Key Points• Significant HLA locus mismatches responsible for transplant-related events were determined in 7898 unrelated marrow donor transplants.• This information provides a rationale for use of an algorithm for unrelated donor selection.We hypothesized that the compatibility of each HLA loci between donor and patient induced divergent transplant-related immunologic responses, which attributed to the individualized manifestation of clinical outcomes. Here, we analyzed 7898 Japanese pairs transplanted with T-cell-replete marrow from an unrelated donor with complete HLA allele typing data. Multivariable competing risk regression analyses were conducted to evaluate the relative risk (RR) of clinical outcomes after transplantation. A significant RR of HLA allele mismatch compared with match was seen with HLA-A, -B, -C, and -DPB1 for grade III-IV acute graft-versus-host disease (GVHD), and HLA-C for chronic GVHD. Of note, only HLA-C and HLA-DPB1 mismatch reduced leukemia relapse, and this graft-versusleukemia effect of HLA-DPB1 was independent of chronic GVHD. HLA-DRB1 and HLA-DQB1 double (DRB1_DQB1) mismatch was revealed to be a significant RR for acute GVHD and mortality, whereas single mismatch was not. Thus, the number of HLA-A, -B, -C, -DPB1, and DRB1_DQB1 mismatches showed a clear-cut risk difference for acute GVHD, whereas the number of mismatches for HLA-A, -B, -C, and DRB1_DQB1 showed the same for mortality. In conclusion, we determined the biological response to HLA locus mismatch in transplant-related immunologic events, and provide a rationale for use of a personalized algorithm for unrelated donor selection. (Blood. 2015;125(7):1189-1197
We previously reported the potent adverse effects of killer immunoglobulin-like receptor (KIR) ligand mismatch (KIR-L-MM) on the outcome of T cell-replete unrelated hematopoietic stem cell transplantation (UR-HSCT) through the Japan Marrow Donor Program. Other UR-HSCT studies have yielded inconsistent results. To address this discrepancy, we evaluated candidate factors contributing to the effects of KIR-L-MM on transplantation outcomes in retrospectively selected hematologic malignancy cases with uniform graft-versus-host disease (GVHD) prophylaxis (n = 1489). KIR-L-MM in the graft-versus-host direction (KIR-L-MM-G) was associated with a higher incidence of acute GVHD (aGVHD; P < .002) and a lower overall survival (OS; P < .0001) only without the preadministration of antithymocyte globulin (ATG). Furthermore, in KIR-L-MM-G, the donor KIR2DS2 gene with the patient cognate C1 ligand was associated with a higher incidence of aGVHD (P = .012). Multivariate analysis by Cox proportional hazard models suggested that donor 2DS2 and ATG preadministration were critical factors in grade III-IV aGVHD (hazard ratio = 1.96; 95% confidence interval = 1.01-3.80; P = .045, and hazard ratio = 0.56; 95% confidence interval = 0.31-0.99; P = .047, respectively). These results indicate that the adverse effects of KIR-L-MM-G depend on combination of donor-activating KIR genotype-patient cognate KIR ligand type and no ATG preadministration, thereby suggesting the importance of these factors in UR-HSCT and in leukemia treatment using natural killer (NK) cell alloreactivity.
Objectives. ACPA is a highly specific marker for RA. It was recently reported that ACPA can be used to classify RA into two disease subsets, ACPA-positive and ACPA-negative RA. ACPA-positive RA was found to be associated with the HLA-DR shared epitope (SE), but ACPA negative was not. However, the suspicion remained that this result was caused by the ACPA-negative RA subset containing patients with non-RA diseases. We examined whether this is the case even when possible non-RA ACPA-negative RA patients were excluded by selecting only patients with bone erosion.Methods. We genotyped HLA-DRB1 alleles for 574 ACPA-positive RA, 185 ACPA-negative RA (including 97 erosive RA) and 1508 healthy donors. We also tested whether HLA-DR SE is associated with RF-negative or ANA-negative RA.Results. ACPA-negative RA with apparent bone erosion was not associated with SE, supporting the idea that ACPA-negative RA is genetically distinct from ACPA-positive RA. We also tested whether these subsets are based on autoantibody-producing activity. In accordance with the ACPA-negative RA subset, the RF-negative RA subset showed a clearly distinct pattern of association with SE from the RF-positive RA. In contrast, ANA-negative as well as ANA-positive RA was similarly associated with SE, suggesting that the subsets distinguished by ACPA are not based simply on differences in autoantibody production.Conclusions. ACPA-negative erosive RA is genetically distinct from ACPA-positive RA.
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