Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study

Abstract

Summary Background The risks after unrelated-donor haemopoietic-cell transplantation with matched HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 alleles between donor and recipient (10/10 matched) can be decreased by selection of unrelated donors who also match for HLA-DPB1; however, such donors are difficult to find. Classification of HLA-DPB1 mismatches based on T-cell-epitope groups could identify mismatches that might be tolerated (permissive) and those that would increase risks (non-permissive) after transplantation. We did a retrospective study to compare outcomes between permissive and non-permissive HLA-DPB1 mismatches in unrelated-donor haemopoietic-cell transplantation. Methods HLA and clinical data for unrelated-donor transplantations submitted to the International Histocompatibility Working Group in haemopoietic-cell transplantation were analysed retrospectively. HLA-DPB1 T-cell-epitope groups were assigned according to a functional algorithm based on alloreactive T-cell crossreactivity patterns. Recipients and unrelated donors matching status were classified as HLA-DPB1 match, non-permissive HLA-DPB1 mismatch (those with mismatched T-cell-epitope groups), or permissive HLA-DPB1 mismatch (those with matched T-cell-epitope groups). The clinical outcomes assessed were overall mortality, non-relapse mortality, relapse, and severe (grade 3–4) acute graft-versus-host disease (aGvHD). Findings Of 8539 transplantations, 5428 (64%) were matched for ten of ten HLA alleles (HLA 10/10 matched) and 3111 (36%) for nine of ten alleles (HLA 9/10 matched). Of the group overall, 1719 (20%) were HLA-DPB1 matches, 2670 (31%) non-permissive HLA-DPB1 mismatches, and 4150 (49%) permissive HLA-DPB1 mismatches. In HLA 10/10-matched transplantations, non-permissive mismatches were associated with a significantly increased risk of overall mortality (hazard ratio [HR] 1·15, 95% CI 1·05–1·25; p=0·002), non-relapse mortality (1·28, 1·14–1·42; p<0·0001), and severe aGvHD (odds ratio [OR] 1·31, 95% CI 1·11–1·54; p=0·001), but not relapse (HR 0·89, 95% CI 0·77–1·02; p=0·10), compared with permissive mismatches. There were significant differences between permissive HLA-DPB1 mismatches and HLA-DPB1 matches in terms of non-relapse mortality (0·86, 0·75–0·98; p=0·03) and relapse (1·34, 1·17–1·54; p<0·0001), but not for overall mortality (0·96, 0·87–1·06; p=0·40) or aGvHD (OR 0·84, 95% CI 0·69–1·03; p=0·09). In the HLA 9/10 matched population, non-permissive HLA-DPB1 mismatches also increased the risk of overall mortality (HR 1·10, 95% CI 1·00–1·22; p=0·06), non-relapse mortality (1·19, 1·05–1·36; p=0·007), and severe aGvHD (OR 1·37, 95% CI 1·13–1·66; p=0·002) compared with permissive mismatches, but the risk of relapse was the same in both groups (HR 0·93, 95% CI 0·78–1·11; p=0·44). Outcomes for HLA 10/10-matched transplantations with non-permissive HLA-DPB1 mismatches did not differ substantially from those for HLA 9/10-matched transplantations with permissive HLA-DPB1 mismatches or HLA-DPB1 matches. Interpretation T-cell-epitope matching de...

Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

“…We further analyzed HLA-DPB1 mismatches through their classification into permissive vs nonpermissive, according to their belonging to different T-cell epitope groups. 36 Although, as previously reported, HLA-DPB1 nonpermissive mismatches were associated with an increased incidence of acute GVHD III-IV and NRM (supplemental Table 5), they did not affect our conclusions (ie, the effect of MICA mismatches on acute GVHD III-IV, chronic GVHD, relapse, and NRM; supplemental Table 5). Finally, we found no association of mismatches at MICA amino acid position 129 (known to affect binding affinity for NKG2D) with any of the tested clinical endpoints (supplemental Table 6).…”

Making the genomic leap in HCT: application of second-generation sequencing to clinical advances in hematopoietic cell transplantation

“…11 However, in a 2012 retrospective analysis of nearly 12 000 HCTs using high-resolution HLA typing, Petersdorf et al showed that HCT transplants with HLA-DPB1 non-permissive mismatching, as defined by T-cell epitope cross-reactivity groups, are significantly associated with poorer TRM in 10/10 and 9/10 MUD-HCT. 12 Similar studies on other classically 'low-expression' HLAs (including HLA-C, DQ and DR51/52/53) have also recently been shown to affect transplant outcome. 13,14 These findings underscore the value of large-scale longitudinal analysis, the use of molecular and sequence-based HLA typing, and the increasing importance of nonclassical HLA genes in HCT outcome as most allogeneic HCTs are now fully or near-fully HLA matched.…”

“…11 As a complement to WES, capture amplicon sequencing (CAS) allows high-throughput, deep resequencing of custom-selected genomic regions (eg, custom panels of genes encoding drug metabolism enzymes). 12,13 CAS exceeds the sensitivity of Sanger sequencing and is particularly useful for heterochimerism detection. For example, a mutation in a single cancer cell among a population of hundreds of normal cells can be identified using CAS.…”

Caspase-8 polymorphisms result in reduced Alemtuzumab-induced T-cell apoptosis and worse survival after transplantation

“…The main requirement for selection of an unrelated donor is well recognized to be one who is a match at 10/10 (or 8/8) HLA alleles. 20,21 Selecting a donor based on secondary selection donor characteristics, such as donor age 22 or other (non-classic HLA) genetic factors, [23][24][25] can further enhance outcomes.…”