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1
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Schinstock CA, Agrawal A, Valenzuela NM. The Significance of Major Histocompatibility Complex Class I Chain-related Molecule A in Solid Organ and Hematopoietic Stem Cell Transplantation: A Comprehensive Overview. Transplantation 2024; 108:115-126. [PMID: 37218026 DOI: 10.1097/tp.0000000000004643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Improving long-term allograft survival and minimizing recipient morbidity is of key importance in all of transplantation. Improved matching of classical HLA molecules and avoiding HLA donor-specific antibody has been a major focus; however, emerging data suggest the relevance of nonclassical HLA molecules, major histocompatibility complex class I chain-related gene A (MICA) and B, in transplant outcomes. The purpose of this review is to discuss the structure, function, polymorphisms, and genetics of the MICA molecule and relates this to clinical outcomes in solid organ and hematopoietic stem cell transplantation. The tools available for genotyping and antibody detection will be reviewed combined with a discussion of their shortcomings. Although data supporting the relevance of MICA molecules have accumulated, key knowledge gaps exist and should be addressed before widespread implementation of MICA testing for recipients pre- or posttransplantation.
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Affiliation(s)
- Carrie A Schinstock
- Von Liebig Center for Transplant and Clinical Regeneration, Mayo Clinic, Rochester, MN
| | - Amogh Agrawal
- Von Liebig Center for Transplant and Clinical Regeneration, Mayo Clinic, Rochester, MN
| | - Nicole M Valenzuela
- UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, Los Angeles, CA
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2
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Gniewkiewicz M, Czerwinska K, Zielniok K, Durlik M. Association of Circulating Anti-HLA Donor-Specific Antibodies and Their Characteristics, including C1q-Binding Capacity, in Kidney Transplant Recipients with Long-Term Renal Graft Outcomes. J Clin Med 2023; 12:jcm12041312. [PMID: 36835848 PMCID: PMC9962721 DOI: 10.3390/jcm12041312] [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: 01/03/2023] [Revised: 02/02/2023] [Accepted: 02/05/2023] [Indexed: 02/10/2023] Open
Abstract
Post-transplant antihuman leukocyte antigen donor-specific antibodies (anti-HLA DSAs) monitoring in kidney transplant recipients remains unclear and is currently under investigation. The pathogenicity of anti-HLA DSAs is determined by antibody classes, specificity, mean fluorescent intensity (MFI), C1q-binding capacity, and IgG subclasses. The aim of this study was to investigate the association of circulating DSAs and their characteristics with renal allograft long-term outcomes. The study included 108 consecutive patients from our transplant center who underwent kidney allograft biopsy between November 2018 and November 2020, 3 to 24 months after kidney transplantation. At the time of biopsy, patients' sera were collected for analysis of anti-HLA DSAs. Patients were followed for a median time of 39.0 months (Q1-Q3, 29.8-45.0). Detection of anti-HLA DSAs at the time of biopsy (HR = 5.133, 95% CI 2.150-12.253, p = 0.0002) and their C1q-binding capacity (HR = 14.639, 95% CI 5.320-40.283, p ≤ 0.0001) were independent predictors of the composite of sustained 30% reduction from estimated glomerular filtration rate or death-censored graft failure. Identification of anti-HLA DSAs and their C1q-binding capacity could be useful in identifying kidney transplant recipients at risk for inferior renal allograft function and graft failure. Analysis of C1q is noninvasive, accessible, and should be considered in clinical practice in post-transplant monitoring.
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Affiliation(s)
- Michal Gniewkiewicz
- Department of Transplantation Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland
- Correspondence:
| | - Katarzyna Czerwinska
- Department of Transplantation Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland
| | - Katarzyna Zielniok
- Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland
| | - Magdalena Durlik
- Department of Transplantation Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland
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3
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Anbalakan K, Chew KM, Loh JK, Sim D, Lai SH, Teo Loon Yee L. Contemporary review of heart transplant immunology and immunosuppressive therapy. PROCEEDINGS OF SINGAPORE HEALTHCARE 2022. [DOI: 10.1177/20101058221138840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Background Survival after heart transplantation (HT) has improved considerably since the first HT was performed in 1967 in Cape Town, South Africa. Understanding immunology behind organ rejection has paved way for advances in the assessment of pre-transplant compatibility, development of newer and more specific immunosuppressive drugs, and management of rejection. Objectives Unlike medical therapy for heart failure, transplant protocols vary considerably between different centers. These variations in protocols generally reflect unique population characteristics and the availability of resources. This review article aims to provide a consolidated update on contemporary cardiac transplant medicine. We also aim to highlight local practice and its difference from our international counterparts. Methods A literature search was performed on Pubmed and Cochrane Central Register of Controlled Trials to identify trials and review articles that discussed heart transplant immunology and protocols. The International Society for Heart and Lung Transplant (ISHLT) guidelines were also reviewed. We focused on risk factors, prevention strategies, and treatment of cardiac rejection. Results A total of 48 articles were selected to provide a comprehensive overview of the contemporary practice of cardiac transplant immunosuppressive therapy. Comparisons were made with local data and practice protocols to highlight key differences. Conclusion Heart transplant covers a small subset of cardiac patients and much of the evidence is derived from empirical observations and retrospective analysis. This accounts for the heterogeneity in care and treatment protocols. More studies are needed to select best practices from around the world to further improve outcomes.
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Affiliation(s)
| | | | - Julian K Loh
- National Heart Centre Singapore, Singapore, Singapore
| | - David Sim
- National Heart Centre Singapore, Singapore, Singapore
| | - Siang Hui Lai
- Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
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4
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Fylaktou A, Sampani E, Kasimatis E, Nikolaidou V, Dimitriadis C, Anastasiou A, Papachristou M, Chatzika G, Papagianni A. Prospective De Novo Donor-Specific Antibody Monitoring in Renal Transplant Patients. Transplant Proc 2021; 53:2765-2768. [PMID: 34598809 DOI: 10.1016/j.transproceed.2021.08.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/27/2021] [Accepted: 08/24/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND De novo donor-specific antibodies (dnDSA) are associated with antibody-mediated rejection leading to kidney transplant failure. However, many transplant patients are stable with no signs of graft dysfunction at the time of dnDSA detection at screening test. METHODS We prospectively studied 26 kidney transplant patients for 3 years, with dnDSA detected using the Luminex single-antigen bead assay in a routine test. Proteinuria and estimated glomerular filtration rate were evaluated along with dnDSA monitoring at least annually. RESULTS Graft loss associated with dnDSA occurred in 8 (31%) patients, 14 ± 11 months after the initial detection of dnDSA. These patients had more frequently multiple dnDSA (P = .004) and remarkable proteinuria, more than 1 g daily (P < .001). The remaining 18 patients were followed for 38 ± 15 months and considered stable as there was no deterioration regarding estimated glomerular filtration rate and proteinuria. In 7 (39%) of these patients, dnDSA waned and were not detected anymore at follow-up. Antibodies against HLA class I had a significantly (P < .001) lower mean fluorescence intensity (MFI) (2603 ± 1098) compared with those against HLA class II (11,109 ± 6414). In regression analysis, they were predictive of dnDSA wane (P = .043; odds ratio, 0.18; 95% confidence interval, 0.04-0.94). Despite fluctuations during follow-up, there was no significant change in MFI for those who retained the dnDSA. CONCLUSIONS The presence of dnDSA is transient in a significant proportion of stable renal transplant patients, especially in those with antibodies against HLA class I and a low MFI. Multiple dnDSA and severe proteinuria adversely affect renal graft survival.
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Affiliation(s)
- Asimina Fylaktou
- National Peripheral Histocompatibility Center, Immunology Department, Hippokration General Hospital, Thessaloniki, Greece
| | - Erasmia Sampani
- Department of Nephrology, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki, Greece
| | - Efstratios Kasimatis
- Department of Nephrology, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki, Greece.
| | - Vasiliki Nikolaidou
- National Peripheral Histocompatibility Center, Immunology Department, Hippokration General Hospital, Thessaloniki, Greece
| | - Chrysostomos Dimitriadis
- Department of Nephrology, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki, Greece
| | - Aikaterini Anastasiou
- National Peripheral Histocompatibility Center, Immunology Department, Hippokration General Hospital, Thessaloniki, Greece
| | - Marianthi Papachristou
- National Peripheral Histocompatibility Center, Immunology Department, Hippokration General Hospital, Thessaloniki, Greece
| | - Georgia Chatzika
- National Peripheral Histocompatibility Center, Immunology Department, Hippokration General Hospital, Thessaloniki, Greece
| | - Aikaterini Papagianni
- Department of Nephrology, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki, Greece
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5
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Alleyn M, Closson K, Gentile A, Gulbis N, Taylor C, Rhyne P. Design and Evaluation of a Multiplexed Assay to Assess Human Immunogenicity Against Humira®. AAPS JOURNAL 2020; 22:104. [PMID: 32748082 PMCID: PMC7399670 DOI: 10.1208/s12248-020-00487-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 07/13/2020] [Indexed: 11/30/2022]
Abstract
The use of biologic-based therapeutics has revolutionized our ability to treat complex diseases such as cancer- and autoimmune-related disorders. Biologic-based therapeutics are known to generate anti-drug immune responses or immunogenicity in clinical patients which can lead to altered pharmacokinetics, decreased drug efficacy, and unwanted adverse clinical events. Assays designed to detect and assess anti-drug immune responses are used to help monitor patients and improve drug safety. Utilizing a tiered approach, screening assays are developed first to identify patients that are potentially positive for anti-drug-specific antibodies. Patients that screen positive are subjected to additional tiers of testing that include a confirmation assay to confirm the presence of expected anti-drug-specific antibodies, a titer assay to assess relative levels of anti-drug-specific antibodies, and, depending on the drug's mechanism of action or concerns of adverse clinical reactions, further characterization such as drug neutralization and anti-drug antibody isotyping. This tiered approach can prove to be detrimental to clinical samples from exposure to multiple cycles of testing, freeze thaws, and repeated handling by lab personnel. Multiplexing some of these assays together may streamline the characterization of anti-drug immune responses and help reduce the repeated usage of clinical samples. In this study, we combined a screening assay and anti-drug isotyping assays into one multiplexed assay using the Luminex® xMAP® Technology. The multiplexed assay was developed and validated to meet the FDA recommended guidelines for immunogenicity assessments. These results show that multiplexed assays perform comparably to industry standards. This study should encourage labs to explore the use of multiplexing immunogenicity assays to characterize anti-drug antibody responses quickly, with less repeat testing and reduced sample handling.
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Affiliation(s)
- Matthew Alleyn
- Immunologix Laboratories, 4710 Eisenhower Blvd, Building D, Tampa, Florida, 33634, USA
| | - Kristin Closson
- Immunologix Laboratories, 4710 Eisenhower Blvd, Building D, Tampa, Florida, 33634, USA
| | - Adam Gentile
- Immunologix Laboratories, 4710 Eisenhower Blvd, Building D, Tampa, Florida, 33634, USA
| | - Nathan Gulbis
- Immunologix Laboratories, 4710 Eisenhower Blvd, Building D, Tampa, Florida, 33634, USA
| | - Christopher Taylor
- Immunologix Laboratories, 4710 Eisenhower Blvd, Building D, Tampa, Florida, 33634, USA
| | - Paul Rhyne
- Immunologix Laboratories, 4710 Eisenhower Blvd, Building D, Tampa, Florida, 33634, USA. .,Bill & Melinda Gates Medical Research Institute, One Kendall Square Building 600 Suite 6-301, Cambridge, Massachusetts, 02139, USA.
