Human Leucocyte Antigen System and Selection of Unrelated Hematopoietic Stem Cell Donors: Impact of Patient–Donor (Mis)matching and New Challenges with the Current Technologies

The selection of hematopoietic stem cell donors for allogeneic transplantation (allo-HSCT) is mainly driven by human leucocyte antigen (HLA) matching between patient and donor, with HLA-identical matched siblings being the preferred choice in most situations. Although other clinical and demographical variables matter, especially, donor age, which is unequivocally associated with better transplant outcomes, the histocompatibility criteria have a central role in the search for the best donor, particularly in the setting of unrelated allo-HSCT where HLA disparities between patient and donor are frequent. The present review is focused on the role of HLA incompatibilities on patient outcome according to the most recent literature, in an attempt to guide transplant physicians and search coordinators during the process of adult unrelated-donor selection. The technological progresses in HLA typing, i.e., with next-generation sequencing (NGS), now allow disclosing a growing number of HLA incompatibilities associated with a heterogeneous and sometimes unknown spectrum of clinical severity. Their immunogenic characteristics, i.e., their position inside or outside the antigen recognition domain (ARD), their permissiveness, their intronic or exonic nature and even the expected expression of the HLA loci where those mismatches occur, will be presented and discussed here, integrating the advances in the immunobiology of transplantation with survival and toxicity outcomes reported in the most relevant studies, within the perspective of improving donor selection in the current practice.