Impact of mismatched HLA on graft-versus-host disease in unrelated stem cell transplantation

Abstract

Graft-versus-host disease (GVHD) caused by patient and donor human leukocyte antigen (HLA) mismatch is a complication of unrelated hematopoietic stem cell transplantation (UR-HSCT) that leads to reduced success rates. To date, studies on HLA alleles in transplant have provided important information on unrelated donor selection. In this study on the effects of specific HLA alleles on acute GVHD in UR-HSCT, HLA-C＊14:02 was found to be significantly associated with an increased risk of acute GVHD. Patient HLA-C＊14:02 and donor HLA-C＊15:02 mismatch was usually KIR2DL-ligand mismatch in the GVH direction in Japanese UR-HSCT cohort, and the higher risk of severe acute GVHD for KIR2DL-ligand mismatch in GVH direction demonstrated in previous Japanese UR-HSCT study was attributable to this particular mismatch combination. Recently, the risk of acute GVHD after UR-HSCT was reported to be associated with the HLA-DP expression level, which is associated with the variant rs9277534 located in the 3'untranslated region (UTR) of the HLA-DPB1 gene. We constructed phylogenetic trees of HLA-DPB1 alleles using next-generation sequencing (NGS) HLA typing data that included introns and 3'UTRs. Results reported that rs9277534 represented a highly conserved region from exon 3 to the 3'UTR, which may lead to acute GVHD via a mechanism different from that observed using T-cell epitope mismatching algorithms, perhaps reflecting exon 2 polymorphisms. The usage of innovative technologies such as NGS in genetic analysis and HLA typing thus has profound implications in this field.