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Adriana Zeevi - One of the best experts on this subject based on the ideXlab platform.
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p001 changes in anti HLA Antibody complement binding capacity reflect the efficacy of Antibody mediated rejection therapy and predict kidney allograft survival
Human Immunology, 2017Co-Authors: Carmen Lefaucheur, Alexandre Loupy, Denis Viglietti, Olivier Aubert, Massimo Mangiola, Adriana ZeeviAbstract:Aim We investigated wether the kinetics of donor-specific anti-HLA Antibody (DSA) characteristics might predict kidney allograft survival in patients with Antibody-mediated rejection (AMR) receiving standard-of-care therapy. Methods We prospectively enrolled 2666 kidney recipients transplanted between 2004 and 2012 and we included in this study all patients diagnosed with active AMR who received standardized therapy including plasma exchanges (×4–5) and intravenous immune globulins (2 g/kg × 3). Patients were systematically assessed at diagnosis and 3 months post-therapy for circulating anti-HLA DSA (specificity, mean fluorescence intensity, C1q-binding capacity) using Luminex SAB, clinical data (eGFR and proteinuria) and histology (allograft biopsy). Results 278 patients with biopsy-proven acute or chronic active AMR received standard-of-care therapy. At rejection, 76 (27%) patients had class I DSA, 127 (46%) class II DSA and 75 (27%) class I and II DSA. Dominant DSA was C1q binding in 85 (31%) patients. The MFImax decreased from 5223 ± 318 to 3611 ± 280 after AMR therapy ( P P = 0.001). Patients showing a reduction of DSA MFImax after therapy ( N = 207) had a better 5-year graft survival than those who had stable or increasing MFImax (N = 71): 80% vs. 62%; P N = 177) and those with pre-therapy positive/post-therapy negative C1q-DSA ( N = 51) showed a better 5-year graft survival (82% and 94%, respectively) than those with C1q-DSA before and after therapy ( N = 34) and those with pre-therapy negative/post-therapy positive C1q-DSA ( N = 16) (36% and 38%, respectively; P Conclusions The kinetics of circulating anti-HLA DSA C1q-binding capacity in kidney recipients with AMR more accurately identify responders to standard-of-care therapy than DSA MFI level, independently of clinical and histological parameters.
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edta treatment of serum unmasks complement mediated prozone inhibition in human leukocyte antigen Antibody testing
American Journal of Clinical Pathology, 2016Co-Authors: Waseem Anani, Adriana Zeevi, John G LunzAbstract:Objectives: Luminex-based single-antigen bead human leukocyte antigen (HLA) Antibody testing is widely used to define HLA antibodies for transplant compatibility. False-negative results can occur with complement-mediated prozone inhibition. This study assessed the effect of EDTA on the assay background reactivity and fluctuations in Antibody mean fluorescent intensity. Methods: Serum specimens were retrospectively tested using Luminex-based single-antigen beads with and without EDTA. Treated and untreated serum samples were compared by two measures: changes in background reactivity and changes in HLA Antibody strength after EDTA treatment. Results: Ten pretransplant and 48 posttransplant specimens were identified: lung (22), heart (10), kidney (21), heart/lung (two), pancreas (one), small bowel (one), and liver (one). After EDTA treatment, weak antibodies (below 2,000 mean florescent intensity) demonstrated the largest fluctuations. Newly identified HLA antibodies were seen in 16% (8/49) of class I and 26% (15/57) of class II beads. EDTA treatment did not result in false-negative reactions compared with untreated serum. Conclusions: EDTA serum pretreatment mitigated complement-mediated prozone inhibition and improved accurate HLA Antibody detection. The background reactivity and the false-negative rate of the assay appear unchanged.
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human leukocyte antigen epitope analysis to assess complement and non complement binding donor specific Antibody repertoire in a pediatric heart transplant recipient
Human Immunology, 2012Co-Authors: Adriana Zeevi, Marilyn Marrari, Brian Feingold, Steven A Webber, Rene J. DuquesnoyAbstract:Abstract This case report summarizes the spectrum of anti–human leukocyte antigen (HLA) Antibody reactivity determined by single-allele Luminex immunoglobulin G and C1q binding assays before transplant, during an episode of Antibody-mediated rejection (AMR), and following treatment in a sensitized pediatric heart transplant (Tx) recipient. We were able to discriminate between complement- and non-complement-binding epitope-specific antibodies present against a single donor antigen (HLA-A2) during the progression of AMR and its resolution. Our findings illustrate the usefulness of determining Antibody specificities against epitopes using various Luminex-based assays.