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6
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Monitoring of Donor-specific Anti-HLA Antibodies and Management of Immunosuppression in Kidney Transplant Recipients: An Evidence-based Expert Paper. Transplantation 2020; 104:S1-S12. [DOI: 10.1097/tp.0000000000003270] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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7
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Kim DG, Lee J, Park Y, Kim MS, Jeong HJ, Kim SI, Kim YS, Kim BS, Huh KH. Transplant outcomes in positive complement-dependent cytotoxicity- versus flow cytometry-crossmatch kidney transplant recipients after successful desensitization: a retrospective study. BMC Nephrol 2019; 20:456. [PMID: 31818254 PMCID: PMC6902609 DOI: 10.1186/s12882-019-1625-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 11/14/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Despite the obvious survival benefit compared to that among waitlist patients, outcomes of positive crossmatch kidney transplantation (KT) are generally inferior to those of human leukocyte antigen (HLA)-compatible KT. This study aimed to compare the outcomes of positive complement-dependent cytotoxicity (CDC) crossmatch (CDC + FC+) and positive flow cytometric crossmatch (CDC-FC+) with those of HLA-compatible KT (CDC-FC-) after successful desensitization. METHODS We retrospectively analyzed 330 eligible patients who underwent KTs between June 2011 and August 2017: CDC-FC- (n = 274), CDC-FC+ (n = 39), and CDC + FC+ (n = 17). Desensitization protocol targeting donor-specific antibody (DSA) involved plasmapheresis, intravenous immunoglobulin (IVIG), and rituximab with/without bortezomib for positive-crossmatch KT. RESULTS Death-censored graft survival and patient survival were not different among the three groups. The median estimated glomerular filtration rate was significantly lower in the CDC + FC+ group than in the compatible group at 6 months (P < 0.001) and 2 years (P = 0.020). Biopsy-proven rejection within 1 year of CDC-FC-, CDC-FC+, and CDC + FC+ were 15.3, 28.2, and 47.0%, respectively. Urinary tract infections (P < 0.001), Pneumocystis jirovecii pneumonia (P < 0.001), and cytomegalovirus viremia (P < 0.001) were more frequent in CDC-FC+ and CDC + FC+ than in CDC-FC-. CONCLUSIONS This study showed that similar graft and patient survival was achieved in CDC-FC+ and CDC + FC+ KT compared with CDC-FC- through DSA-targeted desensitization despite the higher incidence of rejection and infection than that in compatible KT.
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Affiliation(s)
- Deok Gie Kim
- Department of Surgery, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Juhan Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Younhee Park
- Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Myoung Soo Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.,The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyeon Joo Jeong
- The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Republic of Korea.,Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Soon Il Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.,The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yu Seun Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.,The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Beom Seok Kim
- The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Republic of Korea. .,Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
| | - Kyu Ha Huh
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea. .,The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Republic of Korea.
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8
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Navas A, Molina J, Agüera ML, Guler I, Jurado A, Rodríguez-Benot A, Alonso C, Solana R. Characterization of the C1q-Binding Ability and the IgG1-4 Subclass Profile of Preformed Anti-HLA Antibodies by Solid-Phase Assays. Front Immunol 2019; 10:1712. [PMID: 31428086 PMCID: PMC6687874 DOI: 10.3389/fimmu.2019.01712] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Accepted: 07/08/2019] [Indexed: 12/11/2022] Open
Abstract
Humoral alloimmunity, particularly that triggered by preformed antibodies against human leukocyte antigens (HLA), is associated with an increased prevalence of rejection and reduced transplant survival. The high sensitivity of solid phase assays, based on microbeads coated with single antigens (SAB), consolidated them as the gold-standard method to characterize anti-HLA antibodies, ensuring a successful allograft allocation. Mean fluorescence intensity (MFI) provided by SAB is regularly used to stratify the immunological risk, assuming it as a reliable estimation of the antibody-level, but it is often limited by artifacts. Beyond MFI, other properties, such as the complement-binding ability or the IgG1-4 subclass profile have been examined to more accurately define the clinical relevance of antibodies and clarify their functional properties. However, there are still unresolved issues. Neat serum-samples from 20 highly-sensitized patients were analyzed by SAB-panIgG, SAB-IgG1-4 subclass and SAB-C1q assays. All 1:16 diluted serum-samples were additionally analyzed by SAB-panIgG and SAB-IgG1-4 subclass assays. A total of 1,285 anti-HLA antibodies were identified as positive, 473 (36.8%) of which were C1q-binding. As expected, serum-dilution enhanced the correlation between the C1q-binding ability and the antibody-strength, measured as the MFI (rneat = 0.248 vs. rdiluted = 0.817). SAB-subclass assay revealed at least one IgG1-4 subclass in 1,012 (78.8%) positive antibody-specificities. Among them, strong complement-binding subclasses, mainly IgG1, were particularly frequent (98.9%) and no differences were found between C1q- and non-C1q-binding antibodies regarding their presence (99.4 vs. 98.5%; p = 0.193). In contrast, weak or non-C1q-binding subclasses (IgG2/IgG4) were more commonly detected in C1q-binding antibodies (78.9 vs. 38.6%; p < 0.001). Interestingly, a strong association was found between the C1q-binding ability and the IgG1 strength (rIgG1dil = 0.796). Though lower, the correlation between the IgG2 strength and the C1q-binding ability was also strong (rIgG2dil = 0.758), being both subclasses closely related (rIgG1−IgG2 = 0.817). We did not find any correlation with the C1q-binding ability considering the remaining subclasses. In conclusion, we demonstrate that a particular profile of IgG subclasses (IgG1/IgG3) itself does not determine at all the ability to bind complement of anti-HLA antibodies assessed by SAB-C1q assay. It is the IgG subclass strength, mainly of IgG1, which usually appears in combination with IgG2, that best correlates with it.
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Affiliation(s)
- Ana Navas
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain.,Department of Immunology and Allergy, Reina Sofia University Hospital, Cordoba, Spain
| | - Juan Molina
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain.,Department of Immunology and Allergy, Reina Sofia University Hospital, Cordoba, Spain
| | - María-Luisa Agüera
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain.,Department of Nephrology, Reina Sofia University Hospital, Cordoba, Spain
| | - Ipek Guler
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain
| | - Aurora Jurado
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain.,Department of Immunology and Allergy, Reina Sofia University Hospital, Cordoba, Spain
| | - Alberto Rodríguez-Benot
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain.,Department of Nephrology, Reina Sofia University Hospital, Cordoba, Spain
| | - Corona Alonso
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain.,Department of Immunology and Allergy, Reina Sofia University Hospital, Cordoba, Spain
| | - Rafael Solana
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain.,Department of Immunology and Allergy, Reina Sofia University Hospital, Cordoba, Spain
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9
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Understanding the Correlation Between DSA, Complement Activation, and Antibody-Mediated Rejection in Heart Transplant Recipients. Transplantation 2019; 102:e431-e438. [PMID: 29916988 DOI: 10.1097/tp.0000000000002333] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Donor-specific HLA antibodies (DSA) are associated with increased rates of rejection and of graft failure in cardiac transplantation. The goal of this study was to determine the association of preformed and posttransplant development of newly detected DSA (ndDSA) with antibody-mediated rejection (AMR) and characterize the clinical relevance of complement-activating DSA in heart allograft recipients. METHODS The study included 128 adult and 48 pediatric heart transplant patients transplanted between 2010 and 2013. Routine posttransplant HLA antibody testing was performed by IgG single-antigen bead test. The C3d single-antigen bead assay was used to identify complement-activating antibodies. Rejection was diagnosed using International Society for Heart and Lung Transplantation criteria. RESULTS In this study, 22 patients were transplanted with preexisting DSA, and 43 patients developed ndDSA posttransplant. Pretransplant (P < 0.05) and posttransplant (P < 0.001) ndDSA were associated with higher incidence of AMR. Patients with C3d + DSA had significantly higher incidence of AMR compared with patients with no DSA (P < 0.001) or patients with C3d-DSA (P = 0.02). Nine (36%) of 25 patients with AMR developed transplant coronary artery disease compared with 17 (15.9%) of 107 patients without AMR (P < 0.05). Among the 47 patients who received ventricular assistant device (VAD), 7 of 9 VAD+ patients with preformed DSA experienced AMR compared with 7 of 38 VAD+ patients without preformed DSA, indicating presensitization to donor HLA significantly increased the risk of AMR (P < 0.01). CONCLUSIONS Preformed and posttransplant ndDSA were associated with AMR. C3d + DSA correlates with complement deposition on the graft and higher risk of AMR which may permit the application of personalized immunotherapy targeting the complement pathway.
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10
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Anglicheau D, Delville M, Lamarthee B. Non anti-HLA antibodies and acute rejection: A critical viewpoint. Nephrol Ther 2019; 15 Suppl 1:S53-S59. [PMID: 30981396 DOI: 10.1016/j.nephro.2019.03.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 03/04/2019] [Indexed: 10/27/2022]
Abstract
In solid organ transplantation, the deleterious effect of antibodies directed against donor HLA antigens, whether preformed or de novo, is well established. Anti-HLA antibodies have been associated not only with the risk of antibody-mediated rejection but also with late graft dysfunction and are now considered to be the leading cause of allograft loss after renal transplantation. In addition to HLA antibodies, the possible involvement of non-HLA antibodies targeting donor endothelial cells has long been the subject of intense research. The purpose of this review is to discuss current knowledge and remaining issues related to the involvement of non-HLA antibodies in solid organ transplantation. More specifically, the clinical data underlying the hypothesis of the role of non-HLA antibodies will be discussed, as well as the different techniques for antibody detection, their clinical relevance and their antigenic targets.
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Affiliation(s)
- Dany Anglicheau
- Service de néphrologie et transplantation rénale adulte, hôpital Necker-Enfants-Malades, 149, rue de Sèvres, 75015 Paris, France; Université Paris Descartes Sorbonne Paris Cité, 12, rue de l'École-de-Médecine, 75006 Paris, France; Inserm, U1151, 149, rue de Sèvres, 75015 Paris, France.
| | - Marianne Delville
- Université Paris Descartes Sorbonne Paris Cité, 12, rue de l'École-de-Médecine, 75006 Paris, France; Service de biothérapie, hôpital Necker-Enfants-Malades, 149, rue de Sèvres, 75015 Paris, France; Inserm, U1163, 24, boulevard de Montparnasse, 75015 Paris, France
| | - Baptiste Lamarthee
- Service de néphrologie et transplantation rénale adulte, hôpital Necker-Enfants-Malades, 149, rue de Sèvres, 75015 Paris, France; Université Paris Descartes Sorbonne Paris Cité, 12, rue de l'École-de-Médecine, 75006 Paris, France; Inserm, U1151, 149, rue de Sèvres, 75015 Paris, France
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11
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Colvin MM, Cook JL, Chang PP, Hsu DT, Kiernan MS, Kobashigawa JA, Lindenfeld J, Masri SC, Miller DV, Rodriguez ER, Tyan DB, Zeevi A. Sensitization in Heart Transplantation: Emerging Knowledge: A Scientific Statement From the American Heart Association. Circulation 2019; 139:e553-e578. [DOI: 10.1161/cir.0000000000000598] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Sensitization, defined as the presence of circulating antibodies, presents challenges for heart transplant recipients and physicians. When present, sensitization can limit a transplantation candidate’s access to organs, prolong wait time, and, in some cases, exclude the candidate from heart transplantation altogether. The management of sensitization is not yet standardized, and current therapies have not yielded consistent results. Although current strategies involve antibody suppression and removal with intravenous immunoglobulin, plasmapheresis, and antibody therapy, newer strategies with more specific targets are being investigated.
