiliation(s)
- Maria Meneghini
- Transplant Immunology Laboratory, Feinberg School of Medicine, Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA
- Nephrology and Kidney Transplantation Department, Vall d'Hebron University Hospital, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
| | - Anat Roitberg Tambur
- Transplant Immunology Laboratory, Feinberg School of Medicine, Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA
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10
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Kervella D, Heidt S, Fairchild R, Todryk S, Bestard O. Tracking Circulating HLA-Specific IgG-Producing Memory B Cells with the B-Cell ImmunoSpot Assay. Methods Mol Biol 2024; 2768:201-209. [PMID: 38502395 DOI: 10.1007/978-1-0716-3690-9_12] [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] [Indexed: 03/21/2024]
Abstract
Donor-specific antibodies (DSA) against human leukocyte antigen (HLA) molecules are a major risk factor for rejection of transplanted organs (in antibody-mediated rejection [ABMR]), particularly in patients who have prior sensitization or receive insufficient immunosuppression through minimization or noncompliance. These DSA are measured routinely in the serum of patients prior to transplantation mainly using bead-based technologies or cell-based assays. However, the absence of detectable serum DSA does not always reflect the absence of sensitization or histologically defined ABMR, and so it has been proposed that the detection and measurement of memory B cells capable of secreting antibodies against donor HLA antigens could be carried out using B-cell ImmunoSpot, to better inform the degree of immune sensitization of transplant patients prior to as well as after transplantation. Such an assay is described here.
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Affiliation(s)
- Delphine Kervella
- Nephrology and Transplantation Laboratory, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
- Nephrology and Kidney Transplantation Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Sebastiaan Heidt
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - Robert Fairchild
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Stephen Todryk
- Faculty of Health & Life Sciences, Northumbria University, Newcastle upon Tyne, UK.
- Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
- Cellular Technology Limited (CTL) Europe GmbH, Rutesheim, Germany.
| | - Oriol Bestard
- Nephrology and Transplantation Laboratory, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
- Nephrology and Kidney Transplantation Department, Vall d'Hebron University Hospital, Barcelona, Spain
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11
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Battle R, Pritchard D, Peacock S, Hastie C, Worthington J, Jordan S, McCaughlan JA, Barnardo M, Cope R, Collins C, Diaz-Burlinson N, Rosser C, Foster L, Kallon D, Shaw O, Briggs D, Turner D, Anand A, Akbarzad-Yousefi A, Sage D. BSHI and BTS UK guideline on the detection of alloantibodies in solid organ (and islet) transplantation. Int J Immunogenet 2023; 50 Suppl 2:3-63. [PMID: 37919251 DOI: 10.1111/iji.12641] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 10/04/2023] [Indexed: 11/04/2023]
Abstract
Solid organ transplantation represents the best (and in many cases only) treatment option for patients with end-stage organ failure. The effectiveness and functioning life of these transplants has improved each decade due to surgical and clinical advances, and accurate histocompatibility assessment. Patient exposure to alloantigen from another individual is a common occurrence and takes place through pregnancies, blood transfusions or previous transplantation. Such exposure to alloantigen's can lead to the formation of circulating alloreactive antibodies which can be deleterious to solid organ transplant outcome. The purpose of these guidelines is to update to the previous BSHI/BTS guidelines 2016 on the relevance, assessment, and management of alloantibodies within solid organ transplantation.