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HLA Antibody analysis sensitivity specificity and clinical significance in solid organ transplantation
Immunologic Research, 2006Co-Authors: Adriana Zeevi, Alin Girnita, Rene DuquesnoyAbstract:The clinical relevance of humoral allosensitization has gained a lot of attention in the last few years. An increasing number of studies have demonstrated adverse graft survival in patients who have either preformed or post-transplant-developed anti-HLA antibodies. The detection of HLA antibodies and the specificity analysis have evolved over time from primarily cell-based to solid-phase methods, including the availability of single-HLA antigen preparations. These technological advances combined with a better understanding of the epitope structure of HLA antigens have provided a more efficient, structurally based strategy to determine HLA compatibility. In conclusion, these emerging approaches can be reliably used to predict crossmatch results in highly sensitized patients and also to monitor the development of clinically relevant anti-HLA Antibody after transplantation.
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anti HLA Antibody analysis and crossmatching in heart and lung transplantation
Transplant Immunology, 2004Co-Authors: Nancy L Reinsmoen, Karen Nelson, Adriana ZeeviAbstract:Although the clinical significance of anti-HLA antibodies in heart and lung transplantation is less well studied than in renal transplantation, several studies have shown that heart and lung recipients transplanted in the presence of donor-specific antibodies are at increased risk for early acute rejection and have a lower graft survival. In an effort to avoid any increase in organ ischemia time, heart and lung candidates with anti-HLA antibodies have to be identified prior to transplantation and crossmatches performed with donor materials obtained prior to organ recovery. Both class I and II antibodies have been found to be associated with chronic rejection, defined in heart transplantation as transplant-related coronary artery disease (TRCAV) and in lung transplantation as obliterative bronchiolitis (OB) or bronchiolitis obliterative syndrome (BOS). Post-transplant de novo development of donor antigen-specific class II antibodies has been found to be especially deleterious, significantly increasing the risk of chronic rejection and poor graft outcome. Based on the review of studies regarding the development of anti-HLA antibodies and thoracic organ allograft rejection several conclusions can be drawn. The presence of class I and II-directed anti-HLA antibodies, detected by any method, are associated with acute and chronic rejection in heart and lung transplantation. Different therapeutic strategies have been used pre-transplantation to decrease the level of anti-HLA antibodies and post-transplantation to maintain low Antibody levels or treat rejection, thereby improving graft outcome. Thus, monitoring the presence and the level of anti-HLA antibodies is prognostic of graft outcome and allows for measurement of therapeutic efficacy.
Paul I Terasaki - One of the best experts on this subject based on the ideXlab platform.
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beyond histology lowering human leukocyte antigen Antibody to improve renal allograft survival in acute rejection
Transplantation, 2010Co-Authors: Matthew J Everly, Lorita M Rebellato, Miyuki Ozawa, Kimberly P Briley, Paul G Catrou, Carl E Haisch, Paul I TerasakiAbstract:Background. The common endpoint in the treatment of Antibody-mediated rejection (AMR) is functional reversal (creatinine levels). Reduction of human leukocyte antigen (HLA) Antibody strength is not commonly considered as an essential endpoint for AMR resolution. The purpose of this study was to determine whether reduction in HLA Antibody intensity in patients with histologic AMR reversal influences long-term renal allograft survival. Methods. Renal allograft recipients were included if he or she had a biopsy diagnosis of AMR (between August 2000 and October 2008) and serial evaluation for HLA antibodies prebiopsy and postbiopsy. Antibody reduction was defined as mean fluorescence intensity decrease more than 50% in highest intensity Antibody after AMR therapy and the absence of new Antibody formation. Patients were treated with plasmapheresis, thymoglobulin/OKT3, and corticosteroids. Survival analysis was performed using STATA/MP v10 (College Station, TX). Results. Twenty-eight patients were analyzed. Antibody reduction failed to occur in 22 of 28 cases. Baseline characteristics were similar between groups. Antibody nonresponders had significantly shorter allograft survival time (61.4 months) compared with Antibody responders (no failures) (P=0.04, log-rank test). Conclusions. In conclusion, failure to significantly reduce Antibody levels and prevent new formation was strongly predictive of allograft loss. This observation suggests that the therapeutic intervention that reduces Antibody production may prolong graft survival in transplantation.