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12
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Valenzuela NM, Askar M, Heidt S, Jindra P, Madbouly A, Pinelli D, Jackson A, Hidalgo LG. Minimal data reporting standards for serological testing for histocompatibility. Hum Immunol 2018; 79:865-868. [DOI: 10.1016/j.humimm.2018.08.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 08/15/2018] [Indexed: 12/30/2022]
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13
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Habets THPM, Hepkema BG, Kouprie N, Schnijderberg MCA, van Smaalen TC, Bungener LB, Christiaans MHL, Bos GMJ, Vanderlocht J. The prevalence of antibodies against the HLA-DRB3 protein in kidney transplantation and the correlation with HLA expression. PLoS One 2018; 13:e0203381. [PMID: 30192820 PMCID: PMC6128541 DOI: 10.1371/journal.pone.0203381] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Accepted: 08/20/2018] [Indexed: 11/29/2022] Open
Abstract
Human leukocyte antigen (HLA)-DRB3 is a functional HLA class II gene, which has a limited allele diversity in the human population. Furthermore, the HLA-DRB3 gene is only present in a subset of individuals. Therefore, in organ transplantation, this HLA molecule is frequently mismatched between patient and graft donor and thus antibodies against this mismatched HLA molecule can develop. In this study, we aimed to evaluate the prevalence and reactivity of these antibodies and aimed to identify factors that underlie antibody formation against HLA-DRB3. We showed in our patient cohort that HLA-DRB3 antibodies are identified in about 7% of all patients that were screened with solid phase assays. In these assays, we observed multiple antibody reactivity patterns indicating that HLA-DRB3 harbours multiple epitopes. In those cases, where we succeeded at tracing back the induction of these antibodies to the molecular HLA typing of the immunogenic event, we noticed a different frequency of HLA-DRB1 allele groups in the donors as compared to a control group. To a certain extent this distribution (e.g. HLA-DRB1*11 individuals) could be linked to an altered expression level. However, it also appears that different HLA-DRB3 alleles (e.g. HLA-DRB3*01 group) vary in their immunogenicity without having an expression difference. In conclusion, our study provides information on the immunogenicity and reactivity patterns of antibodies against HLA-DRB3 in kidney transplantation, and it points towards the possibility of HLA expression as a factor underlying antibody formation.
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Affiliation(s)
- Thomas H. P. M. Habets
- Department of Transplantation Immunology, Tissue Typing Laboratory, Maastricht University Medical Center +, Maastricht, The Netherlands
- Department of Internal Medicine, Division of Hematology, Maastricht University Medical Center +, Maastricht, The Netherlands
| | - Bouke G. Hepkema
- Transplantation Immunology, Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Niels Kouprie
- Transplantation Immunology, Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Melanie C. A. Schnijderberg
- Department of Internal Medicine, Division of Hematology, Maastricht University Medical Center +, Maastricht, The Netherlands
| | - Tim C. van Smaalen
- Department of Surgery, Maastricht University Medical Center +, Maastricht, The Netherlands
| | - Laura B. Bungener
- Transplantation Immunology, Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Maarten H. L. Christiaans
- Department of Internal Medicine, Division of Nephrology, Maastricht University Medical Center +, Maastricht, The Netherlands
| | - Gerard M. J. Bos
- Department of Internal Medicine, Division of Hematology, Maastricht University Medical Center +, Maastricht, The Netherlands
- CiMaas BV, Maastricht, The Netherlands
| | - Joris Vanderlocht
- Department of Transplantation Immunology, Tissue Typing Laboratory, Maastricht University Medical Center +, Maastricht, The Netherlands
- Department of Internal Medicine, Division of Hematology, Maastricht University Medical Center +, Maastricht, The Netherlands
- Central Diagnostic Laboratory, Maastricht University Medical Center +, Maastricht, The Netherlands
- * E-mail:
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14
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Kamburova EG, Wisse BW, Joosten I, Allebes WA, van der Meer A, Hilbrands LB, Baas MC, Spierings E, Hack CE, van Reekum FE, van Zuilen AD, Verhaar MC, Bots ML, Drop ACAD, Plaisier L, Seelen MAJ, Sanders JS.F, Hepkema BG, Lambeck AJA, Bungener LB, Roozendaal C, Tilanus MGJ, Voorter CE, Wieten L, van Duijnhoven EM, Gelens M, Christiaans MHL, van Ittersum FJ, Nurmohamed SA, Lardy NM, Swelsen W, van der Pant KA, van der Weerd NC, ten Berge IJM, Bemelman FJ, Hoitsma A, van der Boog PJM, de Fijter JW, Betjes MGH, Heidt S, Roelen DL, Claas FH, Otten HG. Differential effects of donor-specific HLA antibodies in living versus deceased donor transplant. Am J Transplant 2018; 18:2274-2284. [PMID: 29464832 PMCID: PMC6175247 DOI: 10.1111/ajt.14709] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 01/29/2018] [Accepted: 01/30/2018] [Indexed: 01/25/2023]
Abstract
The presence of donor-specific anti-HLA antibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAs against HLA class I, class II, or both classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long-term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement-dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAs against class I or II antigens after transplant. Class I and II DSAs combined resulted in decreased 10-year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAs had a 10-year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs (76%). The combination of class I and II DSAs resulted in a 10-year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAs are a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAs seem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence.
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15
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Koch M, Marget M, Sterneck M, Fischer L, Thude H, Nashan B. Limited impact of pre-existing donor specific HLA-antibodies (DSA) on long term allograft survival after first adult liver transplantation. Hum Immunol 2018; 79:545-549. [PMID: 29669260 DOI: 10.1016/j.humimm.2018.04.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 04/10/2018] [Accepted: 04/13/2018] [Indexed: 12/30/2022]
Abstract
The relevance of pre-existing HLA-antibodies (HLA-Ab) in liver transplantation (LTx) is controversial. While livers are allocated without HLA match or preoperative crossmatch testing, several studies point to an impact of donor specific antibodies (DSA) for acute rejection, bile duct complications or even graft loss. To investigate the role of DSA in long term liver allograft survival we analysed 177 pre transplant sera of first LTx patients with Luminex single antigen technology defining a MFI of >1500 as positive. The analyses were done retrospectively, and the DSA results had no impact on graft acceptance or patients' therapy. Three year follow up was available for all patients. 77% of our patients had any HLA-Ab pre transplantation, 55 patients were transplanted with DSA by chance. Acute rejections or ischemic type bile duct lesions (ITBL) were not higher in the DSA group, but ITBL was associated with a higher donor age. There was no difference in long term graft function or survival in patients without HLA-Ab, with non DSA or with DSA (p = 0.712). We suggest that determination of pre-existing DSA in first LTx recipients is not appropriate and we conclude that pre-existing DSA in first LTx patients are not a contraindication for liver transplantation.
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Affiliation(s)
- Martina Koch
- Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
| | - Matthias Marget
- Institute of Transfusion Medicine, HLA Laboratory, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
| | - Martina Sterneck
- I. Medical Clinic, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
| | - Lutz Fischer
- Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
| | - Hansjörg Thude
- Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
| | - Björn Nashan
- Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
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16
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Evidence for an important role of both complement-binding and noncomplement-binding donor-specific antibodies in renal transplantation. Curr Opin Organ Transplant 2017; 21:433-40. [PMID: 27348472 DOI: 10.1097/mot.0000000000000324] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
PURPOSE OF REVIEW The review describes the current clinical relevance of circulating anti-human leukocyte antigen (anti-HLA) antibodies in kidney transplantation and discusses recent improvements in their characterization that provide new insights into the identification and management of important clinical outcomes. RECENT FINDINGS Recent studies addressing the relationships between donor-specific anti-HLA antibody (HLA-DSA) properties (i.e., their strength, complement-binding capacity, and IgG subclass composition) and allograft injury and survival have highlighted their relevance in the prediction of antibody-mediated injury and allograft loss. SUMMARY Antibody-mediated rejection is the leading cause of kidney allograft loss. Although considerable experimental and clinical evidence suggests a causal effect of circulating HLA-DSAs in antibody-mediated rejection and allograft failure, HLA-DSAs induce a wide spectrum of injuries to the allograft that illustrate the need to delineate the characteristics of HLA-DSAs that confer pathogenesis. Current risk stratification is based on HLA-DSA characteristics, including antibody specificity, HLA class, and strength. Recently, the complement-binding capacity of HLA-DSAs has been recognized as a clinically relevant marker for predicting pathogenicity and allograft loss. Emerging data also support a role for HLA-DSA IgG subclass composition in discriminating distinct patterns of antibody-mediated injury. This progress in our understanding of HLA-DSA pathogenicity provides new tools to stratify individual immunological risks. However, specific prospective studies addressing immunological risk stratification in large and unselected populations are required to define the clinical benefit and cost-effectiveness of such a comprehensive assessment of HLA-DSAs before implementation in current clinical practice.
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17
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Kozakowski N, Eskandary F, Herkner H, Bond G, Oberbauer R, Regele H, Böhmig GA, Kikić Ž. Diffuse Extent of Peritubular Capillaritis in Late Antibody-Mediated Rejection: Associations With Levels of Donor-Specific Antibodies and Chronic Allograft Injury. Transplantation 2017; 101:e178-e187. [PMID: 28252564 DOI: 10.1097/tp.0000000000001707] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Recently, diffuse peritubular capillaritis (ptc) has been suggested to independently predict chronic transplant injury and loss, and although the ptc score is a diagnostic criterion for antibody-mediated rejection, the utility of diffuse ptc is under debate. METHODS We evaluated the diagnostic value of ptc characteristics in this cross-sectional study including 85 biopsies of patients with donor-specific antibodies (DSA). Biopsies were reevaluated for the extent (diffuse vs focal), score and leukocytic composition in relation to DSA binding strength (mean fluorescence intensity [MFI]_max). Chronic allograft injury (transplant chronic glomerulopathy [cg] or chronic lesion score CLS]) were associated with ptc features. RESULTS Peritubular capillaritis was detected in 50% (76% mononuclear ptc). Peritubular capillaritis scores 1, 2, and 3 were present in 36%, 55%, and 9%, and focal or diffuse ptc in 36% or 64%. Diffuse ptc was associated with DSA MFI_max (median: 4407 vs 2419 [focal ptc; P = 0.04] or 1946 [no ptc; P = 0.004]), cg (58% vs no ptc 24% [P = 0.02]), and higher CLS (mean: 6.81 vs 4.67 [focal ptc, P = 0.01] or 5.18 [no ptc, P = 0.001]), respectively. The association of ptc score of 2 or greater with cg was slightly better than with diffuse ptc. Diffuse ptc and ptc score of 2 or greater remained independently related to cg after adjusting for DSA_MFI_max, C4d, or previous rejection episodes, however lost their independent relation after adjusting for total microcirculation scores. Diffuse ptc was the only ptc characteristic independently related to CLS. CONCLUSIONS Our results emphasize the clinical relevance of reporting diffuse ptc, which may relate to DSA binding strength and potentially to chronic graft injury.
