Predictive value of HLAMatchmaker and PIRCHE-II scores for de novo donor-specific antibody formation after adult and pediatric liver transplantation

Hamada, Sarah; Dumortier, Jérôme; Thévenin, Céline; Pageaux, Georges‐Philippe; Faure, Stéphanie; Guillaud, Olivier; Boillot, Olivier; Lachaux, A.; Luscalov, Dan-Adrian; Dubois, Valérie; Meszaros, Magdalena

doi:10.1016/j.trim.2020.101306

Cited by 20 publications

(27 citation statements)

References 24 publications

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“…(22,23) The risk factors previously reported for dnDSA formation include young recipient age, a low MELD score, inadequate immunosuppression, and HLA-DQ allele MMs. (22) Recently, Kubal et al reported that the number of class II MM eplets estimated via the HLAMatchmaker algorithm was strongly associated with the risk of class II dnDSA formation following deceased donor LT, (12) and more recently, PIRCHE-II algorithms have been used as effective tools for predicting dnDSA formation following LT. (24) Consistent with previous reports, the degrees of HLA-DQB1 allele MM and the number of DQB1-EpMM were both significantly higher in patients with dnDSA formation than in patients without.…”

Section: Original Article | 1601supporting

confidence: 91%

Molecular Mismatch Predicts T Cell–Mediated Rejection and De Novo Donor‐Specific Antibody Formation After Living Donor Liver Transplantation

et al. 2021

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Human leukocyte antigen (HLA) molecular mismatch (MM) analysis improves the prediction of clinical outcomes in kidney transplantation compared with prediction via traditional antigen MM. However, it remains unclear whether the level of MM can be used for risk stratification among liver transplantation (LT) recipients. A retrospective observational study of 45 living donor LTs was performed to evaluate eplet MM as a risk factor for both T cell-mediated rejection (TCMR) in the first month and de novo donor-specific antibody (dnDSA) formation. A total of 9 (20%) patients displayed TCMR. HLA-A, HLA-B, HLA-C, and HLA-DRB1 eplet MM numbers were not associated with TCMR. By contrast, HLA-DQB1 eplet MM (DQB1-EpMM) number was significantly high in patients with TCMR. The predicted indirectly recognizable HLA epitopes (PIRCHE-II) score for the HLA-DQB1 locus (DQB1-PIRCHE-II) was also significantly higher in the TCMR group than in the no-TCMR group. There was a high probability for TCMR to occur with either a DQB1-EpMM ≥7 or a DQB1-PIRCHE-II ≥13. Pretransplant mixed lymphocyte response analyses indicated that there were no significant differences between the antidonor T cell proliferation activities of patients with low-number (<7) and high-number (≥7) DQB1-EpMMs. However, the proportion of CD25 expression on proliferating antidonor CD8 + T cells, used as a cytotoxic activity marker, was high in DQB1-EpMMs ≥7. Moreover, both DQB1-EpMMs ≥9 and DQB1-PIRCHE-II ≥3 were predictors of dnDSA formation. Thus, MM analysis may be applied toward tailored immunosuppression based on individual risks.

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Section: Original Article | 1601supporting

confidence: 91%

Molecular Mismatch Predicts T Cell–Mediated Rejection and De Novo Donor‐Specific Antibody Formation After Living Donor Liver Transplantation

et al. 2021

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“…First, 1/3rd of our patients were excluded, as they were no longer followed at our center typing is needed for that assessment. 28 It is important to validate our observations prospectively in an independent and confoundercontrolled cohort with NGS-based HLA typing to improve our understanding of alloimunogenicity in pediatric liver transplantation. Note: The exact binomial test shows that the proportion of DSA against DQ7 is higher in patients without TCMR.…”

Section: Limitationsmentioning

confidence: 88%

Mismatch epitope load predicts de novo‐DSA‐free survival in pediatric liver transplantation

Shin

Lee

Dente

et al. 2022

Pediatric Transplantation

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Background: Our knowledge of de novo anti-HLA donor-specific antibodies (dnDSA) in liver transplantation continues to be defined. We hypothesized that differences of HLA-DR/DQ mismatches can improve precision in alloimmune risk categorization and be applied to tailor immunosuppression. Methods:A retrospective chart review of 244 pediatric patients consecutively transplanted at our center between 2003 and 2019 was performed to identify patients tested for dnDSA. Records were queried for: demographics, pre-transplant diagnosis, biopsy-proven T-cell-mediated rejection (TCMR), radiology proven biliary complications, tacrolimus trough levels, dnDSA characteristics, and HLA typing. The eplet mismatch analyses were performed using HLAMatchmaker ™ 3.1. All statistical analyses were conducted using R software version 3.40.Results: There were 99 dnDSA-negative patients and 73 dnDSA-positive patients (n = 70 against class II and n = 3 against class I and II). ROC analysis identified optimal cutoff of eplet mismatch load for dnDSA and defined risk groups for an alloimmune outcome. Kaplan-Meier curves and log-rank tests showed high eplet mismatch load was associated with shorter dnDSA-free survival (log-rank p = .001). Multivariable Cox regression models showed that tacrolimus coefficient of variation and tacrolimus mean levels were significantly associated with dnDSA-free survival (p < .001 and p = .036). Fisher's exact test showed that dnDSA was associated with an increased likelihood of TCMR (OR 14.94;; p < .001). Patients without TCMR were more likely to have dnDSA to HLA-DQ7 and less likely to have dnDSA to HLA-DQ2 (p = .03, p = .080). Conclusions:Mismatched epitope load predicts dnDSA-free survival in pediatric liver transplant, while dnDSA specificity may determine alloimmune outcome.

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“…When perfect matching is not possible to achieve, assessing (in)compatibility at the level of HLA eplets can be used for risk stratification. Indeed, eplet mismatch load has been linked to the development of de novo DSA, T‐cell mediated rejection, transplant glomerulopathy and graft failure (Hamada et al., 2020; Sapir‐Pichhadze et al., 2015; Sapir‐Pichhadze et al., 2020; Senev, Coemans, et al., 2020; Wiebe et al., 2019). While many studies focus on kidney transplantation, the link between eplet (in)compatibility and patient outcomes remains consistent in the context of other solid organ transplants (Hamada et al., 2020; McCaughan et al., 2018; Walton et al., 2016).…”

Section: Assessing Incompatibility At the Level Of Hla Epletsmentioning

confidence: 99%

“…Indeed, eplet mismatch load has been linked to the development of de novo DSA, T‐cell mediated rejection, transplant glomerulopathy and graft failure (Hamada et al., 2020; Sapir‐Pichhadze et al., 2015; Sapir‐Pichhadze et al., 2020; Senev, Coemans, et al., 2020; Wiebe et al., 2019). While many studies focus on kidney transplantation, the link between eplet (in)compatibility and patient outcomes remains consistent in the context of other solid organ transplants (Hamada et al., 2020; McCaughan et al., 2018; Walton et al., 2016). Importantly, a better understanding of immune risk associated with eplet incompatibility can inform surveillance schedules and personalized immunosuppression regimens in both adult and paediatric patients (Sharma et al., 2020; Wiebe et al., 2015; Wiebe & Nickerson, 2020; Wiebe et al., 2017).…”

Section: Assessing Incompatibility At the Level Of Hla Epletsmentioning

confidence: 99%

“…These represent antigens from donor HLA class I that can bind to the donor's class II HLA and can lead to T‐helper cell responses. PIRCHE‐II is associated with an increased risk of DSA development, rejection and graft loss (Hamada et al., 2020; Meszaros et al., 2020; Zheng et al., 2019).…”

Section: Roadmap To Implementation Of Eplet Matching—challenges and Omentioning

confidence: 99%

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Matchmaker, matchmaker make me a match: Opportunities and challenges in optimizing compatibility of HLA eplets in transplantation

Lemieux

Mohammadhassanzadeh

Klement

et al. 2021

Int J Immunogenetics

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The development of donor‐specific antibodies (DSAs) is a major complication in transplantation, which is associated with inferior graft survival, impaired quality of life, and increased healthcare costs. DSA develop upon recognition of nonself HLA by the recipient's immune system. HLA molecules contain epitopes, which are the surface regions of HLA molecules recognized by antibodies. HLAMatchmaker is an algorithm for assessing donor:recipient HLA compatibility at the level of structurally defined HLA targets called eplets. The consideration of eplets, rather than the whole HLA molecule, could offer some advantages when classifying the immune risk associated with particular donor:recipient pairs. Assessing compatibility at the level of HLA eplets could decrease misclassification of post‐transplant immune risk by improving specificity, when antibodies are confirmed to be directed against donor eplets missing from the recipient's repertoire of eplets. Consideration of eplets may also increase the sensitivity of immune risk assessment, when identifying mismatched eplets that could give rise to new, not previously detected, donor‐specific antibodies post‐transplant. Eplet matching can serve as a rational strategy for immune risk mitigation. Herein, we review the evolution of HLA (in) compatibility assessment for organ allocation. We outline challenges in the implementation of eplet‐based donor:recipient matching, including unavailability of allele‐level donor genotypes for 11 HLA loci at the time of organ allocation and difficulty in assessing the hierarchy of immune risk associated with particular HLA eplet mismatches. Opportunities to address some of the current shortcomings of donor genotyping and HLAMatchmaker are also discussed. While there is a demonstrated benefit in the application of HLAMatchmaker for donor: recipient HLA (in)compatibility assessment, evolving long‐read genotyping methods, compilation of large data sets with allele‐level genotypes, and standardization of methods to verify eplets as determinants of immune‐mediated injuries are required before HLA eplet matching is implemented in organ allocation to improve upon transplant outcomes.

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Predictive value of HLAMatchmaker and PIRCHE-II scores for de novo donor-specific antibody formation after adult and pediatric liver transplantation

Cited by 20 publications

References 24 publications

Molecular Mismatch Predicts T Cell–Mediated Rejection and De Novo Donor‐Specific Antibody Formation After Living Donor Liver Transplantation

Molecular Mismatch Predicts T Cell–Mediated Rejection and De Novo Donor‐Specific Antibody Formation After Living Donor Liver Transplantation

Mismatch epitope load predicts de novo‐DSA‐free survival in pediatric liver transplantation

Matchmaker, matchmaker make me a match: Opportunities and challenges in optimizing compatibility of HLA eplets in transplantation

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