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HLA Antibody identification with single antigen beads compared to conventional methods
Human Immunology, 2005Co-Authors: Nadim Elawar, Paul I TerasakiAbstract:Single antigen (SA) beads coated with Class I HLA antigens from recombinant cells lines were tested with 170 mouse monoclonal antibodies (mAbs). The HLA specificities of all mAbs were previously determined by the cytotoxicity assay (CDC). There were 100 mAbs which produced the expected reactions with the SA beads, indicating that the SA beads coated with the antigens had reacted properly. Sixty one mAbs were positive with one or more antigen(s) that shared unique amino acids (aa) possibly constituting a common epitope. Single antigen beads were then tested on 58 alloantisera analyzed by 63 laboratories of the UCLA serum exchange (UCLA-SE). Many specificities detected by the single antigen beads were missed by the laboratories employing conventional methods. Most of the missed specificities were of lower frequency, although in some instances, even common specificities were missed. These findings have important implications regarding the use of specificities to predict positive crossmatch, to selecting platelet donors for highly sensitized recipients, and analysis of sera for donor specific antibodies.
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single human leukocyte antigen flow cytometry beads for accurate identification of human leukocyte antigen Antibody specificities
Transplantation, 2003Co-Authors: Rui Pei, Jarhow Lee, Nengje Shih, Mike Che, Paul I TerasakiAbstract:Background. It is difficult to assign Antibody specificity for highly sensitized patients using a cell panel with multiple antigens per reaction. We describe here a single antigen bead panel for accurate identification of human leukocyte antigen (HLA) Antibody specificities by flow cytometry. Methods. A total of 110 single recombinant HLAs, including 34 A locus alleles, 57 B locus alleles, and 19 C locus alleles, were produced by a mammalian expression system. These single antigens were coated onto eight different colored microbeads, which were mixed together in one tube for simultaneous detection of HLA antibodies against eight different antigens per flow cytometry test. Results. Single HLA reacted specifically with the serologically defined monoclonal antibodies. The single antigen panel provided higher resolution than the regular cell panel for Antibody detection by uncovering the masked specificities. Single antigens also provided higher sensitivity than the multiple antigens coated onto beads for HLA Antibody detection as demonstrated by serum dilution studies. In 10 sera from patients who had rejected a kidney transplant, single antigen beads identified antibodies to 31 of 35 antigens that were mismatched in the donor. Most important, none of the reactions were against antigens present in the recipient. Conclusion. An accurate and sensitive HLA Antibody detection method is described using flow cytometry beads coated with single HLAs produced by recombinant technology. The single antigen beads should be useful in predicting negative crossmatch in highly sensitized organ recipients and highly sensitized patients requiring platelets.
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anti HLA antibodies after solid organ transplantation
Transplantation, 2000Co-Authors: Rachel M Mckenna, Steven K Takemoto, Paul I TerasakiAbstract:: We have cited more than 23 studies showing that de novo development of anti-HLA antibodies is associated with increased acute and chronic rejection and decreased graft survival in kidney, heart, lung, liver, and corneal transplants. Antibodies to both HLA class I and class II antigens seem to be detrimental. Antibodies of the IgG isotype and possibly the IgM isotype were clinically relevant. Most studies showed that donor-specific antibodies were associated with rejection and graft loss. Therefore, HLA antibodies provide a clinical readout for patient alloreactivity that may have the ability to distinguish graft dysfunction due to immunologic and nonimmunologic causes. Antibody may act as a critical trigger for rejection of allografts and may serve as an early indicator of a slowly smoldering chronic rejection that is not manifested at a given time by biochemical measures such as serum creatinine levels. The effectiveness of various drugs on chronic rejection should be evaluable by their effects on HLA Antibody production. We predict that recently developed ELISA and flow cytometry techniques using purified HLA antigen will increase the clinical relevance of posttransplantation HLA Antibody monitoring by (1) allowing the detection of low levels of donor Antibody; (2) easily distinguishing the isotype and target (HLA class I or class II) of the antibodies; and (3) correlating the Antibody with specific graft pathology.
