Correlation and agreement between eplet mismatches calculated using serological, low-intermediate and high resolution molecular human leukocyte antigen typing methods.

Samantha Fidler,Ashley B Irish,Wai H Lim,Germaine Wong,Joshua R Lewis,Lloyd D’Orsogna

doi:10.18632/oncotarget.24349

Abstract

Structural human leukocyte antigen (HLA) matching at the eplet level can be identified by HLAMatchmaker, which requires the entry of four-digit alleles. The aim of this study was to evaluate the agreement between eplet mismatches calculated by serological and two-digit typing methods compared to high-resolution four-digit typing. In a cohort of 264 donor/recipient pairs, the evaluation of measurement error was assessed using intra-class correlation to confirm the absolute agreement between the number of eplet mismatches at class I (HLA-A, -B, C) and II loci (HLA-DQ and -DR) calculated using serological or two-digit molecular typing compared to four-digit molecular typing methods. The proportion of donor/recipient pairs with a difference of >5 eplet mismatches between the HLA typing methods was also determined. Intra-class correlation coefficients between serological and four-digit molecular typing methods were 0.969 (95% confidence intervals [95% CI] 0.960–0.975) and 0.926 (95% CI 0.899–0.944), respectively; and 0.995 (95% CI 0.994–0.996) and 0.993 (95% CI 0.991–0.995), respectively between two-digit and four-digit molecular typing methods. The proportion of donor/recipient pairs with a difference of >5 eplet mismatches at class I and II loci was 4% and 16% for serological versus four-digit molecular typing methods, and 0% and 2% for two-digit versus four-digit molecular typing methods, respectively. In this small predominantly Caucasian population, compared with serology, there is a high level of agreement in the number of eplet mismatches calculated using two-compared to four-digit molecular HLA-typing methods, suggesting that two-digit typing may be sufficient in determining eplet mismatch load in kidney transplantation.

Highlights

The human leukocyte antigen (HLA) system represents the loci of genes that determine tissue compatibility in solid organ transplantation
In a cohort of 264 donor/recipient pairs, the evaluation of measurement error was assessed using intra-class correlation to confirm the absolute agreement between the number of eplet mismatches at class I (HLA-A, -B, C) and II loci (HLA-DQ and -DR) calculated using serological or two-digit molecular typing compared to four-digit molecular typing methods
We have shown that in a predominantly Caucasian cohort, two-digit alleles converted to four-digit alleles reliably calculate the number of eplet mismatches at both class I and II loci compared to four-digit molecular HLA typing method

Summary

Introduction

The human leukocyte antigen (HLA) system represents the loci of genes that determine tissue compatibility in solid organ transplantation. Donor HLA alleles comprise multiple epitopes made up of polymorphic amino acid residues that can elicit a B-cell driven immune response in the recipients (immunogenicity), with a proportion of these epitopes capable of binding donorspecific anti-HLA antibody (antigenicity). Eplets were defined as discontinuous amino acid residues within a 3 Ångstrom radius of a non-self residue [3]. These regions are considered a fundamental component of HLA epitopes recognized by anti-HLA antibodies. Epidemiological studies have consistently shown that a greater number of eplet mismatches between the donor and recipient are associated with adverse graft outcomes after kidney transplantation, including development of de novo donorspecific anti-HLA antibodies [6, 7]. Eplet matching is explicitly considered in several donor kidney allocation programs such as the Eurotransplant Acceptable Mismatch program and the Pediatric Renal Transplant program in Australia [8,9,10]

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