Functional distance between recipient and donor HLA-DPB1 determines nonpermissive mismatches in unrelated HCT

Abstract

Key Points• Nonpermissive mismatches associated with survival after HCT reflect FD between recipient-donor HLA-DPB1.• FD within HLA-DPB1 is determined by the combined impact of nonconservative peptide-binding AA substitutions.The role of HLA amino acid (AA) polymorphism for the outcome of hematopoietic cell transplantation (HCT) is controversial, in particular for HLA class II. Here, we investigated this question in nonpermissive HLA-DPB1 T-cell epitope (TCE) mismatches reflected by numerical functional distance (FD) scores, assignable to all HLA-DPB1 alleles based on the combined impact of 12 polymorphic AAs. We calculated the difference in FD scores (DFD) of mismatched HLA-DPB1 alleles in patients and their 10/10 HLA-matched unrelated donors of 379 HCTs performed at our center for acute leukemia or myelodysplastic syndrome. Receiver-operator curve-based stratification into 2 DFD subgroups showed a significantly higher percentage of nonpermissive TCE mismatches for DFD >2.665, compared with DFD £2.665 (88% vs 25%, P < .0001). In multivariate analysis, DFD >2.665 was significantly associated with overall survival (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.05-1.87; P < .021) and event-free survival (HR, 1.39; 95% CI, 1.05-1.82; P < .021), compared with DFD £2.665. These associations were stronger than those observed for TCE mismatches. There was a marked but not statistically significant increase in the hazards of relapse and nonrelapse mortality in the high DFD subgroup, whereas no differences were observed for acute and chronic graft-versus-host disease. Seven nonconservative AA substitutions in peptide-binding positions had a significantly stronger impact on DFD compared with 5 others (P 5 .0025), demonstrating qualitative differences in the relative impact of AA polymorphism in HLA-DPB1. The novel concept of DFD sheds new light onto nonpermissive HLA-DPB1 mismatches in unrelated HCT. (Blood. 2016;128(1):120-129)

Directionality of non-permissive HLA-DPB1 T-cell epitope group mismatches does not improve clinical risk stratification in 8/8 matched unrelated donor hematopoietic cell transplantation

“…This refined model which has 80% overlap with the original TCE algorithm does not have a direction because the difference is always a positive number. The significant risk associations observed between high ΔFD values and OS and TRM 28 are therefore in concordance with the findings from the present study suggesting limited impact of directionality on the TCE model.…”

“…Recently, the model of non-permissive HLA-DPB1 TCE mismatches was further refined by considering the delta between numerical functional distance scores assigned to HLA-DPB1 alleles in recipient and donor on the basis of the median impact of amino acid polymorphism on T-cell alloreactivity (ΔFD) 28 . This refined model which has 80% overlap with the original TCE algorithm does not have a direction because the difference is always a positive number.…”

HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities

“…72 The expression model is based on the observation that the 2 variants of a biallelic SNP in the HLA-DPB1 39 untranslated region are associated with high or low HLA-DP expression levels, respectively, 73 and that these variants in turn are in tight LD with specific HLA-DPB1 alleles. The expression model was found to be predictive of GVHD in the particular situation of truly single HLA-DPB1 mismatches, that is, 1 HLA-DPB1 allele shared between patient and donor and the other 1 mismatched at least in the GVH vector, in which the latter is high expression in the patient but low expression in the donor.…”

Role of major histocompatibility complex variation in graft-versus-host disease after hematopoietic cell transplantation

“…Patient-donor mismatching for amino acid residues that define the hypervariable regions of DPβ is associated with GVHD risk and can be used to define combinations of patient-donor HLA-DPB1 mismatches that are associated with higher risks (“HLA-DPB1 non-permissive mismatches”) and those associated with GVHD rates not dissimilar to those observed among HLA-DPB1-matched transplants (“HLA-DPB1 permissive mismatches”) 44, 45 . A clinically useful tool for evaluating patient-donor HLA-DPB1 mismatches has been developed with the aid of mutational studies 46 . In an independent study, recipient residues encoded by the DPA1*01:03–DPB1*04:01 haplotype that define the HLA-DP peptide-binding pocket have been shown to correlate with sclerotic GVHD 47 .…”