Steven Kleinman - One of the best experts on this subject based on the ideXlab platform.
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The Leukocyte Antibody Prevalence Study-II (LAPS-II): a retrospective cohort study of transfusion-related acute lung injury in recipients of high-plasma-volume human leukocyte antigen Antibody–positive or –negative components
Transfusion, 2011Co-Authors: Steven Kleinman, Danielle M. Carrick, Darrell J. Triulzi, Edward L. Murphy, Patricia M. Carey, Jerome L. Gottschall, John D. Roback, Sunitha Mathew, David J. Wright, Ritchard G. CableAbstract:Donor-based risk reduction interventions for transfusion-related acute lung injury (TRALI) have been widely adopted in the United States and elsewhere in the past several years.1–5 These strategies are based on data indicating that TRALI has continued to be the leading cause of blood transfusion-related deaths in the United States,6 the consensus that approximately 80% of TRALI cases are mediated by donor human leukocyte antigen (HLA) antibodies,7 and surveillance system findings that TRALI cases are reduced by use of such risk reduction strategies.2,8,9 Thus, as of 2009, almost all US blood centers are transfusing plasma supplied primarily by male or never-pregnant female donors, and many centers are screening previously pregnant platelet (PLT) and/or plasma apheresis donors for HLA Antibody.1,9 Most transfused components containing HLA Antibody do not result in recipients developing TRALI. Reasons for this include transfusion to a recipient who does not have a cognate HLA antigen profile, as well as less established factors such as the titer and/or other undefined characteristics of the specific transfused HLA Antibody or the existence of underlying predisposing recipient risk factors (first hit). Most current theories of TRALI pathogenesis agree that two hits are usually necessary for TRALI to occur: the first is a recipient condition that results in neutrophil priming and the second is the infusion of a biologic response modifier that activates primed neutrophils. The biologic response modifier can be an HLA Antibody, an HNA Antibody, or several candidate nonAntibody substances, such as bioactive lipids.10–12 In terms of this model, HLA Antibody–containing components may fail to cause TRALI in the absence of a first hit. At least four studies have assessed outcomes in recipients of previously donated components from HLA Antibody–positive donors who were implicated as causing TRALI in an index recipient.13–16 In aggregate, these studies detected five new cases of TRALI that were not reported to the blood bank when records of 171 patients were reviewed (2.9%). In addition, two lookback studies were reported on donors who were HLA Antibody positive but had not been implicated in TRALI. In one of these studies, 62 HLA Antibody–positive female donors gave a total of 211 blood components, and only one case of TRALI (which had previously been reported to the blood bank) was identified.17 In the second study, no TRALI cases were detected in 167 recipients of transfusions from four HLA Antibody–positive donors or in 295 recipients from 12 HLA Antibody–negative donors. However, this conclusion appeared to be based solely on review of transfusion service records.18 One additional study did not detect TRALI in any of 265 recipients of either HLA Antibody–positive or HLA Antibody–negative plateletpheresis units but did not clearly delineate the number of recipients in each group.19 Taken as a group, these lookback studies have significant limitations in that they used differing methods for HLA Antibody screening, reviewing recipient outcome data and for diagnosing TRALI; they had small sample sizes considering the low incidence of TRALI; and most did not evaluate TRALI occurrence in recipients of control components using a blinded study design. Since it is well known that TRALI is both underrecognized and underre-ported,20 it is unclear if the findings in these studies can be generalized because methods for ascertainment were not robust. As part of the Retrovirus Epidemiology Donor Study-II (REDS-II), we previously conducted the Leukocyte Antibody Prevalence Study-I (LAPS-I), which identified 1032 whole blood and apheresis donors with HLA Antibody.21 Since LAPS-I was conducted before the implementation of TRALI risk reduction policies, donations from these HLA Antibody–positive donors were transfused to recipients. Given the limitations of previous studies noted above and the recognition that the recent implementation of TRALI risk reduction strategies will reduce the possibility of conducting future large-scale TRALI lookback studies, we designed a large multicenter retrospective cohort study termed the Leukocyte Antibody Prevalence Study-II (LAPS-II). Based on surveillance data showing a higher TRALI risk from transfused plasma components, LAPS-II was confined to high-plasma-volume components (fresh-frozen plasma and other transfusable plasma manufactured from whole blood or apheresis as well as plateletpheresis components).2,8,9 LAPS-II was designed to evaluate a primary endpoint of combined incidence of TRALI and possible TRALI in study recipients of at least one HLA Antibody–positive high-plasma-volume component versus control recipients of at least one HLA Antibody–negative high-plasma-volume component. Secondary endpoints were the association of HLA Antibody class, HLA Antibody specificity, HLA Antibody screening test signal strength, and concomitant HNA Antibody on TRALI occurrence.
