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

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. Tran et al. combine high throughput sequencing, structural biology and computational simulation to determine the HLA allele and antibody-defined epitope frequencies in renal transplant patients and donors. These results demonstrate the feasibility of HLA epitope matching using data from a national transplantation program.