Immunologic risk stratification of pediatric heart transplant patients by combining HLA-EMMA and PIRCHE-II
Mitchell A. Ellison, Massimo Mangiola, Marilyn Marrari, Carol Bentlejewski, J. Sadowski, Dwayne Zern, Cynthia S. M. Kramer, Sebastiaan Heidt, Matthias Niemann, Qingyong Xu, Anne I. Dipchand, William T. Mahle, J. W. Rossano, Charles E. Canter, Tajinder P. Singh, Warren A. Zuckerman, Daphne T. Hsu, Brian Feingold, Steve Webber, Adriana Zeevi
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.