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a national survey of transfusion related acute lung injury risk reduction policies for platelets and plasma in the united states
Transfusion, 2010Co-Authors: Steven Kleinman, Brenda J Grossman, Patricia M KopkoAbstract:BACKGROUND: Little information exists on the specific transfusion-related acute lung injury (TRALI) risk reduction practices used by multiple blood collecting institutions in the United States. STUDY DESIGN AND METHODS: An AABB-appointed TRALI working group designed a set of questions about TRALI risk reduction for platelets (PLTs) and plasma. AABB member institutions were asked to respond via an Internet-based survey during a 3-week period in August through September 2009. RESULTS: Valid responses were received from 47 US blood centers (accounting for 1.57 million apheresis PLT units and 3.15 million whole blood–derived transfusable plasma units) and 56 hospital blood collectors. Among the blood centers, 87 and 98% had initiated some PLT and plasma risk reduction, respectively. HLA Antibody testing of plateletpheresis donors was performed by 20 (43%) blood centers. There was substantial variation in the number of pregnancies (from one to more than four) that triggered testing and most centers did not screen based on a transfusion history. Almost all centers had policies to redirect HLA Antibody–positive donors to whole blood donation and to potentially retest HLA Antibody–negative donors. There were no blood centers performing HNA Antibody testing. Sex-based risk reduction policies for plasma included all male, or predominantly male, and never-pregnant females; these varied by blood center, blood group, and method of plasma collection. A majority of centers indicated increased production of plasma frozen within 24 hours after phlebotomy. CONCLUSIONS: Almost 3 years after the publication of the initial AABB bulletin on this issue, TRALI risk reduction strategies are commonly employed at most US blood centers. However, procedures are not uniform.
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the effect of previous pregnancy and transfusion on HLA alloimmunization in blood donors implications for a transfusion related acute lung injury risk reduction strategy
Transfusion, 2009Co-Authors: Darrell J. Triulzi, Steven Kleinman, Ram Kakaiya, Michael P Busch, Philip J Norris, Whitney R Steele, Simone A Glynn, Christopher D Hillyer, Patricia M Carey, Jerome L GottschallAbstract:BACKGROUND: Antibodies to human leukocyte antigens (HLA) in donated blood have been implicated as a cause of transfusion-related acute lung injury (TRALI). A potential measure to reduce the risk of TRALI includes screening plateletpheresis donors for HLA antibodies. The prevalence of HLA antibodies and their relationship to previous transfusion or pregnancy in blood donors was determined. STUDY DESIGN AND METHODS: A total of 8171 volunteer blood donors were prospectively recruited by six US blood centers from December 2006 to May 2007. Donors provided a detailed history of pregnancy and transfusion and a sample for HLA Class I and II Antibody testing by multiantigen bead flow analysis. RESULTS: A total of 8171 donors were enrolled; 7920 (96.9%) had valid HLA Antibody test results and 7841 (99%) of those had complete pregnancy and transfusion information. The prevalence of any HLA Antibody was similar in nontransfused (n = 1138) and transfused (n = 895) men, 1.0% versus 1.7% (p = 0.16). HLA antibodies were detected in 17.3% of all female donors (n = 5834) and in 24.4% of those with a history of previous pregnancy (n = 3992). The prevalence of HLA antibodies increased in women with greater numbers of pregnancy: 1.7% (zero), 11.2% (one), 22.5% (two), 27.5% (three), and 32.2% (four or more pregnancies; p < 0.0001). CONCLUSION: HLA Class I and Class II antibodies are detectable at low prevalence in male donors regardless of transfusion and in female donors without known immunizing events. The prevalence of HLA antibodies increases significantly with more pregnancies. These data will allow blood centers to estimate the impact of HLA Antibody testing as a potential TRALI risk reduction measure.
