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HLA-B leader and cord-blood transplantation
Eurocord through the EBMT/Promise database following national and Joint Accreditation Committee International Society for Cellular Therapy - Europe & EBMT (JACIE) guide- lines, and shared according to agreements between Eurocord and the Fred Hutchinson Cancer Research Center.
We previously observed a strong effect of the HLA-B leader in single-locus HLA-B-mismatched unrelated transplants who were matched at HLA-A, -C, -DRB1 and -DQB1, an effect that neither depends on HLA-C KIR ligands nor on the level of typing for HLA-A, -C, -DRB1 or -DQB1 allele and antigen mismatch- es.19 Since cord blood units are selected on the basis of HLA-A, - B, -DRB1 and most transplants in the current study lack high- resolution typing including HLA-C, models did not adjust for these factors. We tested the hypothesis that the HLA-B leader dimorphism informs clinical outcome by examining three groups defined by their match status at HLA-A, -B and -DRB1: i) the entire study population of 4,822 patients (Online Supplementary Table S2); ii) a subset of 2,178 transplants with one allele or antigen HLA-B mismatch regardless of mismatching elsewhere to examine whether the leader provides information on well-tolerated HLA-B mismatches (Online Supplementary Table S3), and iii) a subset of 1,013 HLA-A and -DRB1-matched transplants with one allele or antigen HLA-B mismatch which permitted the potential effects of the leader to be examined without disparity from HLA-A and -DRB1 (Online Supplementary Table S4; Figure 1).
Study oversight
Protocols were approved by the Institutional Review Boards of Eurocord and the National Institutes of Health Office for Human Research Protections. The funding agencies had no role
in the study design, data collection and analysis, the decision to submit the manuscript for publication, or the preparation of the manuscript.
HLA typing
Classical HLA alleles were genotyped in the study cohort according to standard criteria and individual transplant center guidelines.25-27 The rs1050458 single nucleotide polymorphism in exon one is defined for World Health Organization-recognized HLA-B alleles and antigens.28 The one-to-one relationship between the leader dimorphism and HLA-B allele and antigen and has been previously confirmed, permitting the assignment of methionine (M) (rs1050458T) or threonine (T) (rs1050458C) leader to each patient and cord blood unit based on typing performed at the time of transplantation (Figure 2).19 The leader genotype (TT, MT or MM) was determined for each patient and each cord blood unit. When the patient and cord blood unit are HLA-B-matched, they have, by definition, the same leader genotype. Transplants mismatched for one HLA-B allele were defined as leader-matched when the patient’s and unit’s mismatched alleles were both M or both T leader. Single HLA-B mismatches were defined as leader- mismatched when the patient’s and unit’s mismatched alleles had different leaders (M leader in the patient’s mismatched allele with T leader in the unit’s mismatched allele, or vice versa). Among sin- gle HLA-B-mismatched transplants, the leader of the matched (shared) allele between the patient and unit was determined (M or T). For single HLA-B-mismatched transplants, leader match status was combined with the leader of the shared matched allele to define four mutually exclusive groups: leader-matched/share T; leader-matched/share M; leader-mismatched/share T, and leader- mismatched/share M (Figure 2).
Figure 1. The clinical significance of the HLA-B leader was evaluat- ed in cord blood transplantation according to HLA matching, leader genotype, and leader-matching. The study population consisted of 4,822 single-unit unrelated cord blood transplantations. The clinical significance of the HLA-B leader in outcome was analyzed in the entire population, among transplants with one HLA-B mismatch (regardless of HLA mismatching elsewhere), and in HLA-A and DRB1-matched transplants with one HLA-B mismatch. The impact of the HLA-B leader was analyzed according to the cord blood unit’s leader genotype (left pie), the leader match status (middle pie), and the leader match status together with the leader of the shared anti- gen (right pie).
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