Noninherited maternal Human Leukocyte Antigens: donor availability and clinical outcome in unrelated cord blood transplantation

Foetal exposure to semi-allogeneic cells from maternal microchimaerism (MMc) has been associated with the development of tolerance towards noninherited maternal antigens (NIMA) through a regulatory T cell response. This concept can be exploited in the selection of permissible Human Leukocyte Antigen (HLA) mismatches in cord blood (CB) transplantation (CBT) due to the availability of maternal samples for HLA typing and the identification of NIMA. CB virtual phenotypes (VPs) were generated by the substitution of 1-3 CB HLA (HLA-A, -B and/or –DRB1) for the corresponding NIMA, to permit the identification of virtual full HLA matches (VFM: 5/6 + 1 NIMA, 4/6 + 2 NIMA or 3/6 + 3 NIMA) for 457 patients. Maternal HLA typing for 4,671 CB donors resulted in the generation of 66,225 VPs and 52,875 of these were unique. When combined with the inherited phenotypes of 21,020 CB donors, the total unique phenotypes to increased to 65,046. VFMs, with adequate cell dose, doubled the cumulative availability of a matched donor for European Caucasoid patients and tripled the availability for patients of other ethnicities. Analyses of NIMA matching and clinical outcomes were performed for 198 transplants but was statistically underpowered to detect an association. High levels of MMc have been associated with transplantation tolerance. HLA qPCR assays with 0.01% sensitivity were optimised. MMc was detected in 27% of 96 samples tested. MMc was more frequent in CB from earlier gestational time points and appeared to be associated with bi-directional maternal-foetal HLA compatibility. The incorporation of NIMA in CB donor selection therefore increases the donor pool available to patients, particularly ethnic minorities, requiring CBT