title: Functional distance between recipient and donor HLA-DPB1 determines nonpermissive mismatches in unrelated HCT.
abstract: 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 (ΔFD) 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 ΔFD subgroups showed a significantly higher percentage of nonpermissive TCE mismatches for ΔFD >2.665, compared with ΔFD ≤2.665 (88% vs 25%, P < .0001). In multivariate analysis, ΔFD >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 ΔFD ≤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 ΔFD 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 ΔFD compared with 5 others (P = .0025), demonstrating qualitative differences in the relative impact of AA polymorphism in HLA-DPB1. The novel concept of ΔFD sheds new light onto nonpermissive HLA-DPB1 mismatches in unrelated HCT.
authors.affiliation: Institute for Experimental Cellular Therapy.
authors.forename: Pietro
authors.identifier: 0000-0001-9668-5013
authors.initials: P
authors.lastname: Crivello
authors.affiliation: Institute for Transfusion Medicine, and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heinold
authors.affiliation: Institute for Transfusion Medicine, and.
authors.forename: Vera
authors.initials: V
authors.lastname: Rebmann
authors.affiliation: Department of Bone Marrow Transplantation, West German Cancer Center, University Hospital Essen, Essen, Germany; and.
authors.forename: Hellmut D
authors.initials: HD
authors.lastname: Ottinger
authors.affiliation: Institute for Transfusion Medicine, and German Cancer Consortium, Heidelberg, Germany.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Horn
authors.affiliation: Department of Bone Marrow Transplantation, West German Cancer Center, University Hospital Essen, Essen, Germany; and.
authors.forename: Dietrich W
authors.identifier: 0000-0001-5050-220X
authors.initials: DW
authors.lastname: Beelen
authors.affiliation: Institute for Experimental Cellular Therapy, German Cancer Consortium, Heidelberg, Germany.
authors.forename: Katharina
authors.identifier: 0000-0002-5827-8000
authors.initials: K
authors.lastname: Fleischhauer
mesh_terms: D000208:Acute Disease; D064591:Allografts; D018572:Disease-Free Survival; D005260:Female; D059868:HLA-DP beta-Chains / Q000235:genetics*; D019337:Hematologic Neoplasms / Q000235:genetics / Q000401:mortality / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D008297:Male; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000401:mortality / Q000628:therapy; D011110:Polymorphism, Genetic; D015996:Survival Rate; D014019:Tissue Donors
chemical_list: D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen