HLA-DQ mismatches stimulate de novo donor specific antibodies in heart transplant recipients

Zhang, Xiaohai; Kransdorf, E.; Levine, R.; Patel, Jignesh; Kobashigawa, J.A.

doi:10.1016/j.humimm.2020.04.003

Cited by 24 publications

(27 citation statements)

References 28 publications

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“…In the current study, it was shown that twenty‐four percent of recipients developed dnDSAs, and most of them (36 or 68% of antibody producers) were against mismatched HLA‐DQB1 determinants. This observation is consistent with the findings of other researchers who showed a high frequency of dnDSA development against DQB1 antigens in kidney, liver, and lung transplant recipients 21,25,26,29,42–45 . The high frequency of anti‐HLA‐DQ antibodies is explained by the polymorphism of genes encoding both α and β chains, which leads to the formation of epitopes/eplets of three types: those localized solely on α or β chains and epitopes involving both chains, the so‐called combined α/β epitopes.…”

Section: Discussionsupporting

confidence: 92%

“…This observation is consistent with the findings of other researchers who showed a high frequency of dnDSA development against DQB1 antigens in kidney, liver, and lung transplant recipients. 21,25,26,29,[42][43][44][45] The high frequency of anti-HLA-DQ antibodies is explained by the polymorphism of genes encoding both α and β chains, which leads to the formation of epitopes/eplets of three types: those localized solely on α or β chains and epitopes involving both chains, the so-called combined α/β epitopes. The analysis of the number of MM HLAs at A, B, DR, and DQ loci with HLAMatchmaker and PIRCHE-II technologies showed that even incompatibility for one HLA is associated with a large variety of epitope loads.…”

Section: Discussionmentioning

confidence: 99%

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Formation of donor‐specific antibodies depends on the epitope load of mismatched HLAs in lung transplant recipients: A retrospective single‐center study

Lobashevsky

Niemann²,

Kowinski

et al. 2022

Clinical Transplantation

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The development of donor-specific antibodies (DSA) has a significant impact on graft outcome in solid organ transplantation. Mismatched HLAs are recognized directly and indirectly by the recipient immune system. Both pathways occur in parallel and result in the generation of plasma cells, DSA, cytotoxic and T helper lymphocytes. Here, we present the results of an analysis of the epitope load of mismatched HLAs in a cohort of 220 lung transplant recipients using two in silico algorithms, HLAMatchmaker and PIRCHE-II (Predicted Indirectly ReCognizable HLA Epitopes). De novo DSA (dnDSA) were detected by single antigen bead assays. The percentage of recipients who developed dnDSA was significantly higher in the group of patients who received lung transplants with a mismatching score above the detected threshold than in the group of patients who received lung transplants with a mismatching score below the threshold.In a multivariate Cox proportional hazard analysis, the PIRCHE-II score appeared to be a superior predictor of dnDSA formation. In addition, PIRCHE-II technology was shown to be useful in predicting separate dnDSA1 and dnDSA2 formation. We conclude that both algorithms can be used for the evaluation of the epitope load of mismatched HLAs and the prediction of DSA development in lung transplant recipients.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Formation of donor‐specific antibodies depends on the epitope load of mismatched HLAs in lung transplant recipients: A retrospective single‐center study

Lobashevsky

Niemann²,

Kowinski

et al. 2022

Clinical Transplantation

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“…Previous studies using HLAMatchmaker, PIRCHE-II or HLA-EMMA have found that patients with greater HLA-DR and/or HLA-DQ epitope mismatch loads have increased risk of poor transplant outcomes including antibody-mediated rejection, dnDSA production, chronic lung allograft dysfunction, cardiac allograft vasculopathy and graft loss in heart and lung transplant patients (Nilsson et al, 2019;Osorio-Jaramillo et al, 2020;Walton et al, 2016;Wu et al, 2020;Zhang et al, 2020). However, published studies are contradictory, and some investigations have observed no relationship between HLA epitope mismatches and poor transplant outcomes (McCaughan et al, 2018; P. M. Sullivan et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Human leukocyte antigen epitope mismatch loads and the development of de novo donor‐specific antibodies in cardiothoracic organ transplantation