Rene J. Duquesnoy - One of the best experts on this subject based on the ideXlab platform.
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are we ready for epitope based HLA matching in clinical organ transplantation
Transplantation, 2017Co-Authors: Rene J. DuquesnoyAbstract:AbstractThis overview describes recent developments demonstrating the significance of epitopes in HLA Antibody responses and matching for organ transplantation. HLA epitopes are defined by molecular modeling and amino acid comparisons between HLA alleles and the HLAMatchmaker algorithm considers epl
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reflections on HLA epitope based matching for transplantation
Frontiers in Immunology, 2016Co-Authors: Rene J. DuquesnoyAbstract:HLA antibodies are primary causes of transplant rejection; they recognize epitopes which can be structurally defined by eplets. There are many reviews about HLA epitope-based matching in transplantation. This article describes some personal reflections about epitopes including a historical perspective of HLA typing at the antigen and allele levels, the repertoires of Antibody-verified HLA epitopes, the use of HLAMatchmaker in determining the specificities of antibodies tested in different assays and finally, possible strategies to control HLA Antibody responses.
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119 p HLA Antibody titration analysis the first step in quantitative signal pattern interpretation
Human Immunology, 2013Co-Authors: Rico Buchli, Arend Mulder, Rene J. Duquesnoy, Daniel Zehnder, Rebecca D Mcadams, Rodney S Vangundy, Curtis Mcmurtrey, Steven Cate, David Philip LoweAbstract:Aim Due to the increasing demand for more accurate and meaningful data in Antibody detection assays, which includes quantitative measures of Antibody titers, we evaluated a series of serological specimens to demonstrate the benefit of Antibody titration analysis. We show that by identifying the linear range of the assay, semi-quantitative observations are possible where titer comparisons can be easily made and saturation issues such as “prozon effects” are eliminated. Methods To determine linear range and half maximal effective concentrations (EC50), serological specimens from highly sensitized patients were diluted to eight different concentrations and their MFI signal determined using an in-house, 120-allele Luminex-based single specificity solid phase assay platform. Results Our results show that individual, single-allele titration curves can be generated to establish optimal performance range. We found that titration analysis has two major benefits: (1) eliminating serological interferences at high concentrations, and (2) semi-quantitative observations within the linear range. According to our test series, most sera will cause interferences and high background if tested undiluted. Accurate determinations can only be made by applying serial dilutions to reach highest signal-to-background ratios. Conclusions Since the physiological responses of the adaptive immune system against an HLA target are highly variable and Antibody composition is distinct to each individual, accurate determination of specificities, titer and strengths of antibodies has been extremely difficult. Titration analysis offers the possibility to evaluate several of such functional traits of antibodies to any given HLA molecule allowing better interpretation of individual Antibody populations in a quantitative matter. This project will likely lead to a better assessment of HLA titers and generate new insights for post-transplant monitoring and early recognition of immunologic rejection.
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human leukocyte antigen epitope analysis to assess complement and non complement binding donor specific Antibody repertoire in a pediatric heart transplant recipient
Human Immunology, 2012Co-Authors: Adriana Zeevi, Marilyn Marrari, Brian Feingold, Steven A Webber, Rene J. DuquesnoyAbstract:Abstract This case report summarizes the spectrum of anti–human leukocyte antigen (HLA) Antibody reactivity determined by single-allele Luminex immunoglobulin G and C1q binding assays before transplant, during an episode of Antibody-mediated rejection (AMR), and following treatment in a sensitized pediatric heart transplant (Tx) recipient. We were able to discriminate between complement- and non-complement-binding epitope-specific antibodies present against a single donor antigen (HLA-A2) during the progression of AMR and its resolution. Our findings illustrate the usefulness of determining Antibody specificities against epitopes using various Luminex-based assays.
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HLAmatchmaker based definition of structural human leukocyte antigen epitopes detected by alloantibodies
Current Opinion in Organ Transplantation, 2009Co-Authors: Rene J. Duquesnoy, Marilyn MarrariAbstract:Purpose of review This review addresses the concept that human leukocyte antigen (HLA) Antibody specificity should be determined to HLA epitopes rather than HLA antigens. Recent findings HLAMatchmaker is a computer algorithm that considers small configurations of polymorphic residues referred to as eplets as essential components of HLA epitopes. This overview describes recent developments that have increased our understanding of structural epitope antigenicity, that is, reactivity with specific Antibody and immunogenicity, that is, its ability to induce an Antibody response. Summary A determination of the repertoire of immunogenic epitopes is important for HLA compatibility testing and the identification of acceptable mismatches for sensitized patients.
