High-throughput sequencing defines donor and recipient HLA B-cell epitope frequencies for prospective matching in transplantation

Jenny Tran ,Lenka L Allan,Oliver P Günther,Ruth Sapir‐Pichhadze ,René J Duquesnoy ,Frans H.j Claas ,W Robert Mcmaster,James H Lan ,Karen Sherwood ,S G E Marsh ,Franz Fenninger,Paul Keown

doi:10.1038/s42003-021-01989-3

Abstract

Compatibility for human leukocyte antigen (HLA) genes between transplant donors and recipients improves graft survival but prospective matching is rarely performed due to the vast heterogeneity of this gene complex. To reduce complexity, we have combined next-generation sequencing and in silico mapping to determine transplant population frequencies and matching probabilities of 150 antibody-binding eplets across all 11 classical HLA genes in 2000 ethnically heterogeneous renal patients and donors. We show that eplets are more common and uniformly distributed between donors and recipients than the respective HLA isoforms. Simulations of targeted eplet matching shows that a high degree of overall compatibility, and perfect identity at the clinically important HLA class II loci, can be obtained within a patient waiting list of approximately 250 subjects. Internal epitope-based allocation is thus feasible for most major renal transplant programs, while regional or national sharing may be required for other solid organs.

Highlights

Compatibility for human leukocyte antigen (HLA) genes between transplant donors and recipients improves graft survival but prospective matching is rarely performed due to the vast heterogeneity of this gene complex
The quantitative mismatch of these eplets between donor and recipient provides an index of the risk of rejection, though not all epitope mismatches may be of equal importance and those occurring at certain HLA class II gene loci may be critical
We describe combinatorial epitypes comprising the array of eplets expressed by the HLA isoforms on each individual donor and recipient, and model the probabilities of achieving eplet identity at all or individual HLA gene loci to confirm the feasibility of prospective eplet matching within a national transplant program

Summary

Introduction

Compatibility for human leukocyte antigen (HLA) genes between transplant donors and recipients improves graft survival but prospective matching is rarely performed due to the vast heterogeneity of this gene complex. Compatibility for HLA genes between donor organs and graft recipients ensures excellent outcome in live donor transplantation, and improves graft survival in deceased donor transplantation[8,9], but is difficult to achieve due to the heterogeneity of this gene complex. Discrete motifs on these proteins are central to both antigen recognition and response. Prospective use of eplet matching to guide recipient selection offers a novel method to actively reduce donor immunogenicity, and the limited number of eplets may enable efficient matching To determine whether this prospective strategy is clinically feasible for patients awaiting transplantation requires precise population data on donor and recipient frequency distributions. We describe combinatorial epitypes comprising the array of eplets expressed by the HLA isoforms on each individual donor and recipient, and model the probabilities of achieving eplet identity at all or individual HLA gene loci to confirm the feasibility of prospective eplet matching within a national transplant program

Methods

Results

Conclusion