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Affiliation(s)
- Richard Battle
- Scottish National Blood Transfusion Service, Edinburgh, UK
| | | | - Sarah Peacock
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | | | | | - Sue Jordan
- National Blood Service Tooting, London, UK
| | | | - Martin Barnardo
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Rebecca Cope
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | | | | | | | - Luke Foster
- Birmingham Blood Donor Centre, Birmingham, UK
| | | | - Olivia Shaw
- Guy's and St Thomas' NHS Foundation Trust, London, UK
| | | | - David Turner
- Scottish National Blood Transfusion Service, Edinburgh, UK
| | - Arthi Anand
- Imperial College Healthcare NHS Trust, London, UK
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12
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Franco-Acevedo A, Comes J, Mack JJ, Valenzuela NM. New insights into maladaptive vascular responses to donor specific HLA antibodies in organ transplantation. FRONTIERS IN TRANSPLANTATION 2023; 2:1146040. [PMID: 38993843 PMCID: PMC11235244 DOI: 10.3389/frtra.2023.1146040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 04/03/2023] [Indexed: 07/13/2024]
Abstract
Transplant vasculopathy (TV) causes thickening of donor blood vessels in transplanted organs, and is a significant cause of graft loss and mortality in allograft recipients. It is known that patients with repeated acute rejection and/or donor specific antibodies are predisposed to TV. Nevertheless, the exact molecular mechanisms by which alloimmune injury culminates in this disease have not been fully delineated. As a result of this incomplete knowledge, there is currently a lack of effective therapies for this disease. The immediate intracellular signaling and the acute effects elicited by anti-donor HLA antibodies are well-described and continuing to be revealed in deeper detail. Further, advances in rejection diagnostics, including intragraft gene expression, provide clues to the inflammatory changes within allografts. However, mechanisms linking these events with long-term outcomes, particularly the maladaptive vascular remodeling seen in transplant vasculopathy, are still being delineated. New evidence demonstrates alterations in non-coding RNA profiles and the occurrence of endothelial to mesenchymal transition (EndMT) during acute antibody-mediated graft injury. EndMT is also readily apparent in numerous settings of non-transplant intimal hyperplasia, and lessons can be learned from advances in those fields. This review will provide an update on these recent developments and remaining questions in our understanding of HLA antibody-induced vascular damage, framed within a broader consideration of manifestations and implications across transplanted organ types.
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Affiliation(s)
- Adriana Franco-Acevedo
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, United States
| | - Johanna Comes
- Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Julia J Mack
- Department of Medicine, Division of Cardiology, University of California, Los Angeles, CA, United States
| | - Nicole M Valenzuela
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, United States
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13
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Kim JJ, Fichtner A, Copley HC, Gragert L, Süsal C, Dello Strologo L, Oh J, Pape L, Weber LT, Weitz M, König J, Krupka K, Tönshoff B, Kosmoliaptsis V. Molecular HLA mismatching for prediction of primary humoral alloimmunity and graft function deterioration in paediatric kidney transplantation. Front Immunol 2023; 14:1092335. [PMID: 37033962 PMCID: PMC10080391 DOI: 10.3389/fimmu.2023.1092335] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 02/23/2023] [Indexed: 03/17/2023] Open
Abstract
Introduction Rejection remains the main cause of allograft failure in paediatric kidney transplantation and is driven by donor-recipient HLA mismatching. Modern computational algorithms enable assessment of HLA mismatch immunogenicity at the molecular level (molecular-mismatch, molMM). Whilst molMM has been shown to correlate with alloimmune outcomes, evidence demonstrating improved prediction performance against traditional antigen mismatching (antMM) is lacking. Methods We analysed 177 patients from the CERTAIN registry (median follow-up 4.5 years). molMM scores included Amino-Acid-Mismatch-Score (AAMS), Electrostatic-Mismatch-Score (EMS3D) and netMHCIIpan (netMHC1k: peptide binding affinity ≤1000 nM; netMHC: binding affinity ≤500 nM plus rank <2%). We stratified patients into high/low-risk groups based on risk models of DSA development. Results Donor-specific HLA antibodies (DSA) predominantly targeted the highest scoring molMM donor antigen within each HLA locus. MolMM scores offered superior discrimination versus antMM in predicting de novo DSA for all HLA loci; the EMS3D algorithm had particularly consistent performance (area under the receiver operating characteristic curve (AUC) >0.7 for all HLA loci vs. 0.52-0.70 for antMM). ABMR (but not TCMR) was associated with HLA-DQ molMM scores (AAMS, EMS3D and netMHC). Patients with high-risk HLA-DQ molMM had increased risk of graft function deterioration (50% reduction in baseline eGFR (eGFR50), adjusted HR: 3.5, 95% CI 1.6-8.2 high vs. low EMS3D). Multivariable modelling of the eGFR50 outcome using EMS3D HLA-DQ stratification showed better discrimination (AUC EMS3D vs. antMM at 2 years: 0.81 vs. 0.77, at 4.5 years: 0.72 vs. 0.64) and stratified more patients into the low-risk group, compared to traditional antMM. Conclusion Molecular mismatching was superior to antigen mismatching in predicting humoral alloimmunity. Molecular HLA-DQ mismatching appears to be a significant prognostic factor for graft function deterioration in paediatric kidney transplantation.
