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

Abstract

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.

Role of HLA in cardiothoracic transplantation

“…By focusing on specific algorithms, the study provides insights into the predictive power of these tools in identifying transplant recipients at risk of developing complications like DSA and AMR. The findings may have practical implications for clinicians, as they suggest that certain molecular mismatches could serve as early warning signs, allowing for proactive interventions to prevent or manage rejection episodes 37,38 . In summary, both studies by Mangiola et al and Ellison et al contribute significantly to the field of transplant immunology by emphasizing the importance of molecular mismatch algorithms in predicting immunological responses and clinical outcomes in pHTR.…”

“…By using HLAMatchmaker, PIRCHE, or HLA‐EMMA, some authors have found that heart and lung transplant patients with higher HLA‐DR and/or HLA‐DQ epitope mismatch loads showed an enhanced risk of poor transplant outcomes compared with other patients 20,21,32 Recenlty the studies by Mangiola et al and Ellison et al in the pediatric heart cohort, which explore the impact of various algorithms like Matchmaker, PIRCHE II, and EMMA on the development of de‐novo DSA and AMR, are important additions that should be included to provide a more well‐rounded perspective on the topic. By incorporating these recent studies and acknowledging the contributions of Nickerson and Wiebe's group, the review can offer a more up‐to‐date and comprehensive view of the role of molecular mismatch in kidney and thoracic organ transplantation, enhancing its overall quality and relevance 37,38 . In their study, Mangiola and colleagues investigated the impact of combined algorithms, including Matchmaker, PIRCHE II, and EMMA, on the development of de‐novo DSA and AMR in a large pediatric heart cohort.…”