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Affiliation(s)
- Nicolas Kozakowski
- 1 Institute of Clinical Pathology, Medical University Vienna, Vienna, Austria. 2 Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Vienna, Austria. 3 Department of Emergency Medicine, Medical University Vienna, Vienna, Austria
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18
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Garg N, Samaniego MD, Clark D, Djamali A. Defining the phenotype of antibody-mediated rejection in kidney transplantation: Advances in diagnosis of antibody injury. Transplant Rev (Orlando) 2017; 31:257-267. [PMID: 28882367 DOI: 10.1016/j.trre.2017.08.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Revised: 08/08/2017] [Accepted: 08/10/2017] [Indexed: 11/29/2022]
Abstract
The diagnostic criteria for antibody-mediated rejection (ABMR) are constantly evolving in light of the evidence. Inclusion of C4d-negative ABMR has been one of the major advances in the Banff Classification in recent years. Currently Banff 2015 classification requires evidence of donor specific antibodies (DSA), interaction between DSA and the endothelium, and acute tissue injury (in the form of microvasculature injury (MVI); acute thrombotic microangiopathy; or acute tubular injury in the absence of other apparent cause). In this article we review not only the ABMR phenotypes acknowledged in the most recent Banff classification, but also the phenotypes related to novel pathogenic antibodies (non-HLA DSA, antibody isoforms and subclasses, complement-binding functionality) and molecular diagnostic tools (gene transcripts, metabolites, small proteins, cytokines, and donor-derived cell-free DNA). These novel tools are also being considered for the prognosis and monitoring of treatment response. We propose that improved classification of ABMR based on underlying pathogenic mechanisms and outcomes will be an important step in identifying patient-centered therapies to extend graft survival.
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Affiliation(s)
- Neetika Garg
- Department of Medicine, Nephrology Division, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States.
| | - Milagros D Samaniego
- Department of Medicine, Nephrology Division, University of Michigan, Ann Arbor, MI 48109, United States
| | - Dana Clark
- Department of Medicine, Nephrology Division, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
| | - Arjang Djamali
- Department of Medicine, Nephrology Division, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
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19
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Torque Teno Virus Load-Inverse Association With Antibody-Mediated Rejection After Kidney Transplantation. Transplantation 2017; 101:360-367. [PMID: 27525643 DOI: 10.1097/tp.0000000000001455] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Antibody-mediated rejection (AMR) represents one of the cardinal causes of late allograft loss after kidney transplantation, and there is great need for noninvasive tools improving early diagnosis of this rejection type. One promising strategy might be the quantification of peripheral blood DNA levels of the highly prevalent and apathogenic Torque Teno virus (TTV), which might mirror the overall level of immunosuppression and thus help determine the risk of alloimmune response. METHODS To assess the association between TTV load in the peripheral blood and AMR, 715 kidney transplant recipients (median, 6.3 years posttransplantation) were subjected to a systematical cross-sectional AMR screening and, in parallel, TTV quantification. RESULTS Eighty-six of these recipients had donor-specific antibodies and underwent protocol biopsy, AMR-positive patients (n = 46) showed only 25% of the TTV levels measured in patients without AMR (P = 0.003). In a generalized linear model, higher TTV levels were associated with a decreased risk for AMR after adjustment for potential confounders (risk ratio 0.94 per TTV log level; 95% confidence interval 0.90-0.99; P = 0.02). CONCLUSIONS Future studies will have to clarify whether longitudinal assessment of TTV load might predict AMR risk and help guide the type and intensity of immunosuppression to prevent antibody-mediated graft injury.
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20
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Diagnostic Contribution of Donor-Specific Antibody Characteristics to Uncover Late Silent Antibody-Mediated Rejection-Results of a Cross-Sectional Screening Study. Transplantation 2017; 101:631-641. [PMID: 27120452 DOI: 10.1097/tp.0000000000001195] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Circulating donor-specific antibodies (DSA) detected on bead arrays may not inevitably indicate ongoing antibody-mediated rejection (AMR). Here, we investigated whether detection of complement-fixation, in parallel to IgG mean fluorescence intensity (MFI), allows for improved prediction of AMR. METHODS Our study included 86 DSA+ kidney transplant recipients subjected to protocol biopsy, who were identified upon cross-sectional antibody screening of 741 recipients with stable graft function at 6 months or longer after transplantation. IgG MFI was analyzed after elimination of prozone effect, and complement-fixation was determined using C1q, C4d, or C3d assays. RESULTS Among DSA+ study patients, 44 recipients (51%) had AMR, 24 of them showing C4d-positive rejection. Although DSA number or HLA class specificity were not different, patients with AMR or C4d + AMR showed significantly higher IgG, C1q, and C3d DSA MFI than nonrejecting or C4d-negative patients, respectively. Overall, the predictive value of DSA characteristics was moderate, whereby the highest accuracy was computed for peak IgG MFI (AMR, 0.73; C4d + AMR, 0.71). Combined analysis of antibody characteristics in multivariate models did not improve AMR prediction. CONCLUSIONS We estimate a 50% prevalence of silent AMR in DSA+ long-term recipients and conclude that assessment of IgG MFI may add predictive accuracy, without an independent diagnostic advantage of detecting complement-fixation.
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21
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Mehrotra S, Sharma RK, Mayya M, Gupta A, Prasad N, Kaul A, Bhadauria DS. Luminex Solid-Phase Crossmatch for De Novo Donor-Specific Antibodies in Living-Donor Related Transplants. EXP CLIN TRANSPLANT 2017; 15:394-399. [PMID: 28447925 DOI: 10.6002/ect.2016.0178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES There are no reports of de novo donor-specific antibody monitoring by a low-cost solid-phase crossmatch assay using donor lysate after renal transplant. MATERIALS AND METHODS We prospectively evaluated 121 complement-dependant cytotoxicity crossmatch-negative living-donor kidney transplant recipients for development of de novo donor-specific antibodies (class I and II HLA) by solid-phase crossmatch Luminex assay after transplant. RESULTS Of 121 recipients in our study group, 26 (21.5%) developed de novo donor-specific antibody within 3 months after transplant. Fifteen (58%) of these 26 recipients developed class II de novo donor-specific antibody, 8 patients (30%) developed class I, and 3 (12%) developed both class I and class II. Of the remaining 95 patients (79%) who did not develop de novo donor-specific antibody, 6 (33.3%) had antibody-mediated rejection with glomerulitis (2 with C4d-positive disease). Donor-specific antibody was detected by Luminex solid-phase crossmatch in 18 patients (5 with class I, 11 with class II, and 2 with both class I and II), all with no evidence of clinical rejection. Development of de novo donor-specific antibody detected by solid-phase crossmatch was associated with more acute rejection (31% in de novo donor-specific antibody-positive group versus 19% in the negative group). The positive group had more antibody-mediated rejection (75% of acute rejections), whereas only 33.3% of acute rejections in the negative group were antibody-mediated rejection. Of 12 patients with antibody-mediated rejection, 9 were C4d negative (75%) and were diagnosed by donor-specific antibody positivity detected by solid-phase cros?match testing and histologic findings. The use of donor lysate in solid-phase crossmatch assays is more economical than the single-antigen bead Luminex assay (per test cost of US $45.20 vs $403.20).
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Affiliation(s)
- Sonia Mehrotra
- From the Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
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22
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Kauke T, Oberhauser C, Lin V, Coenen M, Fischereder M, Dick A, Schoenermarck U, Guba M, Andrassy J, Werner J, Meiser B, Angele M, Stangl M, Habicht A. De novo donor-specific anti-HLA antibodies after kidney transplantation are associated with impaired graft outcome independently of their C1q-binding ability. Transpl Int 2017; 30:360-370. [PMID: 27862352 DOI: 10.1111/tri.12887] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 07/28/2016] [Accepted: 11/09/2016] [Indexed: 12/16/2022]
Abstract
Many aspects of post-transplant monitoring of donor-specific (DSA) and non-donor-specific (nDSA) anti-HLA antibodies on renal allograft survival are still unclear. Differentiating them by their ability to bind C1q may offer a better risk assessment. We retrospectively investigated the clinical relevance of de novo C1q-binding anti-HLA antibodies on graft outcome in 611 renal transplant recipients. Acute rejection (AR), renal function, and graft survival were assessed within a mean follow-up of 6.66 years. Post-transplant 6.5% patients developed de novo DSA and 11.5% de novo nDSA. DSA (60.0%; P < 0.0001) but not nDSA (34.1%, P = 0.4788) increased rate of AR as compared with controls (27.4%). C1q-binding anti-HLA antibodies did not alter rate of AR in both groups. Renal function was only significantly diminished in patients with DSAC1q+ . However, DSA significantly impaired 5-year graft survival (65.2%; P < 0.0001) in comparison with nDSA (86.7%; P = 0.0054) and controls (90.7%). While graft survival did not differ between DSAC1q- and DSAC1q+ recipients, 5-year allograft survival was reduced in nDSAC1q+ (80.9%) versus nDSAC1q- (90.7%, P = 0.0251). De novo DSA independently of their ability to bind C1q are associated with diminished graft survival.
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Affiliation(s)
- Teresa Kauke
- Laboratory of Immunogenetics, University Hospital Munich, Munich, Germany.,Clinic of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital Munich, Munich, Germany.,Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Cornelia Oberhauser
- Department of Medical Informatics, Biometry and Epidemiology - IBE, Chair for Public Health and Health Services Research, Munich, Germany.,Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Viviane Lin
- Laboratory of Immunogenetics, University Hospital Munich, Munich, Germany.,Transplant Center, University Hospital Munich, Munich, Germany.,Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Michaela Coenen
- Department of Medical Informatics, Biometry and Epidemiology - IBE, Chair for Public Health and Health Services Research, Munich, Germany.,Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Michael Fischereder
- Renal Division, Department of Internal Medicine IV, University Hospital Munich, Munich, Germany.,Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Andrea Dick
- Laboratory of Immunogenetics, University Hospital Munich, Munich, Germany.,Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Ulf Schoenermarck
- Renal Division, Department of Internal Medicine IV, University Hospital Munich, Munich, Germany.,Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Markus Guba
- Clinic of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital Munich, Munich, Germany.,Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Joachim Andrassy
- Clinic of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital Munich, Munich, Germany.,Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Jens Werner
- Clinic of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital Munich, Munich, Germany.,Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Bruno Meiser
- Transplant Center, University Hospital Munich, Munich, Germany.,Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Martin Angele
- Clinic of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital Munich, Munich, Germany.,Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Manfred Stangl
- Clinic of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital Munich, Munich, Germany.,Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Antje Habicht
- Transplant Center, University Hospital Munich, Munich, Germany.,Ludwig-Maximilians-University (LMU), Munich, Germany
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23
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From Humoral Theory to Performant Risk Stratification in Kidney Transplantation. J Immunol Res 2017; 2017:5201098. [PMID: 28133619 PMCID: PMC5241462 DOI: 10.1155/2017/5201098] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 12/15/2016] [Indexed: 12/17/2022] Open
Abstract
The purpose of the present review is to describe how we improve the model for risk stratification of transplant outcomes in kidney transplantation by incorporating the novel insights of donor-specific anti-HLA antibody (DSA) characteristics. The detection of anti-HLA DSA is widely used for the assessment of pre- and posttransplant risks of rejection and allograft loss; however, not all anti-HLA DSA carry the same risk for transplant outcomes. These antibodies have been shown to cause a wide spectrum of effects on allografts, ranging from the absence of injury to indolent or full-blown acute antibody-mediated rejection. Consequently, the presence of circulating anti-HLA DSA does not provide a sufficient level of accuracy for the risk stratification of allograft outcomes. Enhancing the predictive performance of anti-HLA DSA is currently one of the most pressing unmet needs for facilitating individualized treatment choices that may improve outcomes. Recent advancements in the assessment of anti-HLA DSA properties, including their strength, complement-binding capacity, and IgG subclass composition, significantly improved the risk stratification model to predict allograft injury and failure. Although risk stratification based on anti-HLA DSA properties appears promising, further specific studies that address immunological risk stratification in large and unselected populations are required to define the benefits and cost-effectiveness of such comprehensive assessment prior to clinical implementation.