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Affiliation(s)
- Jon Jin Kim
- Department of Surgery, University of Cambridge, Cambridge, United Kingdom
- Department of Paediatric Nephrology, Nottingham University Hospital, Nottingham, United Kingdom
| | - Alexander Fichtner
- Department of Pediatrics I, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Hannah C. Copley
- Department of Surgery, University of Cambridge, Cambridge, United Kingdom
| | - Loren Gragert
- School of Medicine, Tulane University, New Orleans, LA, United States
| | - Caner Süsal
- Transplantation Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Jun Oh
- University Hospital Hamburg, Pediatric Nephrology, Hamburg, Germany
| | - Lars Pape
- Clinic for Paediatrics III, Essen University Hospital, Essen, Germany
| | - Lutz T. Weber
- Pediatric Nephrology, Children’s and Adolescents’ Hospital, University Hospital Cologne, Cologne, Germany
| | - Marcus Weitz
- University Hospital Tübingen, Pediatric Nephrology, Tübingen, Germany
| | - Jens König
- Department of General Pediatrics, University Children’s Hospital, Münster, Germany
| | - Kai Krupka
- Department of Pediatrics I, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Burkhard Tönshoff
- Department of Pediatrics I, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Vasilis Kosmoliaptsis
- Department of Surgery, University of Cambridge, Cambridge, United Kingdom
- NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation at the University of Cambridge and the NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom
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14
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Abstract
Access to kidney transplantation is limited by HLA-specific sensitization. Desensitization strategies enable crossmatch-positive kidney transplantation. In this review, we describe clinical experience gained over the last 20 y using desensitization strategies before kidney transplantation and describe the different tools used (both drugs and apheresis options), including IVIg, rituximab, apheresis techniques, interleukin-6 interference, proteasome inhibition, enzymatic degradation of HLA antibodies, complement inhibition, and B cytokine interference. Although access to transplantation for highly sensitized kidney transplantation candidates has been vastly improved by desensitization strategies, it remains, however, limited by the recurrence of HLA antibodies after transplantation and the occurrence of antibody-mediated rejection.
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15
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Senev A, Van Loon E, Lerut E, Coemans M, Callemeyn J, Daniëls L, Kerkhofs J, Koshy P, Kuypers D, Lamarthée B, Sprangers B, Tinel C, Van Craenenbroeck AH, Van Sandt V, Emonds MP, Naesens M. Association of Predicted HLA T-Cell Epitope Targets and T-Cell-Mediated Rejection After Kidney Transplantation. Am J Kidney Dis 2022; 80:718-729.e1. [PMID: 35690154 DOI: 10.1053/j.ajkd.2022.04.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 04/09/2022] [Indexed: 02/02/2023]
Abstract
RATIONALE & OBJECTIVE The relationship between human leukocyte antigen (HLA) molecular mismatches and T-cell-mediated rejection (TCMR) is unknown. We investigated the associations between the different donor HLA-derived T-cell targets and the occurrence of TCMR and borderline histologic changes suggestive of TCMR after kidney transplantation. STUDY DESIGN Retrospective cohort study. SETTING & PARTICIPANTS All kidney transplant recipients at a single center between 2004 and 2013 with available biopsy data and a DNA sample for high-resolution HLA donor/recipient typing (N = 893). EXPOSURE Scores calculated by the HLA matching algorithm PIRCHE-II and HLA eplet mismatches. OUTCOME TCMR, borderline changes suggestive of TCMR, and allograft failure. ANALYTICAL APPROACH Multivariable cause-specific hazards models were fit to characterize the association between HLA epitopes targets and study outcomes. RESULTS We found 277 patients developed TCMR, and 134 developed only borderline changes suggestive of TCMR on at least 1 biopsy. In multivariable analyses, only the PIRCHE-II scores for HLA-DRB1 and HLA-DQB1 were independently associated with the occurrence of TCMR and with allograft failure; this was not the case for HLA