HLA diversity: detection and impact on unrelated hematopoietic stem cell donor characterization and selection

Matching of patient and unrelated donor for HLA molecules significantly decreases the probability of graft rejection, graft vs. host disease, and transplant-related mortality in hematopoietic stem cell transplantation. A significant challenge in the identification of matched donors is the diversity of the HLA system. Almost 1500 alleles have been identified at 12 HLA loci. Significant progress has been made in the application of DNA-based testing to identify this diversity in patients and unrelated volunteer donors; however, the resolution of registry testing remains limited by the need to test many donors inexpensively. Thus, the transplant center must predict which donor might be a match for their patient using incomplete typing information. Design of a typing strategy based on knowledge of allele and haplotype frequencies is critical to speed donor identification. A further challenge is to compare patient HLA assignments to the over 7.7 million volunteer donors on registries carrying both DNA and serologic assignments. The links between alleles and serologic specificities remain unclear in many cases and complicate the design of computer algorithms used to match patients and donors. Finally, since few patients will find donors who are allele matched for all HLA loci, studies are underway to understand which of the HLA loci are most critical to match and to define rules of permissive mismatching to achieve an acceptable outcome.