Denis Glotz - One of the best experts on this subject based on the ideXlab platform.
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value of donor specific anti HLA Antibody monitoring and characterization for risk stratification of kidney allograft loss
Journal of The American Society of Nephrology, 2017Co-Authors: Denis Viglietti, Christophe Legendre, Alexandre Loupy, Dewi Vernerey, Olivier Aubert, Xavier Jouven, Carol Bentlejewski, Clement Gosset, Jeanpaul Duong Van Huyen, Denis GlotzAbstract:The diagnosis system for allograft loss lacks accurate individual risk stratification on the basis of donor–specific anti–HLA Antibody (anti-HLA DSA) characterization. We investigated whether systematic monitoring of DSA with extensive characterization increases performance in predicting kidney allograft loss. This prospective study included 851 kidney recipients transplanted between 2008 and 2010 who were systematically screened for DSA at transplant, 1 and 2 years post-transplant, and the time of post–transplant clinical events. We assessed DSA characteristics and performed systematic allograft biopsies at the time of post–transplant serum evaluation. At transplant, 110 (12.9%) patients had DSAs; post-transplant screening identified 186 (21.9%) DSA-positive patients. Post–transplant DSA monitoring improved the prediction of allograft loss when added to a model that included traditional determinants of allograft loss (increase in c statistic from 0.67; 95% confidence interval [95% CI], 0.62 to 0.73 to 0.72; 95% CI, 0.67 to 0.77). Addition of DSA IgG3 positivity or C1q binding capacity increased discrimination performance of the traditional model at transplant and post-transplant. Compared with DSA mean fluorescence intensity, DSA IgG3 positivity and C1q binding capacity adequately reclassified patients at lower or higher risk for allograft loss at transplant (category–free net reclassification index, 1.30; 95% CI, 0.94 to 1.67; P P P P
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igg donor specific anti human HLA Antibody subclasses and kidney allograft Antibody mediated injury
Journal of The American Society of Nephrology, 2016Co-Authors: Carmen Lefaucheur, Christophe Legendre, Dewi Vernerey, Jeanpaul Duong Van Huyen, Denis Viglietti, Jerome Verine, Olivier Aubert, Xavier Jouven, Carol Bentlejewski, Denis GlotzAbstract:Antibodies may have different pathogenicities according to IgG subclass. We investigated the association between IgG subclasses of circulating anti-human HLA antibodies and Antibody-mediated kidney allograft injury. Among 635 consecutive kidney transplantations performed between 2008 and 2010, we enrolled 125 patients with donor-specific anti-human HLA antibodies (DSA) detected in the first year post-transplant. We assessed DSA characteristics, including specificity, HLA class specificity, mean fluorescence intensity (MFI), C1q-binding, and IgG subclass, and graft injury phenotype at the time of sera evaluation. Overall, 51 (40.8%) patients had acute Antibody-mediated rejection (aABMR), 36 (28.8%) patients had subclinical ABMR (sABMR), and 38 (30.4%) patients were ABMR-free. The MFI of the immunodominant DSA (iDSA, the DSA with the highest MFI level) was 6724±464, and 41.6% of patients had iDSA showing C1q positivity. The distribution of iDSA IgG1-4 subclasses among the population was 75.2%, 44.0%, 28.0%, and 26.4%, respectively. An unsupervised principal component analysis integrating iDSA IgG subclasses revealed aABMR was mainly driven by IgG3 iDSA, whereas sABMR was driven by IgG4 iDSA. IgG3 iDSA was associated with a shorter time to rejection (P<0.001), increased microcirculation injury (P=0.002), and C4d capillary deposition (P<0.001). IgG4 iDSA was associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions (P<0.001 for all comparisons). Integrating iDSA HLA class specificity, MFI level, C1q-binding status, and IgG subclasses in a Cox survival model revealed IgG3 iDSA and C1q-binding iDSA were strongly and independently associated with allograft failure. These results suggest IgG iDSA subclasses identify distinct phenotypes of kidney allograft Antibody-mediated injury.