class I molecules. If restricted to rejection episodes within the first 3 months after transplantation, only the T-cell epitope targets originating from the donor's HLA-DRB1 and HLA-DQB1, but not class I molecules, were associated with the early acute TCMR. Also, the median PIRCHE-II score for HLA class II was statistically different between the patients with TCMR compared to the patients without TCMR (129 [IQR, 60-240] vs 201 [IQR, 96-298], respectively; P < 0.0001). These differences were not observed for class I PIRCHE-II scores. LIMITATIONS Observational clinical data and residual confounding. CONCLUSIONS In the absence of HLA-DSA, HLA class II but not class I mismatches are associated with early episodes of acute TCMR and allograft failure. This suggests that current immunosuppressive therapies are largely able to abort the most deleterious HLA class I-directed alloimmune processes; however, alloresponses against HLA-DRB1 and HLA-DQB1 molecular mismatches remain insufficiently suppressed. PLAIN-LANGUAGE SUMMARY Genetic differences in the human leukocyte antigen (HLA) complex between kidney transplant donors and recipients play a central role in T-cell-mediated rejection (TCMR), which can lead to failure of the transplanted kidney. Evaluating this genetic disparity (mismatch) in the HLA complex at the molecular (epitope) level could contribute to better prediction of the immune response to the donor organ posttransplantation. We investigated the associations of the different donor HLA-derived T-cell epitope targets and scores obtained from virtual crossmatch algorithms with the occurrence of TCMR, borderline TCMR, and graft failure after kidney transplantation after taking into account the influence of donor-specific anti-HLA antibodies. This study illustrates the greater importance of the molecular mismatches in class II molecules compared to class I HLA molecules.
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Affiliation(s)
- Aleksandar Senev
- KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium; Histocompatibility and Immunogenetics Laboratory (HILA), Belgian Red Cross-Flanders, Mechelen, Belgium
| | - Elisabet Van Loon
- KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium
| | - Evelyne Lerut
- Department of Imaging & Pathology, University Hospitals Leuven, Leuven, Belgium
| | - Maarten Coemans
- KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium
| | - Jasper Callemeyn
- KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium
| | - Liesbeth Daniëls
- Histocompatibility and Immunogenetics Laboratory (HILA), Belgian Red Cross-Flanders, Mechelen, Belgium
| | - Johan Kerkhofs
- Histocompatibility and Immunogenetics Laboratory (HILA), Belgian Red Cross-Flanders, Mechelen, Belgium
| | - Priyanka Koshy
- Department of Imaging & Pathology, University Hospitals Leuven, Leuven, Belgium
| | - Dirk Kuypers
- KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Baptiste Lamarthée
- KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium
| | - Ben Sprangers
- KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Claire Tinel
- KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium
| | - Amaryllis H Van Craenenbroeck
- KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Vicky Van Sandt
- Histocompatibility and Immunogenetics Laboratory (HILA), Belgian Red Cross-Flanders, Mechelen, Belgium
| | - Marie-Paule Emonds
- KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium; Histocompatibility and Immunogenetics Laboratory (HILA), Belgian Red Cross-Flanders, Mechelen, Belgium
| | - Maarten Naesens
- KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
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16
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Charnaya O, Levy Erez D, Amaral S, Monos DS. Pediatric Kidney Transplantation-Can We Do Better? The Promise and Limitations of Epitope/Eplet Matching. Front Pediatr 2022; 10:893002. [PMID: 35722502 PMCID: PMC9204054 DOI: 10.3389/fped.2022.893002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 05/16/2022] [Indexed: 12/02/2022] Open
Abstract