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24
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Ramon DS, Huang Y, Zhao L, Rendulic T, Park JM, Sung RS, Samaniego M. Use of complement binding assays to assess the efficacy of antibody mediated rejection therapy and prediction of graft survival in kidney transplantation. Hum Immunol 2016; 78:57-63. [PMID: 27894836 DOI: 10.1016/j.humimm.2016.11.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 09/17/2016] [Accepted: 11/23/2016] [Indexed: 10/20/2022]
Abstract
BACKGROUND The Luminex® single antigen bead assay (SAB) is the method of choice for monitoring the treatment for antibody-mediated rejection (AMR). A ⩾50% reduction of the dominant donor-specific antibody (IgG-DSA) mean fluorescence intensity (MFI) has been associated with improved kidney allograft survival, and C1q-fixing DSA activity is associated with poor outcomes in patients with AMR. We aimed to investigate if C1q-DSA can be used as a reliable predictor of response to therapy and allograft survival in patients with biopsy-proven AMR. METHODS We tested pre- and post-treatment sera of 30 kidney transplant patients receiving plasmapheresis and low-dose IVIG for biopsy-proven AMR. IgG-DSA and C1q-DSA MFI were measured and correlated with graft loss or survival. Patients were classified as nonresponders (NR) when treatment resulted in <50% reduction in MFI of IgG-DSA and/or C1q-DSA was detectable following therapy. RESULTS Differences in the percentage of patients deemed NR depended upon the end-point criterion (73% by reduction in IgG-DSA MFI vs. 50% by persistent C1q-DSA activity). None of the seven patients with <50% reduction of IgG-DSA but non-detectable C1q-DSA-fixing activity after therapy experienced graft loss, suggesting that C1q-DSA activity may better correlate with response. Reduction of C1q-DSA activity predicted graft survival better than IgG-DSA in the univariate Cox analysis (20.1% vs. 5.9% in NR; log-rank P-value=0.0147). CONCLUSIONS A rapid reduction of DSA concentration below the threshold required for complement activation is associated with better graft survival, and C1q-DSA is a better predictor of outcomes than IgG-DSA MFI reduction.
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Affiliation(s)
- Daniel S Ramon
- Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
| | - Yihung Huang
- Department of Internal Medicine, Division of Nephrology, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Lili Zhao
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
| | - TrisAnn Rendulic
- Department of Pharmacy Services, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Jeong M Park
- Department of Pharmacy Services, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Randall S Sung
- Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Milagros Samaniego
- Department of Internal Medicine, Division of Nephrology, University of Michigan School of Medicine, Ann Arbor, MI, USA
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25
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Kwok J, Choi LCW, Ho JCY, Chan GSW, Mok MMY, Lam MF, Chak WL, Cheuk A, Chau KF, Tong M, Chan KW, Chan TM. A Modified Protocol with Improved Detection Rate for Mis-Matched Donor HLA from Low Quantities of DNA in Urine Samples from Kidney Graft Recipients. PLoS One 2016; 11:e0166427. [PMID: 27861530 PMCID: PMC5115744 DOI: 10.1371/journal.pone.0166427] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 10/17/2016] [Indexed: 11/26/2022] Open
Abstract
Background Urine from kidney transplant recipient has proven to be a viable source for donor DNA. However, an optimized protocol would be required to determine mis-matched donor HLA specificities in view of the scarcity of DNA obtained in some cases. Methods In this study, fresh early morning urine specimens were obtained from 155 kidney transplant recipients with known donor HLA phenotype. DNA was extracted and typing of HLA-A, B and DRB1 loci by polymerase chain reaction-specific sequence primers was performed using tailor-made condition according to the concentration of extracted DNA. Results HLA typing of DNA extracted from urine revealed both recipient and donor HLA phenotypes, allowing the deduction of the unknown donor HLA and hence the degree of HLA mis-match. By adopting the modified procedures, mis-matched donor HLA phenotypes were successfully deduced in all of 35 tested urine samples at DNA quantities spanning the range of 620–24,000 ng. Conclusions This urine-based method offers a promising and reliable non-invasive means for the identification of mis-matched donor HLA antigens in kidney transplant recipients with unknown donor HLA phenotype or otherwise inadequate donor information.
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Affiliation(s)
- Janette Kwok
- Division of Transplantation and Immunogenetics, Department of Pathology,Queen Mary Hospital, Hong Kong SAR, China
- * E-mail:
| | - Leo C. W. Choi
- Division of Transplantation and Immunogenetics, Department of Pathology,Queen Mary Hospital, Hong Kong SAR, China
| | - Jenny C. Y. Ho
- Division of Transplantation and Immunogenetics, Department of Pathology,Queen Mary Hospital, Hong Kong SAR, China
| | - Gavin S. W. Chan
- Division of Anatomical Pathology, Department of Pathology, Queen Mary Hospital, Hong Kong SAR, China
| | - Maggie M. Y. Mok
- Department of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Man-Fei Lam
- Department of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Wai-Leung Chak
- Department of Medicine, Queen Elizabeth Hospital, Hong Kong SAR, China
| | - Au Cheuk
- Department of Medicine & Geriatrics, Princess Margaret Hospital, Hong Kong SAR, China
| | - Ka-Foon Chau
- Department of Medicine, Queen Elizabeth Hospital, Hong Kong SAR, China
| | - Matthew Tong
- Department of Medicine & Geriatrics, Princess Margaret Hospital, Hong Kong SAR, China
| | - Kwok-Wah Chan
- Department of Pathology, The University of Hong Kong, Hong Kong SAR, China
| | - Tak-Mao Chan
- Department of Medicine, The University of Hong Kong, Hong Kong SAR, China
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26
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Pathogenesis of non-HLA antibodies in solid organ transplantation: Where do we stand? Hum Immunol 2016; 77:1055-1062. [PMID: 27237040 DOI: 10.1016/j.humimm.2016.05.021] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Revised: 04/29/2016] [Accepted: 05/23/2016] [Indexed: 11/20/2022]
Abstract
Antibody-mediated rejection (ABMR) is associated with poor transplant outcome. Pathogenic alloantibodies are usually directed against human leukocyte antigens (HLAs). Histological findings suggestive of ABMR usually demonstrate an anti-HLA donor-specific antibody (DSA)-mediated injury, while a small subset of patients develop acute dysfunction with histological lesions suggestive of ABMR in the absence of anti-HLA DSAs. Although this non-HLA ABMR is not well recognized by current diagnostic classifications, it is associated with graft dysfunction and allograft loss. These clinical descriptions suggest a pathogenic role for non-HLA anti-endothelial cell antibodies. Diverse antigenic targets have been described during the last decade. This review discusses recent findings in the field and addresses the clinical relevance of anti-endothelial cell antibodies (AECAs).
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27
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In vivo heat inactivation of serum can distinguish false positive cross matches in renal transplants. Int J Artif Organs 2016; 39:63-7. [PMID: 26953900 DOI: 10.5301/ijao.5000470] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2016] [Indexed: 11/20/2022]
Abstract
INTRODUCTION Renal transplants have traditionally been performed despite positive cross match if results are presumptively due to IgM antibodies. False positives have been distinguishable from true positives by dithiothreitol or dithioerythritol treatment to inactivate IgM antibodies. Heat inactivation, which renders the antibodies inactive, is an alternative to chemical amelioration. METHODS We retrospectively evaluated clinical outcomes of patients who had positive cross matches presumed to be falsely positive as determined by treatment with heat inactivation compared to controls with negative cross matches over a six-year period. A total of 414 transplanted patients had available cross match data: 355 with a negative cross match and 59 with a positive cross match rendered negative after heat inactivation. Serum creatinine was reviewed at 6, 12 and 24 months posttransplant. RESULTS Graft function was considered stable at 12 and 24 months post-transplant if the change in creatinine compared to the 6-month value was >0.5 mg/dL. Repeated and nonrepeated measures analysis showed equivalence in the change in sCr from 6 to 12 (p = 0.525) and from 6 to 24 months (p = 0.752). Kaplan-Meier curves to evaluate graft survival demonstrated no significant difference in function over 24 months. Curves were censored for patient death, treated as death with functioning (p = 0.48) and nonfunctioning (p = 0.64) grafts. DISCUSSIONS We have demonstrated comparable long-term function and survival for living donor renal transplants using heat inactivation to detect false positive cross matches. This simple and cost-effective method can be used to safely evaluate histocompatibility for living donor renal transplant recipients.
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28
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Redondo-Pachón D, Pascual J, Pérez-Sáez MJ, García C, Hernández JJ, Gimeno J, Mir M, Crespo M. Impact of preformed and de novo anti-HLA DP antibodies in renal allograft survival. Transpl Immunol 2015; 34:1-7. [PMID: 26603314 DOI: 10.1016/j.trim.2015.11.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 11/12/2015] [Accepted: 11/17/2015] [Indexed: 11/26/2022]
Abstract
The influence of antibodies against HLA-DP antigens detected with solid-phase assays on graft survival after kidney transplantation (KT) is uncertain. We evaluated with Luminex® the prevalence of pre- and posttransplant DP antibodies in 440 KT patients and their impact on graft survival. For 291 patients with available pretransplant samples, DP antibodies were present in 39.7% KT with pretransplant HLA antibodies and 47.7% with DSA. Graft survival of KT with pretransplant class-II DSA was worse than with non-DSA (p=0.01). DP antibodies did not influence graft survival. Of 346 patients monitored post-KT, 17.1% had HLA class-II antibodies, 56% with DP antibodies. Class-II DSA was detected in 39%, 60.9% of them had DP antibodies. Graft survival was worse in patients with class-II DSA (p=0.022). DP antibodies did not change these results. The presence of isolated DP antibodies was a rare event both pre- and posttransplantation (1.03 and 0.86%). The presence of pretransplant and posttransplant DSA is associated with a negative impact on graft survival. However, the presence of DP antibodies does not modify this impact significantly.
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Affiliation(s)
- Dolores Redondo-Pachón
- Department of Nephrology, Institute Mar for Medical Research, Hospital del Mar, Barcelona, Spain
| | - Julio Pascual
- Department of Nephrology, Institute Mar for Medical Research, Hospital del Mar, Barcelona, Spain.
| | - María J Pérez-Sáez
- Department of Nephrology, Institute Mar for Medical Research, Hospital del Mar, Barcelona, Spain
| | - Carmen García
- Laboratori de Referencia de Catalunya, Barcelona, Spain
| | | | - Javier Gimeno
- Department of Pathology, Hospital del Mar, Barcelona, Spain
| | - Marisa Mir
- Department of Nephrology, Institute Mar for Medical Research, Hospital del Mar, Barcelona, Spain
| | - Marta Crespo
- Department of Nephrology, Institute Mar for Medical Research, Hospital del Mar, Barcelona, Spain
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29
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Guidicelli G, Guerville F, Lepreux S, Wiebe C, Thaunat O, Dubois V, Visentin J, Bachelet T, Morelon E, Nickerson P, Merville P, Taupin JL, Couzi L. Non-Complement-Binding De Novo Donor-Specific Anti-HLA Antibodies and Kidney Allograft Survival. J Am Soc Nephrol 2015; 27:615-25. [PMID: 26047793 DOI: 10.1681/asn.2014040326] [Citation(s) in RCA: 108] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 04/24/2015] [Indexed: 01/29/2023] Open
Abstract
C1q-binding ability may indicate the clinical relevance of de novo donor-specific anti-HLA antibodies (DSA). This study investigated the incidence and risk factors for the appearance of C1q-binding de novo DSA and their long-term impact. Using Luminex Single Antigen Flow Bead assays, 346 pretransplant nonsensitized kidney recipients were screened at 2 and 5 years after transplantation for de novo DSA, which was followed when positive by a C1q Luminex assay. At 2 and 5 years, 12 (3.5%) and eight (2.5%) patients, respectively, had C1q-binding de novo DSA. De novo DSA mean fluorescence intensity >6237 and >10,000 at 2 and 5 years, respectively, predicted C1q binding. HLA mismatches and cyclosporine A were independently associated with increased risk of C1q-binding de novo DSA. When de novo DSA were analyzed at 2 years, the 5-year death-censored graft survival was similar between patients with C1q-nonbinding de novo DSA and those without de novo DSA, but was lower for patients with C1q-binding de novo DSA (P=0.003). When de novo DSA were analyzed at 2 and 5 years, the 10-year death-censored graft survival was lower for patients with C1q-nonbinding de novo DSA detected at both 2 and 5 years (P<0.001) and for patients with C1q-binding de novo DSA (P=0.002) than for patients without de novo DSA. These results were partially confirmed in two validation cohorts. In conclusion, C1q-binding de novo DSA are associated with graft loss occurring quickly after their appearance. However, the long-term persistence of C1q-nonbinding de novo DSA could lead to lower graft survival.
