Biological significance of HLA locus matching in unrelated donor bone marrow transplantation

Abstract

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-versus-leukemia 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.

Figure 1

Acute GVHD and survival curve by the number of multiple HLA locus mismatches. The number of HLA 1-allele mismatches in the GVH direction, with exclusion of 2-allele mismatches, in each HLA locus was summed. (A) Cumulative incidence of grade III-IV acute GVHD by the mismatch number of HLA-A, -B, -C, -DRB1_DQB1, and -DPB1 at the allele level in the GVH direction. DRB1_DQB1: both HLA-DRB1 mismatch and HLA-DQB1 mismatch treated as 1 mismatch. 0: no mismatch (n = 1476); 1: 1 mismatch (n = 2549); 2: 2 mismatches (n = 1379); 3: 3 mismatches (n = 415); 4: 4 mismatches (n = 60). Cumulative incidence at 100 days was 0, 11% (95% CI, 9%-12%); 1, 14% (13%-16%); 2, 21% (19%-23%); 3, 27% (23%-31%); and 4, 32% (20%-44%). (B) Kaplan-Meier curve of survival by the mismatch number of HLA-A, -B, -C, and -DRB1_DQB1 at the allele level. Survival rate at 5 years was 0, 53% (95% CI, 51%-54%); 1, 46% (44%-49%); 2, 41% (38%-45%); 3, 38% (30%-47%); and 4, 20% (3%-47%). (C) Kaplan-Meier curve of survival by the mismatch number of HLA-A, -B, -C, -DRB1, and -DQB1 at the allele level.