Kidney transplant is the optimal treatment for end-stage kidney disease as it offers significant survival and quality of life advantages over dialysis. While recent advances have significantly improved early graft outcomes, long-term overall graft survival has remained largely unchanged for the last 20 years. Due to the young age at which children receive their first transplant, most children will require multiple transplants during their lifetime. Each subsequent transplant becomes more difficult because of the development of de novo donor specific HLA antibodies (dnDSA), thereby limiting the donor pool and increasing mortality and morbidity due to longer time on dialysis awaiting re-transplantation. Secondary prevention of dnDSA through increased post-transplant immunosuppression in children is constrained by a significant risk for viral and oncologic complications. There are currently no FDA-approved therapies that can meaningfully reduce dnDSA burden or improve long-term allograft outcomes. Therefore, primary prevention strategies aimed at reducing the risk of dnDSA formation would allow for the best possible long-term allograft outcomes without the adverse complications associated with over-immunosuppression. Epitope matching, which provides a more nuanced assessment of immunological compatibility between donor and recipient, offers the potential for improved donor selection. Although epitope matching is promising, it has not yet been readily applied in the clinical setting. Our review will describe current strengths and limitations of epitope matching software, the evidence for and against improved outcomes with epitope matching, discussion of eplet load vs. variable immunogenicity, and conclude with a discussion of the delicate balance of improving matching without disadvantaging certain populations.
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Affiliation(s)
- Olga Charnaya
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Daniella Levy Erez
- Schneider Children's Medical Center, Institute of Pediatric Nephrology, Petah Tikvah, Israel
- Departments of Pediatric Nephrology and Biostatistics, Epidemiology and Informatics, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Sandra Amaral
- Departments of Pediatric Nephrology and Biostatistics, Epidemiology and Informatics, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Dimitrios S. Monos
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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17
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Lezoeva E, Nilsson J, Wüthrich R, Mueller TF, Schachtner T. High PIRCHE Scores May Allow Risk Stratification of Borderline Rejection in Kidney Transplant Recipients. Front Immunol 2022; 13:788818. [PMID: 35250973 PMCID: PMC8894244 DOI: 10.3389/fimmu.2022.788818] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 01/31/2022] [Indexed: 12/11/2022] Open
Abstract
Background The diagnosis of borderline rejection (BLR) ranges from mild inflammation to clinically significant TCMR and is associated with an increased risk of allograft dysfunction. Currently, there is no consensus regarding its treatment due in part to a lack of biomarkers to identify cases with increased risk for immune-mediated injury. Methods We identified 60 of 924 kidney transplant recipients (KTRs) with isolated and untreated BLR. We analyzed the impact of predicted indirectly recognizable HLA epitopes (PIRCHE) score on future rejection, de novo DSA development, and recovery to baseline allograft function. Additionally, we compared the outcomes of different Banff rejection phenotypes. Results Total PIRCHE scores were significantly higher in KTRs with BLR compared to the entire study population (p=0.016). Among KTRs with BLR total PIRCHE scores were significantly higher in KTRs who developed TCMR/ABMR in follow-up biopsies (p=0.029). Notably, the most significant difference was found in PIRCHE scores for the HLA-A locus (p=0.010). PIRCHE scores were not associated with the development of de novo DSA or recovery to baseline allograft function among KTRs with BLR (p>0.05). However, KTRs under cyclosporine-based immunosuppression were more likely to develop de novo DSA (p=0.033) than those with tacrolimus, whereas KTRs undergoing retransplantation were less likely to recover to baseline allograft function (p=0.003). Conclusions High PIRCHE scores put KTRs with BLR at an increased risk for future TCMR/ABMR and contribute to improved immunological risk stratification. The benefit of anti-rejection treatment, however, needs to be evaluated in future studies.
