Graft-versus-host disease and chromosome Y-encoded antigens in sex-mismatched stem cell transplant

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an efficient treatment option for patients with hematological malignancies. However, graft-versus-host disease (GvHD) remains a serious complication of allo‐HSCT which significantly affect transplant-related morbidity and mortality. Transplant outcomes can be improved by matching human leukocyte antigens, but other factors are needed to reduce the risk of GvHD.

Wei Wang from Center for International Blood and Marrow Transplant Research, Minneapolis, MN, USA, and colleagues aimed to identify genetic associations outside the major histocompatibility complex. Therefore, they conducted a genome-wide study on clinical outcomes including 205 acute myeloid leukemia (AML) patients (n = 102 acute GvHD; n = 103 non-GvHD), and their fully HLA-A–, HLA-B–, HLA-C–, HLA-DRB1–, and HLA-DQB1–matched (10/10) unrelated donors. Data was collected from the Center for International Blood and Bone Marrow Transplant Research (CIBMTR) database. Results were published in Blood Advances on October 9.

Key findings:

• Donor-recipient matching was observed to be extended beyond five HLA loci
• HLA-DPB1 T-cell epitope permissibility mismatches were found in 45% of acute GvHD cases
• A novel bioinformatics workflow altered from neoantigen discovery found no associations between acute GvHD and known HLA-restricted minor histocompatibility antigens (MiHAs); the two cohorts showed similar numbers of missense variants, P = 0.32, and known MiHAs, P = 0.80
• Y-chromosome–encoded single-nucleotide polymorphisms in 4 genes (PCDH11Y, USP9Y, UTY, and NLGN4Y) significantly associated with the occurrence of acute GvHD in male patients with female donors
• Males with acute GvHD with female donors more likely to have Y-encoded variant peptides with higher predicted HLA-binding affinity than males without GvHD who matched X-paralogous alleles in their female donors

This study indicates that sex-linked variation exposed multiple MiHAs encoded on the Y chromosome contribute to the development of acute GvHD, particularly in female > male allo-HSCT patients. The authors added that “methods and results described here have an immediate impact for allo-HSCT, warranting further development and larger genomic studies where MiHAs are clinically relevant, including cancer immunotherapy, solid organ transplant, and pregnancy.”