Search

Summary: The impact of human leukocyte antigen (HLA) mismatching at the HLA‐A, ‐B, ‐C, and ‐DRB1 loci after unrelated bone marrow transplantation in paediatric patients with haematological malignancies has not been fully examined. Here, we analysed patients with haematological malignancies (all aged ≤15 years; n = 1330) who underwent a first unrelated bone marrow transplantation between 1993 and 2017 in Japan. The results show that although an HLA mismatch was significantly associated with a low relapse rate, it was also associated with higher non‐relapse mortality. There was a significant association between HLA mismatch and low overall survival. Locus mismatch analysis revealed that, as in adults, an HLA‐C mismatch had a significant negative impact on survival; however, in paediatric patients, an HLA‐DRB1 mismatch did not have a negative impact, although these HLA mismatch effects are weakened in recent cases. Taken together, the results suggest that an HLA‐matched donor should be the first candidate for paediatric patients; however, for patients without a matched sibling or matched unrelated donor, we can select an unrelated donor with a mismatch at HLA‐DRB1 if available. [ABSTRACT FROM AUTHOR]

Recent advances in unrelated cord blood transplantation (UCBT) and high-resolution typing of human leukocyte antigen (HLA) from an unrelated donor have increased choices in alternative donor/stem cell source selection. We assessed HLA-mismatched locus-specific comparison of the outcomes of 351 single-unit UCB and 1,028 unrelated bone marrow (UBM) adult recipients 16 years old or older at the time of transplantation who received first stem cell transplantation with myeloablative conditioning for acute leukemia or myelodysplastic syndromes. With adjusted analyses, HLA 0 to 2 mismatched UCBT showed similar overall mortality (relative risk [RR] = 0.85, 95% confidence interval [CI], 0.68-1.06; P = .149) compared with that of single-HLA-DRB1-mismatched UBMT. UCBT showed inferior neutrophil recovery (RR = 0.50, 95% CI, 0.42-0.60; P < .001), lower risk of acute graft-versus-host disease (RR = 0.55, 95% CI, 0.42-0.72; P < .001), and lower risk of transplantation-related mortality (RR = 0.68, 95% CI, 0.50-0.92; P = .011) compared with single-HLA-DRB1-mismatched UBMT. No significant difference was observed for risk of relapse (RR = 1.28, 95% CI, 0.93-1.76; P = .125). HLA 0 to 2 antigen-mismatched UCBT is a reasonable second alternative donor/stem cell source with a survival outcome similar to that of single-HLA-DRB1-mismatched or other 7 of 8 UBMT. [Copyright &y& Elsevier]

Abstract: The responsible human leukocyte antigen (HLA) locus and the role of killer immunoglobulin-like receptor (KIR) ligand matching on transplantation outcome were simultaneously identified by multivariate analysis in 1790 patients with leukemia who underwent transplantation with T-cell–replete marrow from an unrelated donor (UR-BMT) through the Japan Marrow Donor Program. The graft-versus-leukemia (GVL) effect depended on leukemia cell type. HLA-C mismatch reduced the relapse rate in acute lymphoblastic leukemia (ALL) (hazard ratio [HR] = 0.47; P = .003), and HLA-DPB1 mismatch reduced it in chronic myeloid leukemia (CML) (HR = 0.35; P < .001). In contrast, KIR2DL ligand mismatch in the graft-versus-host (GVH) direction (KIR-L-MM-G) increased in ALL (HR = 2.55; P = .017). An increased rejection rate was observed in KIR2DL ligand mismatch in the host-versus-graft direction (HR = 4.39; P = .012). Acute GVH disease (GVHD) was increased not only in the mismatch of HLA-A, -B, -C, and -DPB1, but also in KIR-L-MM-G. As a whole, the mismatch of HLA-A, -B, and -DQB1 locus and KIR-L-MM-G resulted in increased mortality. In conclusion, not only the mismatch of HLA-C and -DPB1, but also KIR-L-MM-G affected leukemia relapse, which should be considered based on leukemia cell type. Furthermore, KIR-L-MM induced adverse effects on acute GVHD (aGVHD) and rejection, and brought no survival benefits to patients with T-cell–replete UR-BMT. [Copyright &y& Elsevier]