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Affiliation(s)
- Gwendaline Guidicelli
- Departments of Immunology, Bordeaux University, Bordeaux, France; National Center for Scientific Research (CNRS), UMR 5164, Bordeaux, France
| | - Florent Guerville
- Bordeaux University, Bordeaux, France; National Center for Scientific Research (CNRS), UMR 5164, Bordeaux, France; Nephrology-Transplantation-Dialysis, and
| | - Sébastien Lepreux
- Bordeaux University, Bordeaux, France; Histopathology, Bordeaux University Hospital, Bordeaux, France
| | - Chris Wiebe
- Department of Medicine and Immunology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Olivier Thaunat
- Transplantation, Nephrology and Clinical Immunology Department, Lyon University Hospital, Lyon, France; National Institute for Health and Medical Research (INSERM) U1111, Lyon, France; Lyon Est Teaching and Research Unit, Lyon University, Lyon, France; and
| | - Valérie Dubois
- Histocompatibility Laboratory, French National Blood Service, Lyon, France
| | - Jonathan Visentin
- Departments of Immunology, Bordeaux University, Bordeaux, France; National Center for Scientific Research (CNRS), UMR 5164, Bordeaux, France
| | - Thomas Bachelet
- Bordeaux University, Bordeaux, France; National Center for Scientific Research (CNRS), UMR 5164, Bordeaux, France; Nephrology-Transplantation-Dialysis, and
| | - Emmanuel Morelon
- Transplantation, Nephrology and Clinical Immunology Department, Lyon University Hospital, Lyon, France; National Institute for Health and Medical Research (INSERM) U1111, Lyon, France; Lyon Est Teaching and Research Unit, Lyon University, Lyon, France; and
| | - Peter Nickerson
- Department of Medicine and Immunology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Pierre Merville
- Bordeaux University, Bordeaux, France; National Center for Scientific Research (CNRS), UMR 5164, Bordeaux, France; Nephrology-Transplantation-Dialysis, and
| | - Jean-Luc Taupin
- Departments of Immunology, Bordeaux University, Bordeaux, France; National Center for Scientific Research (CNRS), UMR 5164, Bordeaux, France
| | - Lionel Couzi
- Bordeaux University, Bordeaux, France; National Center for Scientific Research (CNRS), UMR 5164, Bordeaux, France; Nephrology-Transplantation-Dialysis, and
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30
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Chong AS, Alegre ML. Transplantation tolerance and its outcome during infections and inflammation. Immunol Rev 2015; 258:80-101. [PMID: 24517427 DOI: 10.1111/imr.12147] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Much progress has been made toward understanding the mechanistic basis of transplantation tolerance in experimental models, which implicates clonal deletion of alloreactive T and B cells, induction of cell-intrinsic hyporesponsiveness, and dominant regulatory cells mediating infectious tolerance and linked suppression. Despite encouraging success in the laboratory, achieving tolerance in the clinic remains challenging, although the basis for these challenges is beginning to be understood. Heterologous memory alloreactive T cells generated by infections prior to transplantation have been shown to be a critical barrier to tolerance induction. Furthermore, infections at the time of transplantation and tolerance induction provide a pro-inflammatory milieu that alters the stability and function of regulatory T cells as well as the activation requirements and differentiation of effector T cells. Thus, infections can result in enhanced alloreactivity, resistance to tolerance induction, and destabilization of the established tolerance state. We speculate that these experimental findings have relevance to the clinic, where infections have been associated with allograft rejection and may be a causal event precipitating the loss of grafts after long periods of stable operational tolerance. Understanding the mechanisms by which infections prevent and destabilize tolerance can lead to therapies that promote stable life-long tolerance in transplant recipients.
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Affiliation(s)
- Anita S Chong
- Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL, USA
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31
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Leto Barone AA, Sun Z, Montgomery RA, Lee WPA, Brandacher G. Impact of donor-specific antibodies in reconstructive transplantation. Expert Rev Clin Immunol 2014; 9:835-44. [PMID: 24070047 DOI: 10.1586/1744666x.2013.824667] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
For many devastating injuries and tissue defects where conventional reconstruction is not possible, reconstructive transplantation such as hand and face transplantation has become a viable alternative. This novel approach allows for improved restoration of appearance, anatomy and function not feasible by other available treatment options. However, clinical management of these injuries prior to transplantation frequently requires multiple blood transfusion or skin grafts resulting in the formation of alloantibodies (anti-HLA IgG Abs) and a high degree of sensitization. The role of donor-specific antibodies (DSA) and mechanisms of antibody-mediated rejection (AMR) in reconstructive transplantation are still largely unknown. Thus there is an imminent need to develop a better understanding of the mechanisms related to DSA and AMR after reconstructive transplantation. In this review, we will define the role of DSA and mechanisms of AMR in reconstructive transplantation and compare them to established measures and treatment concepts in solid organ transplantation.
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Affiliation(s)
- Angelo A Leto Barone
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Ross Research Building 749D, 720 Rutland Avenue, Baltimore, MD, 21205 USA
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32
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Salvadori M, Bertoni E. Impact of donor-specific antibodies on the outcomes of kidney graft: Pathophysiology, clinical, therapy. World J Transplant 2014; 4:1-17. [PMID: 24669363 PMCID: PMC3964192 DOI: 10.5500/wjt.v4.i1.1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 01/23/2014] [Accepted: 03/03/2014] [Indexed: 02/05/2023] Open
Abstract
Allo-antibodies, particularly when donor specific, are one of the most important factors that cause both early and late graft dysfunction. The authors review the current state of the art concerning this important issue in renal transplantation. Many antibodies have been recognized as mediators of renal injury. In particular donor-specific-Human Leukocyte Antigens antibodies appear to play a major role. New techniques, such as solid phase techniques and Luminex, have revealed these antibodies from patient sera. Other new techniques have uncovered alloantibodies and signs of complement activation in renal biopsy specimens. It has been acknowledged that the old concept of chronic renal injury caused by calcineurine inhibitors toxicity should be replaced in many cases by alloantibodies acting against the graft. In addition, the number of patients on waiting lists with preformed anti-human leukocyte antigens (HLA) antibodies is increasing, primarily from patients with a history of renal transplant failure already been sensitized. We should distinguish early and late acute antibody-mediated rejection from chronic antibody-mediated rejection. The latter often manifets late during the course of the post-transplant period and may be difficult to recognize if specific techniques are not applied. Different therapeutic strategies are used to control antibody-induced damage. These strategies may be applied prior to transplantation or, in the case of acute antibody-mediated rejection, after transplantation. Many new drugs are appearing at the horizon; however, these drugs are far from the clinic because they are in phase I-II of clinical trials. Thus the pipeline for the near future appears almost empty.
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33
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Dahi PB, Barone J, Devlin SM, Byam C, Lubin M, Ponce DM, Giralt S, Kernan NA, Scaradavou A, Hsu SH, Barker JN. Sustained donor engraftment in recipients of double-unit cord blood transplantation is possible despite donor-specific human leukoctye antigen antibodies. Biol Blood Marrow Transplant 2014; 20:735-9. [PMID: 24462980 DOI: 10.1016/j.bbmt.2014.01.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Accepted: 01/18/2014] [Indexed: 10/25/2022]
Abstract
The impact of human leukocyte antigen (HLA) donor-specific antibodies (DSA) on cord blood (CB) engraftment is controversial. We evaluated the influence of pre-existing HLA-antibodies (HLA-Abs) on engraftment in 82 double-unit CB recipients (median age, 48 years) who underwent transplantation for hematologic malignancies. Of 28 patients (34%) with HLA-Abs, 12 had DSA (median mean fluorescence intensity 5255; range, 1057 to 9453). DSA patients had acute leukemia (n = 11) or myelodysplasia (n = 1) and all received either high-dose or reduced-intensity (but myeloablative) conditioning. After myeloablative CB transplantation (CBT) (n = 67), sustained donor engraftment was observed in 95% without HLA-Abs (median, 23 days), 100% with nonspecific HLA-Abs (median, 23 days), and 92% with DSA (median, 31 days, P = .48). Of 6 patients with HLA-Abs to 1 unit, 3 engrafted with that unit and 3 with the other. Of 6 patients with HLA-Abs against both units, 1 had graft failure despite being 100% donor, and 5 engrafted with 1 unit. Successful donor engraftment is possible in patients with DSA after myeloablative double-unit CBT. Our data suggest potential deleterious effects of DSA can be abrogated in patients with hematologic malignancies.
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Affiliation(s)
- Parastoo B Dahi
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Jonathan Barone
- Department of Histocompatibility/Molecular Genetics, American Red Cross Blood Services/Penn Jersey Region, Philadelphia, Pennsylvania
| | - Sean M Devlin
- Department of Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Courtney Byam
- Pediatric Bone Marrow Transplantation Service, Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Marissa Lubin
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Doris M Ponce
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Sergio Giralt
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Nancy A Kernan
- Pediatric Bone Marrow Transplantation Service, Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Andromachi Scaradavou
- Department of Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Susan H Hsu
- Department of Histocompatibility/Molecular Genetics, American Red Cross Blood Services/Penn Jersey Region, Philadelphia, Pennsylvania
| | - Juliet N Barker
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.
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34
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Nascimento E, Fabreti de Oliveira R, Maciel M, Pereira A, das Mercêz de Lucas F, Salomão-Filho A, Pereira W, Moreira J, Vilaça S, de Castro Gontijo R, Lasmar M, Vianna H, Magalhâes A, Calazans C, Simão-Filho C, Vilela B. Kidney Transplantation: Evaluation and Clinical Outcome of 237 Recipients at Low, Medium, High, or Strong Immunological Risk of Rejection. Transplant Proc 2014; 46:101-7. [DOI: 10.1016/j.transproceed.2013.10.041] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2013] [Revised: 10/28/2013] [Accepted: 10/28/2013] [Indexed: 11/16/2022]
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35
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Hoshino J, Everly M, Kaneku H, Ubara Y, Takaichi K, Terasaki P. Impact of the Presence and Duration of Donor-Specific Antibodies on Renal Function. Transplant Proc 2014; 46:75-80. [DOI: 10.1016/j.transproceed.2013.09.032] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Revised: 09/19/2013] [Accepted: 09/26/2013] [Indexed: 01/15/2023]
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Schlaf G, Pollok-Kopp B, Altermann WW. Sensitive solid-phase detection of donor-specific antibodies as an aid highly relevant to improving allograft outcomes. Mol Diagn Ther 2013; 18:185-201. [PMID: 24170304 DOI: 10.1007/s40291-013-0063-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Transplant recipients who have had sensitizing events such as pregnancies, blood transfusions and previous transplants often develop antibodies directed against human leukocyte antigen (HLA)-molecules of the donor tissue. These pre-formed donor-specific antibodies (DSA) represent a high risk of organ failure as a consequence of antibody-mediated hyper-acute or acute allograft rejection. As a first assay to detect DSA, the complement-dependent lymphocytotoxicity assay (CDC) was established more than 40 years ago. However, this assay is characterized by several drawbacks such as a low sensitivity and a high susceptibility to various artificial factors generally not leading to valid and reliable outcomes under several circumstances that are reviewed in this article. Furthermore, only those antibodies that exert complement-fixing activity are detected. As a consequence, novel procedures that act independently of the complement system and that do not represent functional assays were generated in the format of solid phase assays (SPAs) (bead- or ELISA-based). In this article, we review the pros and cons of these sensitive SPA in comparison with the detection of DSA through the use of the traditional methods such as CDC and flow cytometric analyses. Potential drawbacks of the alternative methodological approaches comprising high background reactivity, susceptibility to environmental factors and the possible influence of subjective operators' errors concerning the interpretation of the results are summarized and critically discussed for each method. We provide a forecast on the future role of SPAs reliably excluding highly deleterious DSA, thus leading to an improved graft survival.
