Unrelated Stem Cell Donor HLA Match Likelihood in the US Registry Incorporating HLA-DPB1 Permissive Mismatching

Donor-recipient HLA matching at the DPB1 locus improves the outcomes of hematopoietic stem cell transplantation (HCT). Retrospective outcome studies found that in HCTs matched for all 8 alleles of the A, B, C, and DRB1 loci at high resolution (8/8 match), few transplantations were also allele-matched at the DPB1 locus. DPB1 allele matching was once thought to be logistically impractical; however, a DPB1-permissive mismatch model based on T cell epitope (TCE) reactivity expands the proportion of suitable donors. To understand the likelihood of finding a DPB1-permissive donor, we sought to expand population genetic match likelihood models for the US unrelated donor registry, the National Marrow Donor Program (NMDP). After extending HLA haplotype frequency estimates to include the DPB1 locus, our models found that the likelihood of having a DPB1-permissive donor was not much lower than likelihood of 8/8 matching. A maximum of 5 additional donors would need to be typed to find a more optimal DPB1-permissive donor at least 90% of the time. Linkage disequilibrium patterns between the DPB1 locus and other classical HLA loci varied markedly by haplotype and population, indicating that the known recombination hotspot between DQ and DP gene complexes has not had a uniform impact; thus, DPB1-permissive donors are easier to identify within minority populations. DPB1 TCE categories were highly predictable from HLA typing at other loci when imputed with extended haplotype frequency data. Our overall results indicate that registry search strategies that seek a more optimally matched HCT donor encompassing HLA-DPB1 permissibility are likely to be highly productive. (c) 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Automated summary

Matching the HLA at the DPB1 locus between donor and recipient improves the outcomes of hematopoietic stem cell transplantation. Through a DPB1-permissive mismatch model based on T cell epitope reactivity, it is possible to expand the pool of suitable donors. Our models show that the likelihood of finding a DPB1-permissive donor is not significantly lower than the likelihood of an 8/8 match, and only a small number of additional donors need to be typed to find an optimal DPB1-permissive donor. The presence of linkage disequilibrium patterns between the DPB1 locus and other HLA loci suggests that DPB1-permissive donors are easier to identify within minority populations.