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... Show moreHuman 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. Show less
Duquesnoy, R.J.; Marrari, M.; Jelenik, L.; Zeevi, A.; Claas, F.H.J.; Mulder, A. 2013
Aim. Humoral sensitization affects transplant outcome, and it is now apparent that human leukocyte antigen (HLA) antibodies are specific for epitopes rather than antigens. Such epitopes can be... Show moreAim. Humoral sensitization affects transplant outcome, and it is now apparent that human leukocyte antigen (HLA) antibodies are specific for epitopes rather than antigens. Such epitopes can be structurally defined by HLAMatchmaker, an algorithm that considers eplets as critical elements of epitopes recognized by alloantibodies. This study addressed the question how mismatched HLA antigens induce specific antibodies in context with eplet differences with the antibody producer. Methods. HLA class I-specific human monoclonal antibodies derived from women sensitized during pregnancy were tested in Luminex assays with single allele panels. Their epitope specificity was determined from reactivity patterns and eplet differences between immunizing antigen and the antibody producer. Results. This study focuses on the reactivity patterns of 10 monoclonal antibodies specific for epitopes defined by a mismatched eplet paired with a self-eplet shared between immunizing HLA antigens and HLA antigens of the antibody producer. The eplets in these pairs are between 7 and 16 angstrom apart, a sufficient distance for contact by two separate complementarity-determining regions of antibody. Conclusions. These findings demonstrate that immunizing antigens have mismatched eplets that can form antibody-reactive epitopes with self-configurations on the molecular surface. They seem to suggest that HLA antibodies can be produced by autoreactive B cells that have undergone receptor editing to accommodate the recognition of nonself-eplets, the driving force of the humoral alloresponse. This concept enhances our understanding of structural epitope immunogenicity and the interpretation of antibody reactivity patterns with HLA panels. Show less
