High rates of MHC mismatches in HLA matched unrelated donor/recipient pairs and potential impact on hematopoietic cell transplant outcome

Introduction: Donors for patients requiring hematopoietic cell transplant (HCT) are selected based on matching genetic sequences encoding the antigen recognition domain of specific HLA loci. However, differences in transplant outcomes in fully matched unrelated HCT compared with sibling HCT suggest that other genetic regions within the major histocompatibility complex (MHC) may contribute to HCT outcomes. Methods: We sequenced the non-classical MHC loci (NCML) HLA-E, A-F, -G, -H, MICA and MICB on a well- characterized retrospective cohort of 157 unrelated donor/recipient HCT pairs to determine the extent of MHC mismatching in matched pairs. Results: Mismatches were seen in one or more NCML in 131 of the 157 pairs (83 %), including 44 of 60 pairs (73 %) that were matched at 4th field resolution for HLA-A, HLA-C and HLA-B and 3rd field resolution for HLA- DRB1, HLA-DRB3,4,5, HLA-DQA1 and HLA-DQB1. Though not statistically significant, transplant outcome analysis suggested that highly HLA matched/NCML matched recipients had a greater risk of disease relapse and reduced likelihood of progression-free survival than recipients that were highly HLA matched/NCML mismatched. Conclusion: NCML mismatching is present in HLA-matched unrelated HCT donor and recipient pairs and may contribute to outcomes in unrelated HLA-matched HCT.