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Affiliation(s)
- Ekaterina Lezoeva
- Department of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Jakob Nilsson
- Department of Immunology, University Hospital Zurich, Zurich, Switzerland
| | - Rudolf Wüthrich
- Department of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Thomas F. Mueller
- Department of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Thomas Schachtner
- Department of Nephrology, University Hospital Zurich, Zurich, Switzerland
- *Correspondence: Thomas Schachtner, ; orcid.org/0000-0001-5549-4798
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18
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Yeung MY. Histocompatibility Assessment in Precision Medicine for Transplantation: Towards a Better Match. Semin Nephrol 2022; 42:44-62. [DOI: 10.1016/j.semnephrol.2022.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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19
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Cornaby C, Schmitz JL, Weimer ET. Next-generation sequencing and clinical histocompatibility testing. Hum Immunol 2021; 82:829-837. [PMID: 34521569 DOI: 10.1016/j.humimm.2021.08.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/12/2021] [Accepted: 08/16/2021] [Indexed: 11/28/2022]
Abstract
Histocompatibility testing is essential for donor identification and risk assessment in solid organ and hematopoietic stem cell transplant. Additionally, it is useful for identifying donor specific alleles for monitoring donor specific antibodies in post-transplant patients. Next-generation sequence (NGS) based human leukocyte antigen (HLA) typing has improved many aspects of histocompatibility testing in hematopoietic stem cell and solid organ transplant. HLA disease association testing and research has also benefited from the advent of NGS technologies. In this review we discuss the current impact and future applications of NGS typing on clinical histocompatibility testing for transplant and non-transplant purposes.
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Affiliation(s)
- Caleb Cornaby
- McLendon Clinical Laboratories, UNC Health, Chapel Hill, NC, USA
| | - John L Schmitz
- McLendon Clinical Laboratories, UNC Health, Chapel Hill, NC, USA; Department of Pathology & Laboratory Medicine, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Eric T Weimer
- McLendon Clinical Laboratories, UNC Health, Chapel Hill, NC, USA; Department of Pathology & Laboratory Medicine, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
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20
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Lin Y, Wang L, Ge W, Hui Y, Zhou Z, Hu L, Pan H, Huang Y, Shen B. Multi-omics network characterization reveals novel microRNA biomarkers and mechanisms for diagnosis and subtyping of kidney transplant rejection. J Transl Med 2021; 19:346. [PMID: 34389032 PMCID: PMC8361655 DOI: 10.1186/s12967-021-03025-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 08/05/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Kidney transplantation is an optimal method for treatment of end-stage kidney failure. However, kidney transplant rejection (KTR) is commonly observed to have negative effects on allograft function. MicroRNAs (miRNAs) are small non-coding RNAs with regulatory role in KTR genesis, the identification of miRNA biomarkers for accurate diagnosis and subtyping of KTR is therefore of clinical significance for active intervention and personalized therapy. METHODS In this study, an integrative bioinformatics model was developed based on multi-omics network characterization for miRNA biomarker discovery in KTR. Compared with existed methods, the topological importance of miRNA targets was prioritized based on cross-level miRNA-mRNA and protein-protein interaction network analyses. The biomarker potential of identified miRNAs was computationally validated and explored by receiver-operating characteristic (ROC) evaluation and integrated "miRNA-gene-pathway" pathogenic survey. RESULTS Three miRNAs, i.e., miR-145-5p, miR-155-5p, and miR-23b-3p, were screened as putative biomarkers for KTR monitoring. Among them, miR-155-5p was a previously reported signature in KTR, whereas the remaining two were novel candidates both for KTR diagnosis and subtyping. The ROC analysis convinced the power of identified miRNAs as single and combined biomarkers for KTR prediction in kidney tissue and blood samples. Functional analyses, including the latent crosstalk among HLA-related genes, immune signaling pathways and identified miRNAs, provided new insights of these miRNAs in KTR pathogenesis. CONCLUSIONS A network-based bioinformatics approach was proposed and applied to identify candidate miRNA biomarkers for KTR study. Biological and clinical validations are further needed for translational applications of the findings.