Aim The aim of this research is to understand the possible functional changes that may result from variations in non-coding areas of HLA. Examining RNA by performing nucleotide sequencing and sequence copy enumeration using next-generation sequencing (NGS) methods may lead to identification of the causes of variation at the gene expression level. Method Mononuclear cells (MC) were isolated using Ficoll-Paque density separation method from 121 umbilical cord blood (UBC) samples which were registered at Tokai University Cord Blood Bank from 2000 through 2012. The total 48 RNA samples were selected based on both quality and quantity of 18 s and 28 s rRNAs. SeqCap RNA Enrichment System with customized capture beads (Roche) was applied for preparation of libraries. Barcoded 24 samples were pooled together and sequenced using MiSeq Reagent Kit v.2 (300-cycle) on MiSeq System (Illumina). DNA typing and calculation of read number in each of alleles were performed by SeaBass (in-house program) and other software. Results In total 110 HLA alleles including 11 A, 22 B, 14 C, 2 DRA, 18 DRB1, 4 DRB3, 2 DRB4, 2 DRB5, 11 DQA1, 13 DQB1, 3 DPA1 and 9 DPB1 were assigned from DNA typing of the 48 samples. Of them, one novel allele was detected in DQB1. In comparison to Class I loci, HLA-B had higher expression than HLA-A and -C which were lower but similar in expression. The expression level of HLA-DR (DRA + DRB1 + DRB3/4/5) was the highest among Class II loci. HLA-DP (DPA1 + DPB1) was higher than HLA-DQ (DQA1 + DQB1). Different expression levels between alpha and beta chains were observed in both HLA-DP and -DQ. HLA-DPB1 expression level was higher than HLA-DPA1. Trend differences among allele expression were observed; for example, HLA-A ∗ 24:02:02, HLA-DQA1 ∗ 03:02, and HLA-DQB1 ∗ 06:04 had higher expression than other alleles. Conclusions This study is the first report of UCB HLA expression level differences in the Japanese population. Our finding potentially provides more advantageous information for bone marrow transplant such as predicting risks of rejections due to higher expression HLA phenotypes. However, analyzing and generating statistic data in detail is necessary before application for clinical utilization. [ABSTRACT FROM AUTHOR]

Background: The requirements with respect to HLA compatibility and the relative importance of matching for individual class I and class II HLA alleles in the transplantation of hematopoietic stem cells from unrelated donors have not yet been established. Methods: We performed retrospective DNA typing of alleles at 11 polymorphic loci of HLA genes in 440 recipients of hematopoietic stem cells from unrelated donors who were serologically identical with their respective recipients for HLA-A, B, and DR antigens. Of these recipients, 80 percent had leukemia; the rest had lymphoma, marrow failure, or a congenital disorder. Results: Multivariate analysis showed that incompatibility for HLA-A alleles and incompatibility for HLA-C alleles were independent risk factors for severe acute graft-versus-host disease (GVHD) (HLA-A, P=0.006; HLA-C, P=0.001). Mismatching of HLA-A, but not of HLA-C, alleles was an independent risk factor for death (P<0.001). Mismatching of HLA-C alleles was a significant risk factor for relapse of leukemia (P=0.035). HLA-B disparity was a significant risk factor for both GVHD and death in the univariate analysis, but not in the multivariate analysis. Disparities in class II HLA alleles of the DRB1, DQA1, DQB1, DPA1, and DPB1 loci were not identified as significant risk factors for acute GVHD or death in the multivariate analysis. Conclusions: Genomic typing of class I HLA alleles adds substantially to the success of transplantation of hematopoietic stem cells from unrelated donors, even if the donors are serologically identical to their recipients with respect to HLA-A, B, and DR antigens. (N Engl J Med 1998;339:1177-85.) [ABSTRACT FROM AUTHOR]