How to select the best available related or unrelated donor of hematopoietic stem cells?

Abstract

Recognition of HLA incompatibilities by the immune system represents a major barrier to allogeneic hematopoietic stem cell transplantation. HLA genotypically identical sibling donors are, therefore, the gold standard for transplantation purposes, but only 30% patients have such a donor. For the remaining 70% patients alternative sources of stem cells are a matched unrelated adult volunteer donor, a haploidentical donor or a cord blood unit. The definition of 'HLA matching' depends on the level of resolution and on which loci are tested. The development of HLA molecular typing technologies and the availability of more than 27 million donors in the international database has greatly facilitated unrelated donor searches. The gold standard is high resolution typing at the HLA-A, -B, -C, -DRB1, and -DQB1 loci (10/10 match). Single disparities for HLA-A, -B, - C, or -DRB1 are associated with increased risk of post-transplant complications, but less so in patients with advanced disease, and in those undergoing T-cell-depleted allografting. HLA-DQB1 mismatches seem to be better tolerated and some HLA-C, -DRB1 and -DPB1 disparities are potentially less immunogenic. HLA typing by next-generation sequencing methods is likely to change matching algorithms by providing full sequence information on all HLA loci in a single step. In most European populations a 10/10 matched donor can be found for at least 50% of patients and an additional 20-30% patients may have a 9/10 matched donor. Genetic factors that help in identifying donors with less immunogenic mismatches are discussed. Haploidentical donors are increasingly used as an alternative source of stem cells for those patients lacking a matched unrelated donor.

Figure 1.

Schematic map of the 4 Mb human major histocompatibility complex. The map is not drawn to scale, double separators (//) indicate larger distances and correspond to the regions where recombinations occur most frequently. C: centromere. The first row below the map indicates the number of well-defined serotypes for each locus. The DR serotypes include the antigens (heterodimers) encoded by the DRA/DRB1 (DR1-DR18), DRA/DRB3 (DR52), DRA/DRB4 (DR53) and DRA/DRB5 (DR51) genes. In the second row the total number of alleles is given (IMGT/HLA database version 3.23.0). The third row indicates the total number of different proteins. A total of 387 class I alleles with no surface expression (null alleles) and 90 class II null alleles have been described. Alleles that share identical sequences in the peptide-binding region represent 9% of the A, 6% of the B, 7.7% of the C, 1.7% of the DRB1, 17.2% of the DQB1 and 6.2% of the DPB1 alleles. Matching for the HLA-A, -B,- C,- DRB1 and -DQB1 loci is referred to as a 10/10 match, when HLA-DPB1 is included it becomes a 12/12 match. Matching for HLA-A, -B, -C, and -DRB1 loci is an 8/8 match. There is still no international standard for reporting DRB3/4/5 as well as DQA1 and DPA1 mismatches. Donor search algorithms do not include DQA1 and DPA1 testing because of strong linkage disequilibrium with the corresponding DQB1 and DPB1 loci.