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Affiliation(s)
- Yuxin Lin
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, 215000 China
| | - Liangliang Wang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, 215000 China
| | - Wenqing Ge
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, 215000 China
| | - Yu Hui
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, 215000 China
| | - Zheng Zhou
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, 215000 China
| | - Linkun Hu
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, 215000 China
| | - Hao Pan
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, 215000 China
| | - Yuhua Huang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, 215000 China
| | - Bairong Shen
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610212 China
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21
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Bestard O, Meneghini M, Crespo E, Bemelman F, Koch M, Volk HD, Viklicky O, Giral M, Banas B, Ruiz JC, Melilli E, Hu L, van Duivenvoorden R, Nashan B, Thaiss F, Otto NM, Bold G, Stein M, Sefrin A, Lachmann N, Hruba P, Stranavova L, Brouard S, Braudeau C, Blancho G, Banas M, Irure J, Christakoudi S, Sanchez-Fueyo A, Wood KJ, Reinke P, Grinyó JM. Preformed T cell alloimmunity and HLA eplet mismatch to guide immunosuppression minimization with tacrolimus monotherapy in kidney transplantation: Results of the CELLIMIN trial. Am J Transplant 2021; 21:2833-2845. [PMID: 33725408 DOI: 10.1111/ajt.16563] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/08/2021] [Accepted: 02/26/2021] [Indexed: 02/06/2023]
Abstract
Personalizing immunosuppression is a major objective in transplantation. Transplant recipients are heterogeneous regarding their immunological memory and primary alloimmune susceptibility. This biomarker-guided trial investigated whether in low immunological-risk kidney transplants without pretransplant DSA and donor-specific T cells assessed by a standardized IFN-γ ELISPOT, low immunosuppression (LI) with tacrolimus monotherapy would be non-inferior regarding 6-month BPAR than tacrolimus-based standard of care (SOC). Due to low recruitment rates, the trial was terminated when 167 patients were enrolled. ELISPOT negatives (E-) were randomized to LI (n = 48) or SOC (n = 53), E+ received the same SOC. Six- and 12-month BPAR rates were higher among LI than SOC/E- (4/35 [13%] vs. 1/43 [2%], p = .15 and 12/48 [25%] vs. 6/53 [11.3%], p = .073, respectively). E+ patients showed similarly high BPAR rates than LI at 6 and 12 months (12/55 [22%] and 13/66 [20%], respectively). These differences were stronger in per-protocol analyses. Post-hoc analysis revealed that poor class-II eplet matching, especially DQ, discriminated E- patients, notably E-/LI, developing BPAR (4/28 [14%] low risk vs. 8/20 [40%] high risk, p = .043). Eplet mismatch also predicted anti-class-I (p = .05) and anti-DQ (p < .001) de novo DSA. Adverse events were similar, but E-/LI developed fewer viral infections, particularly polyoma-virus-associated nephropathy (p = .021). Preformed T cell alloreactivity and HLA eplet mismatch assessment may refine current baseline immune-risk stratification and guide immunosuppression decision-making in kidney transplantation.