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Affiliation(s)
- Gerald Schlaf
- Tissue Typing Laboratory, University Hospital Halle/Saale, Martin-Luther University of Halle-Wittenberg, Magdeburger Strasse 16, 06112, Halle (Saale), Germany,
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Taniguchi M, Rebellato LM, Cai J, Hopfield J, Briley KP, Haisch CE, Catrou PG, Bolin P, Parker K, Kendrick WT, Kendrick SA, Harland RC, Terasaki PI. Higher risk of kidney graft failure in the presence of anti-angiotensin II type-1 receptor antibodies. Am J Transplant 2013; 13:2577-89. [PMID: 23941128 DOI: 10.1111/ajt.12395] [Citation(s) in RCA: 174] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2012] [Revised: 04/21/2013] [Accepted: 05/11/2013] [Indexed: 01/25/2023]
Abstract
Reports have associated non-HLA antibodies, specifically those against angiotensin II type-1 receptor (AT1R), with antibody-mediated kidney graft rejection. However, association of anti-AT1R with graft failure had not been demonstrated. We tested anti-AT1R and donor-specific HLA antibodies (DSA) in pre- and posttransplant sera from 351 consecutive kidney recipients: 134 with biopsy-proven rejection and/or lesions (abnormal biopsy group [ABG]) and 217 control group (CG) patients. The ABG's rate of anti-AT1R was significantly higher than the CG's (18% vs. 6%, p < 0.001). Moreover, 79% of ABG patients with anti-AT1R lost their grafts (vs. 0%, CG), anti-AT1R levels in 58% of those failed grafts increasing posttransplant. With anti-AT1R detectable before DSA, time to graft failure was 31 months-but 63 months with DSA detectable before anti-AT1R. Patients with both anti-AT1R and DSA had lower graft survival than those with DSA alone (log-rank p = 0.007). Multivariate analysis showed that de novo anti-AT1R was an independent predictor of graft failure in the ABG, alone (HR: 6.6), and in the entire population (HR: 5.4). In conclusion, this study found significant association of anti-AT1R with graft failure. Further study is needed to establish causality between anti-AT1R and graft failure and, thus, the importance of routine anti-AT1R monitoring and therapeutic targeting.
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Affiliation(s)
- M Taniguchi
- Terasaki Foundation Laboratory, Los Angeles, CA
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Filippone EJ, Farber JL. The specificity of acute and chronic microvascular alterations in renal allografts. Clin Transplant 2013; 27:790-8. [PMID: 24118527 PMCID: PMC4232865 DOI: 10.1111/ctr.12258] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2013] [Indexed: 01/10/2023]
Abstract
The diagnosis of an antibody-mediated rejection (AMR) is made when there is evident histologic injury in the presence of detectable donor-specific alloantibodies (DSA) and diffuse peritubular capillary C4d staining (C4d-pos). In the presence of only detectable DSA or C4d-pos, the tissue injury is currently considered "presumptive" for antibody causation. In acute antibody-mediated rejection (AAMR), diagnostic morphologic features include microvascular inflammation (MVI), specifically glomerulitis and peritubular capillaritis. In the case of chronic active AMR (CAAMR), these inflammatory lesions have progressed to chronic microvascular injury, transplant glomerulopathy (TG) and peritubular capillary basement membrane multilayering (PTCBMML). Either TG or PTCBMML is sufficient morphological evidence for a diagnosis of CAAMR. Unfortunately, these lesions are not specific. MVI, TG, and PTCBMML are found in the setting of cell-mediated immunity, as well as in association with non-alloimmune mechanisms. The available treatments for AMR and CMR are different, and it is important to ascertain the dominant mechanism when approaching an individual patient. At present, no gold standard exists to establish the specific pathogenesis in the more ambiguous cases. We detail here the differential diagnosis of MVI, TG, and PTCBMML.
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Affiliation(s)
- Edward J Filippone
- Division of Nephrology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA
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Amirzargar MA, Amirzargar A, Basiri A, Hajilooi M, Roshanaei G, Rajabi G, Mohammadiazar S, Solgi G. Early post-transplant immune monitoring can predict long-term kidney graft survival: soluble CD30 levels, anti-HLA antibodies and IgA-anti-Fab autoantibodies. Hum Immunol 2013; 75:47-58. [PMID: 24055694 DOI: 10.1016/j.humimm.2013.09.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2013] [Revised: 08/25/2013] [Accepted: 09/11/2013] [Indexed: 12/01/2022]
Abstract
This study aimed to investigate the predictive power of anti-HLA antibodies, sCD30 levels and IgA-anti-Fab autoantibody before and early after transplantation in relation to long-term kidney allograft survival. Pre- and post-transplant sera samples of 59 living-unrelated donor kidney recipients were tested for above risk factors by enzyme-linked immunoabsorbent assay. 15 out of 59 cases experienced rejection episodes (failure group). Pre- and post-transplant high sCD30 levels were significantly associated with graft failure (P=0.02 and P=0.004) and decreased 4 year graft survival (P = 0.009 and P = 0.001). Higher frequency of post-transplant HLA class-II antibody in the absence of class-I antibody was observed in failure group (P=0.007). Patients with post-transplant HLA class-I and class-II antibodies either alone or in combination showed significant lower 4 year graft survival. Recipients with high sCD30 levels in the presence of HLA class-I or class-II antibodies within 2 weeks post-transplant had poor graft survival (P = 0.004 and P = 0.002, respectively). High levels of post-transplant IgA-anti-Fab antibody was more frequent in functioning-graft patients (P = 0.00001), correlated with decreased serum creatinine levels (P = 0.01) and associated with improved graft survival (P = 0.008). Our findings indicate the deleterious effect of early post-transplant HLA antibodies and increased sCD30 levels dependently and protective effect of IgA-anti-Fab antibodies on long-term renal graft outcomes.
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Affiliation(s)
- Mohammad Ali Amirzargar
- Department of Urology, Medical School, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Aliakbar Amirzargar
- Molecular Immunology Research Center, Medical School, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Basiri
- Urology Research Center, Labbafinejad Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehrdad Hajilooi
- Immunology Department, Medical School, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ghodratollah Roshanaei
- Research Center for Health Science, Department of Biostatistics and Epidemiology, School of Health, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Gholamreza Rajabi
- Department of Urology, Medical School, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Sina Mohammadiazar
- Department of Urology, Medical School, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ghasem Solgi
- Immunology Department, Medical School, Hamadan University of Medical Sciences, Hamadan, Iran.
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Naber U, Feingold B. The interplay of donor-specific antibodies, allograft C4d deposition, and antibody-mediated rejection. Pediatr Transplant 2013; 17:409-11. [PMID: 23672434 DOI: 10.1111/petr.12097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Urs Naber
- Pediatric Cardiology; Children's Hospital of Pittsburgh of UPMC; Pittsburgh; PA; USA
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The role of immunoglobulin-G subclasses and C1q in de novo HLA-DQ donor-specific antibody kidney transplantation outcomes. Transplantation 2013; 95:1113-9. [PMID: 23514959 DOI: 10.1097/tp.0b013e3182888db6] [Citation(s) in RCA: 149] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Anti-HLA-DQ antibodies are the predominant HLA class II donor-specific antibodies (DSAs) after transplantation. Recently, de novo DQ DSA has been associated with worse allograft outcomes. The aim of this study was to determine the further complement-binding characteristics of the most harmful DQ DSA. METHODS Single-antigen bead technology was used to screen 284 primary kidney transplant recipients for the presence of posttransplantation DQ DSA. Peak DSA sera of 34 recipients with only de novo DQ DSA and of 20 recipients with de novo DQ plus other DSAs were further analyzed by a modified single-antigen bead assay using immunoglobulin (Ig)-G subclass-specific reporter antibodies and a C1q-binding assay. RESULTS Compared with recipients who did not have DSA, those with de novo persistent DQ-only DSA and with de novo DQ plus other DSAs had more acute rejection (AR) episodes (22%, P=0.005; and 36%, P=0.0009), increased risk of allograft loss (hazards ratio, 3.7, P=0.03; and hazards ratio, 11.4, P=0.001), and a lower 5-year allograft survival. De novo DQ-only recipients with AR had more IgG1/IgG3 combination and C1q-binding antibodies (51%, P=0.01; and 63%, P=0.001) than patients with no AR. Furthermore, the presence of C1q-binding de novo DQ DSA was associated with a 30% lower 5-year allograft survival (P=0.003). CONCLUSIONS The presence of de novo persistent, complement-binding DQ DSA negatively impacts kidney allograft outcomes. Therefore, early posttransplantation detection, monitoring, and removal of complement-binding DQ might be crucial for improving long-term kidney transplantation outcomes.
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Koch M, Gräser C, Lehnhardt A, Pollok JM, Kröger N, Verboom M, Thaiss F, Eiermann T, Nashan B. Four-year allograft survival in a highly sensitized combined liver-kidney transplant patient despite unsuccessful anti-HLA antibody reduction with rituximab, splenectomy, and bortezomib. Transpl Int 2013; 26:e64-8. [PMID: 23672514 DOI: 10.1111/tri.12120] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2012] [Revised: 10/10/2012] [Accepted: 04/20/2013] [Indexed: 01/14/2023]
Abstract
Although donor-specific lymphocytotoxic antibodies are regarded as a contraindication for kidney transplantation (KTx), the data available for liver or combined liver or kidney transplantation (cLKTx) are scarce. Here, we report a case of a highly sensitized young man receiving his sixth liver and second kidney graft. Multiple anti-HLA antibodies were present at the time of transplantation. As a result of suspected antibody-mediated graft damage, the patient was treated with rituximab, plasmapheresis, intravenous immunoglobulins, splenectomy, and bortezomib to decrease the antibody production. So far, patient and allograft survival has reached 4 years despite failure to achieve a permanent reduction of anti-HLA antibodies, and particularly nondonor directed antibodies.
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Affiliation(s)
- Martina Koch
- Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, UKE, Hamburg, Germany.
