Assessment of human leukocyte antigen immunogenicity: current methods, challenges and opportunities

Abstract

Purpose of reviewDonor–recipient human leukocyte antigen (HLA) matching improves outcomes after solid-organ transplantation, but current assessment of HLA incompatibility is inadequate as it does not consider the relative immunogenicity of individual HLA mismatches. In this article, we review existing strategies for assessing HLA immunogenicity and discuss current challenges and future opportunities in this field.Recent findingsCurrent HLA immunogenicity algorithms focus primarily on the humoral component of the alloimmune response and aim to determine a measure of ‘dissimilarity’ between donor and recipient HLA. This can be achieved by deriving information from comparison of donor and recipient HLA at the amino acid sequence, structural and/or the physicochemical level, accounting for both B-cell and T-cell pathways of alloreactivity. Substantial evidence now supports the superiority of this molecular definition of HLA incompatibility, over conventional enumeration of HLA antigenic differences, for assessing the risk of humoral alloimmunity and for predicting graft outcomes after transplantation.SummarySignificant progress has been made in developing computational HLA immunogenicity algorithms that offer exciting opportunities for a more rational approach to determining the degree of donor–recipient HLA incompatibility and to defining HLA-related immunological risk. A number of challenges now need to be overcome to enable their implementation into clinical practice.

Predicting Humoral Alloimmunity from Differences in Donor and Recipient HLA Surface Electrostatic Potential

“…However, simple enumeration of differences at the whole Ag level is constrained by limited possible values (zero, one, or two mismatches per locus) and does not account for differences in donor HLA immunogenicity for a given recipient. Current approaches for determining the potential of a donor HLA to induce an alloantibody response are based on quantifying the degree of dissimilarity between the donor and recipient HLA molecules ( 12 , 17 , 19 , 21 , 65 ). The most frequently used methods (HLAMatchmaker and Cambridge HLA immunogenicity algorithm) evaluate differences in the number and location of amino acid mismatches at continuous and discontinuous (eplets) positions on the HLA sequence, and multiple studies have suggested they provide superior risk stratification over conventional HLA mismatch grade for predicting development of DSA, allograft rejection, transplant glomerulopathy, and allograft survival ( 14 , 16 , 18 , 20 , 63 ).…”

Does HLA matching matter in the modern era of renal transplantation?

“…Amino acids might be contiguous on the HLA molecule but adjacent to different amino acids in three-dimensional space. The eplet analysis through HLAMatchmaker takes this spacial configuration into account in defining three amino acid sequences as epitopes on the surface of the HLA molecule [ 46 , 47 ]. HLA MM is performed based on a score of potential epitope mismatches between donor and recipient rather than limited to 0/1 for each allele.…”

“…Some patients with 0 HLA-DR MM had high eplet MM and vice versa. The tertiary HLA structure can also be computed based on the electrostatic interaction between amino acid molecules (EMS-3D score) [ 47 , 50 , 51 ]. The electrostatic forces are also postulated to affect affinity binding of antibody to HLA epitopes.…”

Working towards an ERAS Protocol for Pancreatic Transplantation: A Narrative Review

“…A scoring system accounting for the risks of rejection due to donor factors, recipient factors and intra-operative factors would allow for quantification of this risk and tailored immunosuppression. One specific area of interest is HLA immunogenicity calculating the exact immunological risk based on donor and recipient phenotypes [ 158 ]. There are many methods of quantifying this, with studies showing a possible benefit in both kidney and pancreas transplantation [ 159 , 160 , 161 , 162 , 163 ].…”