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Affiliation(s)
- Oriol Bestard
- Kidney Transplant Unit, Nephrology department, Bellvitge University Hospital, IDIBELL, Barcelona University, Barcelona, Spain.,Nephrology and Transplantation Laboratory, IDIBELL, Barcelona University, Barcelona, Spain
| | - Maria Meneghini
- Kidney Transplant Unit, Nephrology department, Bellvitge University Hospital, IDIBELL, Barcelona University, Barcelona, Spain.,Nephrology and Transplantation Laboratory, IDIBELL, Barcelona University, Barcelona, Spain
| | - Elena Crespo
- Nephrology and Transplantation Laboratory, IDIBELL, Barcelona University, Barcelona, Spain
| | - Frederike Bemelman
- Renal Transplant Unit, Department of Internal Medicine, Amsterdam University Medical Centers, Academic Medical Center - University of Amsterdam, Amsterdam, the Netherlands
| | - Martina Koch
- Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hans D Volk
- BeCAT, BCRT, and Department of Nephrology & Intensive Care, Charité Universitätsmedizin Berlin, Berlin Institute of Health, Berlin, Germany
| | - Ondrej Viklicky
- Transplant Laboratory, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic.,Department of Nephrology, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic
| | - Magali Giral
- Nantes Université, Inserm, CHU Nantes, Centre de Recherche en Transplantation et Immunologie UMR1064, ITUN, Nantes, France
| | - Bernhard Banas
- Department of Nephrology, University Medical Center Regensburg, Regensburg, Germany
| | - Juan C Ruiz
- Department of Nephrology, Hospital Universitario "Marqués de Valdecilla", Instituto de Investigación "Marqués de Valdecilla" (IDIVAL, Santander, Spain
| | - Edoardo Melilli
- Kidney Transplant Unit, Nephrology department, Bellvitge University Hospital, IDIBELL, Barcelona University, Barcelona, Spain
| | - Liu Hu
- Renal Transplant Unit, Department of Internal Medicine, Amsterdam University Medical Centers, Academic Medical Center - University of Amsterdam, Amsterdam, the Netherlands
| | - Raphael van Duivenvoorden
- Renal Transplant Unit, Department of Internal Medicine, Amsterdam University Medical Centers, Academic Medical Center - University of Amsterdam, Amsterdam, the Netherlands
| | - Björn Nashan
- Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Friedrich Thaiss
- Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Natalie M Otto
- BeCAT, BCRT, and Department of Nephrology & Intensive Care, Charité Universitätsmedizin Berlin, Berlin Institute of Health, Berlin, Germany
| | - Gantuja Bold
- BeCAT, BCRT, and Department of Nephrology & Intensive Care, Charité Universitätsmedizin Berlin, Berlin Institute of Health, Berlin, Germany
| | - Maik Stein
- BeCAT, BCRT, and Department of Nephrology & Intensive Care, Charité Universitätsmedizin Berlin, Berlin Institute of Health, Berlin, Germany
| | - Anett Sefrin
- BeCAT, BCRT, and Department of Nephrology & Intensive Care, Charité Universitätsmedizin Berlin, Berlin Institute of Health, Berlin, Germany
| | - Nils Lachmann
- HLA-Laboratory, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Petra Hruba
- Transplant Laboratory, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic.,Department of Nephrology, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic
| | - Lucia Stranavova
- Transplant Laboratory, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic.,Department of Nephrology, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic
| | - Sophie Brouard
- Nantes Université, Inserm, CHU Nantes, Centre de Recherche en Transplantation et Immunologie UMR1064, ITUN, Nantes, France
| | - Cécile Braudeau
- Nantes Université, Inserm, CHU Nantes, Centre de Recherche en Transplantation et Immunologie UMR1064, ITUN, Nantes, France.,CHU Nantes, Laboratoire d'immunologie, CIMNA, Nantes, France
| | - Gilles Blancho
- Nantes Université, Inserm, CHU Nantes, Centre de Recherche en Transplantation et Immunologie UMR1064, ITUN, Nantes, France
| | - Miriam Banas
- Department of Nephrology, University Medical Center Regensburg, Regensburg, Germany
| | - Juan Irure
- Immunology Department, University Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain
| | - Sophia Christakoudi
- Institute of Liver Studies, MRC Centre for Transplantation, Department of Inflammation Biology, Faculty of Sciences & Medicine, King's College London, London, UK
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, MRC Centre for Transplantation, Department of Inflammation Biology, Faculty of Sciences & Medicine, King's College London, London, UK
| | - Kathryn J Wood
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Petra Reinke
- BeCAT, BCRT, and Department of Nephrology & Intensive Care, Charité Universitätsmedizin Berlin, Berlin Institute of Health, Berlin, Germany
| | - Josep M Grinyó
- Kidney Transplant Unit, Nephrology department, Bellvitge University Hospital, IDIBELL, Barcelona University, Barcelona, Spain.,Nephrology and Transplantation Laboratory, IDIBELL, Barcelona University, Barcelona, Spain
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