The role of HLA transcription in unrelated hematopoietic cell transplantation

Expression levels of human leukocyte antigen (HLA) are associated with susceptibility to various diseases and outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). However, there has been no comprehensive analysis of the effect of the expression levels of the HLA-A, -B, -C, and -DRB1 alleles in unrelated (UR)-HCT. Using the Capture RNA-Seq method, we analyzed the gene expression of HLA alleles in 443 healthy donors and determined the allele-specific transcription levels (AST levels). We assigned median (M)-AST levels to HLA typing data of patients who received a transplant from HLA-A, -B, -C, and -DRB1-matched unrelated donors using transplant registry data. All 6,084 patients were divided into low, middle, and high tertile groups according to the distribution of the sum of the two alleles of the M-AST level for each HLA locus and the sum of the eight alleles of the M-AST level for all four loci. The risk of grade II-IV acute graft-versus-host disease (GVHD) was significantly higher in the middle group (hazard ratio, 1.11; P = 0.044) and high group (hazard ratio, 1.20; P < 0.001) than in the low group for the sum of the HLA-A, -B, -C, and -DRB1 loci. Similar results were observed at the HLA-A, -B, -C, and -DRB1 loci. Higher transcription levels were also associated with a lower risk of relapse at the HLA-B, -C, and -DRB1 loci. Our data suggest that a high transcription level of patient and/or donor HLA may evoke strong alloimmune responses and affect UR-HCT outcomes.