Bedford

Jervis

Worthington

et al. 2021

Int J Immunogenetics

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De novo donor-specific human leucocyte antigen (HLA) antibodies (dnDSA) are associated with increased risk of rejection and mortality in solid organ transplantation. Such dnDSA is produced in some recipients upon allorecognition of mismatched HLA posttransplant. HLA matching is not currently considered in the allocation of deceased donor hearts and lungs and pre-transplant immunological risk stratification is based entirely on the mean fluorescence intensity (MFI) of circulating donor-directed HLA antibodies. HLA epitope-based matching tools predict B-cell or T-cell HLA epitopes that are present in the donor's HLA but absent in the recipient's HLA. We hypothesized that patients with higher epitope mismatch loads would be at increased risk of dnDSA development. We retrospectively analysed 73 heart and/or lung transplant recipients who were tested for DSA between 2015 and 2020. HLAMatchmaker, PIRCHE-II and HLA epitope mismatch algorithm (HLA-EMMA) were used to calculate eplet mismatch (EpMM) loads, T-cell epitope mismatch (TEpMM) loads and solvent accessible amino acid mismatch (SAMM) loads, respectively. Multivariate analyses showed that HLA-EMMA was the only tool with a significant association between the total score for all HLA loci and dnDSA production [odds ratio (OR) 1.021, 95% confidence interval (CI) 1.003-1.042, p = .0225] though this increased risk was marginal. The majority of dnDSA were directed against HLA-DQ and patients with higher HLA-DQ TEpMM loads (OR = 1.008, CI = 1.002-1.014, p = .007), and HLA-DR+DQ SAMM loads (OR = 1.035, CI = 1.010-1.064, p = .0077) were most at risk of producing dnDSA.We also showed that patients with a risk epitope within the HLA molecule encoded for by HLA-DQA1*05 + HLA-DQB1*02/03:01 were significantly more likely to produce dnDSA. The use of HLA epitope-based matching tools could be used for cardiothoracic transplant risk stratification to enable early intervention and monitoring of patients at increased risk of producing dnDSA.

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“…The value of evaluating HLA mismatch in heart transplantation has been demonstrated in numerous studies ( 1 , 23 – 25 ) and HLAMatchmaker, HLA-EMMA, and PIRCHE-II have been described as useful tools for predicting risk and managing patient and graft survival ( 18 ). Our study supports these findings and is the first ever to use HLA-EMMA to define risk cut-offs in pediatric heart transplant ( Figure 2 ).…”

Section: Discussionmentioning

confidence: 99%

Immunologic risk stratification of pediatric heart transplant patients by combining HLA-EMMA and PIRCHE-II

et al. 2023

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Human leukocyte antigen (HLA) molecular mismatch is a powerful biomarker of rejection. Few studies have explored its use in assessing rejection risk in heart transplant recipients. We tested the hypothesis that a combination of HLA Epitope Mismatch Algorithm (HLA-EMMA) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II) algorithms can improve risk stratification of pediatric heart transplant recipients. Class I and II HLA genotyping were performed by next-generation sequencing on 274 recipient/donor pairs enrolled in the Clinical Trials in Organ Transplantation in Children (CTOTC). Using high-resolution genotypes, we performed HLA molecular mismatch analysis with HLA-EMMA and PIRCHE-II, and correlated these findings with clinical outcomes. Patients without pre-formed donor specific antibody (DSA) (n=100) were used for correlations with post-transplant DSA and antibody mediated rejection (ABMR). Risk cut-offs were determined for DSA and ABMR using both algorithms. HLA-EMMA cut-offs alone predict the risk of DSA and ABMR; however, if used in combination with PIRCHE-II, the population could be further stratified into low-, intermediate-, and high-risk groups. The combination of HLA-EMMA and PIRCHE-II enables more granular immunological risk stratification. Intermediate-risk cases, like low-risk cases, are at a lower risk of DSA and ABMR. This new way of risk evaluation may facilitate individualized immunosuppression and surveillance.

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HLA-DQ mismatches stimulate de novo donor specific antibodies in heart transplant recipients

Cited by 24 publications

References 28 publications

Formation of donor‐specific antibodies depends on the epitope load of mismatched HLAs in lung transplant recipients: A retrospective single‐center study

Formation of donor‐specific antibodies depends on the epitope load of mismatched HLAs in lung transplant recipients: A retrospective single‐center study

Human leukocyte antigen epitope mismatch loads and the development of de novo donor‐specific antibodies in cardiothoracic organ transplantation

Immunologic risk stratification of pediatric heart transplant patients by combining HLA-EMMA and PIRCHE-II

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