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Lachmann N, Todorova K, Schulze H, Schönemann C. Luminex(®) and its applications for solid organ transplantation, hematopoietic stem cell transplantation, and transfusion. ACTA ACUST UNITED AC 2013; 40:182-9. [PMID: 23922543 DOI: 10.1159/000351459] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Accepted: 03/19/2013] [Indexed: 01/29/2023]
Abstract
SUMMARY The detection of antibodies against the human leukocyte antigen (HLA) complex has become indispensable in every clinical practice. The development of solid-phase assays like the Luminex allows the standardized measurement of anti-HLA antibodies (HLAab) with high sensitivity, albeit the relevance for some clinical settings remains a matter of debate. In this review we aim to describe the principle of Luminex-based antibody detection, including two modifications that allow identifying solely complement-activating antibodies. We then describe three applications for Luminex: i) detection of HLAab preceding solid-organ transplantation and monitoring of donor-specific antibodies posttransplant as a risk factor for antibody-mediated rejection; ii) presence of HLAab in recipients as a risk for graft failure in hematopoietic stem cell transplantation, especially in haploidentical or mismatched transplantations; iii) role of HLAab in blood transfusion including refractory thrombocytopenia and selection of suitable platelet donors, transfusion-related lung injury after plasma transfusion, and immunization against HLA after red blood cell transfusion despite leukodepletion. Although the Luminex platform constitutes a potent technology for HLA antibody detection, some drawbacks require the well-educated analysis and interpretation of data in critical cases. In addition, Luminex has become an important tool to identify clinically relevant antibodies.
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Affiliation(s)
- Nils Lachmann
- Center for Tumor Medicine, Charité-Universitätsmedizin Berlin - Campus Virchow-Klinikum, Berlin, Germany ; ZTB Zentrum für Transfusionsmedizin und Zelltherapie Berlin, HLA Tissue Typing Laboratory, Berlin, Germany
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Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation 2013; 95:19-47. [PMID: 23238534 DOI: 10.1097/tp.0b013e31827a19cc] [Citation(s) in RCA: 614] [Impact Index Per Article: 51.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The introduction of solid-phase immunoassay (SPI) technology for the detection and characterization of human leukocyte antigen (HLA) antibodies in transplantation while providing greater sensitivity than was obtainable by complement-dependent lymphocytotoxicity (CDC) assays has resulted in a new paradigm with respect to the interpretation of donor-specific antibodies (DSA). Although the SPI assay performed on the Luminex instrument (hereafter referred to as the Luminex assay), in particular, has permitted the detection of antibodies not detectable by CDC, the clinical significance of these antibodies is incompletely understood. Nevertheless, the detection of these antibodies has led to changes in the clinical management of sensitized patients. In addition, SPI testing raises technical issues that require resolution and careful consideration when interpreting antibody results. METHODS With this background, The Transplantation Society convened a group of laboratory and clinical experts in the field of transplantation to prepare a consensus report and make recommendations on the use of this new technology based on both published evidence and expert opinion. Three working groups were formed to address (a) the technical issues with respect to the use of this technology, (b) the interpretation of pretransplantation antibody testing in the context of various clinical settings and organ transplant types (kidney, heart, lung, liver, pancreas, intestinal, and islet cells), and (c) the application of antibody testing in the posttransplantation setting. The three groups were established in November 2011 and convened for a "Consensus Conference on Antibodies in Transplantation" in Rome, Italy, in May 2012. The deliberations of the three groups meeting independently and then together are the bases for this report. RESULTS A comprehensive list of recommendations was prepared by each group. A summary of the key recommendations follows. Technical Group: (a) SPI must be used for the detection of pretransplantation HLA antibodies in solid organ transplant recipients and, in particular, the use of the single-antigen bead assay to detect antibodies to HLA loci, such as Cw, DQA, DPA, and DPB, which are not readily detected by other methods. (b) The use of SPI for antibody detection should be supplemented with cell-based assays to examine the correlations between the two types of assays and to establish the likelihood of a positive crossmatch (XM). (c) There must be an awareness of the technical factors that can influence the results and their clinical interpretation when using the Luminex bead technology, such as variation in antigen density and the presence of denatured antigen on the beads. Pretransplantation Group: (a) Risk categories should be established based on the antibody and the XM results obtained. (b) DSA detected by CDC and a positive XM should be avoided due to their strong association with antibody-mediated rejection and graft loss. (c) A renal transplantation can be performed in the absence of a prospective XM if single-antigen bead screening for antibodies to all class I and II HLA loci is negative. This decision, however, needs to be taken in agreement with local clinical programs and the relevant regulatory bodies. (d) The presence of DSA HLA antibodies should be avoided in heart and lung transplantation and considered a risk factor for liver, intestinal, and islet cell transplantation. Posttransplantation Group: (a) High-risk patients (i.e., desensitized or DSA positive/XM negative) should be monitored by measurement of DSA and protocol biopsies in the first 3 months after transplantation. (b) Intermediate-risk patients (history of DSA but currently negative) should be monitored for DSA within the first month. If DSA is present, a biopsy should be performed. (c) Low-risk patients (nonsensitized first transplantation) should be screened for DSA at least once 3 to 12 months after transplantation. If DSA is detected, a biopsy should be performed. In all three categories, the recommendations for subsequent treatment are based on the biopsy results. CONCLUSIONS A comprehensive list of recommendations is provided covering the technical and pretransplantation and posttransplantation monitoring of HLA antibodies in solid organ transplantation. The recommendations are intended to provide state-of-the-art guidance in the use and clinical application of recently developed methods for HLA antibody detection when used in conjunction with traditional methods.
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Congy-Jolivet N, Drocourt D, Portet S, Tiraby G, Blancher A. Production and characterization of chimeric anti-HLA monoclonal antibodies targeting public epitopes as tools for standardizations of the anti-HLA antibody detection. J Immunol Methods 2013; 390:41-51. [DOI: 10.1016/j.jim.2013.01.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Revised: 01/14/2013] [Accepted: 01/16/2013] [Indexed: 10/27/2022]
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Abstract
PURPOSE OF REVIEW Classical complement activation is a key step in the process of antibody-mediated rejection. Emphasizing novel diagnostic strategies, this study will discuss recent studies highlighting the particular relevance of alloantibodies with complement-fixing ability. RECENT FINDINGS Reinforcing the pivotal role of complement, numerous studies have shown tight associations of capillary C4d deposition, a 'footprint' of alloantibody-triggered complement activation, with the occurrence of allograft injury. Distribution patterns of immunoglobulin isotypes or subclasses, which strongly differ in their ability to activate complement, may not adequately reflect the actual pathogenetic relevance of detected allosensitization. This fact may be explained by the finding that other variables, such as antibody-binding density or a synergism of antibodies against different epitopes of the same antigen, may contribute to complement activation. An attractive approach to distinguish between complement-fixing and presumably less harmful noncomplement-fixing alloreactivities could be the detection of C4d deposition in vitro. Applying such techniques, recent studies have shown that human leukocyte antigen reactivity with C4d-fixing ability, in contrast to noncomplement-fixing sensitization, may strongly predict antibody-mediated rejection and inferior graft survival. SUMMARY Considering the pivotal role of complement, technologies that uncover the complement-fixing ability of alloantibodies may be of particular interest for the selective detection of deleterious sensitization.
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Picascia A, Infante T, Napoli C. Luminex and antibody detection in kidney transplantation. Clin Exp Nephrol 2012; 16:373-81. [PMID: 22552384 DOI: 10.1007/s10157-012-0635-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Accepted: 04/06/2012] [Indexed: 10/28/2022]
Abstract
Preformed anti-human leukocyte antigen (HLA) antibodies have a negative effect on kidney transplantation outcome with an increased rejection rate and reduction in survival. Posttransplantation production of donor-specific anti-HLA antibodies is indicative of an active immune response and risk of transplantation rejection. For many years the primary technique for anti-HLA antibody detection was complement-dependent cytotoxicity (CDC), which has been integrated by solid-phase assays as HLA antigen-coated bead methods (Luminex). This new technological approach has allowed identification of anti-HLA antibodies, not detectable using conventional CDC method, in patients awaiting kidney transplantation. Moreover, use of Luminex technology has enabled better definition of acceptable or unacceptable antigens favoring transplantation in highly immunized patients. However, there are still many unresolved issues, including the clinical relevance of antibodies detected with this system.
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Affiliation(s)
- Antonietta Picascia
- U.O.C. Immunohematology, Transfusion Medicine and Transplant Immunology, Regional Reference Laboratory of Transplant Immunology, Azienda Universitaria Policlinico, Second University of Naples, Naples, Italy.
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Bosch A, Llorente S, Diaz JA, Salgado G, López M, Boix F, López-Hernández R, González-Soriano MJ, Campillo JA, Moya-Quiles MR, Perez-Lopez N, Minguela A, Jimeno L, Álvarez-López MR, Muro M. Low median fluorescence intensity could be a nonsafety concept of immunologic risk evaluation in patients with shared molecular eplets in kidney transplantation. Hum Immunol 2012; 73:522-5. [DOI: 10.1016/j.humimm.2012.02.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Revised: 02/24/2012] [Accepted: 02/27/2012] [Indexed: 10/28/2022]
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Role of morphologic parameters on endomyocardial biopsy to detect sub-clinical antibody-mediated rejection in heart transplantation. J Heart Lung Transplant 2011; 30:1381-8. [DOI: 10.1016/j.healun.2011.07.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2011] [Revised: 06/22/2011] [Accepted: 07/17/2011] [Indexed: 11/24/2022] Open
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Carrick DM, Norris PJ, Endres RO, Pandey S, Kleinman SH, Wright D, Sun Y, Busch MP. Establishing assay cutoffs for HLA antibody screening of apheresis donors. Transfusion 2011; 51:2092-101. [PMID: 21332726 PMCID: PMC3108003 DOI: 10.1111/j.1537-2995.2010.03048.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Collaborators] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
BACKGROUND Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related deaths. Donor HLA antibodies have been implicated in TRALI cases. Blood centers are implementing TRALI risk reduction strategies based on HLA antibody screening of some subpopulations of ever-pregnant apheresis platelet (PLT) donors. However, if screening assay cutoffs are too sensitive, donation loss may adversely impact blood availability. STUDY DESIGN AND METHODS Pregnancy history and HLA antibody screening and single-antigen bead data from blood donors in the Retrovirus Epidemiology Donor Study-II Leukocyte Antibody Prevalence Study were evaluated for correlations between assay screening values, HLA antibody titer, and number of HLA antigen specificities. The probabilities of matching a cognate antigen in a recipient were calculated and examined in association with total number of specificities observed and screening values. The relative impact of imposing various screening assay cutoffs or pregnancy stratification was examined in relation to detection of HLA antibody-reactive donations and loss of donors and donations. RESULTS We provide evidence that higher HLA antibody screening assay values are associated with maintaining higher screening signals upon dilution and an increased breadth of specificities compared with lower screening values; the latter correlated with an increased risk of a cognate antigen match in potential recipients. Depending on the TRALI risk reduction strategy used, the potential loss of donations ranged between 0.9 and 6.0%. CONCLUSION This analysis should enable blood centers to decide upon a TRALI risk reduction strategy for apheresis PLTs that is consistent with how much donation loss the blood center can tolerate.
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Affiliation(s)
| | - Philip J. Norris
- Blood Systems Research Institute, San Francisco, CA, USA
- University of California, San Francisco. Depts of Laboratory Medicine and Medicine, San Francisco, CA, USA
| | | | | | - Steven H. Kleinman
- Westat, Inc., Rockville, MD, USA
- University of British Columbia, Dept of Pathology, Vancouver BC, Canada
| | | | - Yu Sun
- Westat, Inc., Rockville, MD, USA
| | - Michael P. Busch
- Blood Systems Research Institute, San Francisco, CA, USA
- University of California, San Francisco. Dept of Laboratory Medicine, CA, USA
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Collaborators
R Cable, J Rios, R Benjamin, J D Roback, R A Sacher, S L Wilkinson, P M Carey, E L Murphy, B Custer, N Hirschler, D Triulzi, R Kakaiya, J Kiss, J Gottschall, A Mast, J Schulman, M King, G J Nemo, M P Busch, P Norris,
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