Interindividual HLA evolutionary divergence in mismatched unrelated donor allo-HCT for malignant hematological disorders

Allogeneic hematopoietic cell transplantation (allo-HCT) hinges on a delicate trade-off between graft-versus-tumor control and graft-versus-host disease (GvHD), mediated by donor T-cell recognition of antigens presented by recipient human leukocyte antigen (HLA) molecules. We hypothesized that, beyond allele-level matching, sequence divergence at peptide-binding grooves across donor and recipient HLA loci shapes these responses. To this end, we evaluated the effect of HLA evolutionary divergence (HED), a metric quantifying amino acid variability at HLA peptide-binding sites, on selected hematological malignancies in 4,695 patients undergoing allo-HCT from a 9/10 mismatched unrelated donor (MMUD), reported to the EBMT database. We examined (i) locus-specific recipient HED (HED-R) and (ii) "HED-mismatch" (HED-MM), capturing immunopeptidome divergence at the mismatched locus. While dichotomous mismatch status explained differences in survival and acute GvHD risk (with overall greater detriment for class I loci), HED metrics uncovered substantial within-mismatch heterogeneity. In DRB1 mismatched subgroup, HED-MM at this locus, independently predicted inferior relapse-free survival (RFS) with an attenuating time-dependent association, further modulated by cross-locus HED-R. In this subgroup, higher HED-R at HLA-A and HLA-C associated with increased risks of acute GvHD and non-relapse mortality, respectively. Among HLA-B-mismatched pairs, higher DRB1 HED-R associated with worse overall survival (OS) and RFS and higher relapse risk. In the HLA-A-mismatched subgroup, higher HED-R at HLA-A increased chronic GvHD risk. Collectively, HED-derived metrics complement conventional mismatch classification by capturing qualitative differences in donor-recipient immunopeptidome interactions and reveal a complex, non-linear interplay among alleles across mismatch subgroups that modulates the clinical impact of mismatching.

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Journal
Blood Advances
Published
2026-08-25
DOI
https://doi.org/10.1182/bloodadvances.2026020341
Primary Topic
vaccines and immunoinformatics approaches
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article
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article

Interindividual HLA evolutionary divergence in mismatched unrelated donor allo-HCT for malignant hematological disorders

Liesbeth C. de Wreede, Jakob Robert Passweg, Marco Andreani, Wolfgang Andreas Bethge et al.
Blood Advances
vaccines and immunoinformatics approaches
article

Interindividual HLA evolutionary divergence in mismatched unrelated donor allo-HCT for malignant hematological disorders

Liesbeth C. de Wreede, Jakob Robert Passweg, Marco Andreani, Wolfgang Andreas Bethge, Katharina Fleischhauer, Francesca Kinsella, David Michonneau, Inken Hilgendorf, Pietro Merli, Stephan Mielke, Alessandro Rambaldi, Jurgen H. E. Kuball, Carmelo Gurnari, Christian Chabannon, Tobias Gedde‐Dahl, Simona Pagliuca, Pietro Crivello, Jarl Mooyaart, Robert Zeiser, Deborah Richardson, Henrik Sengeloev, Jorinde Desiree Hoogenboom, Tobias Lenz, Peter Dreger, Francis Ayuketang Ayuk, Victoria Potter, Annalisa Ruggeri, Matthias Edinger, Matthias Eder
article en

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) hinges on a delicate trade-off between graft-versus-tumor control and graft-versus-host disease (GvHD), mediated by donor T-cell recognition of antigens presented by recipient human leukocyte antigen (HLA) molecules. We hypothesized that, beyond allele-level matching, sequence divergence at peptide-binding grooves across donor and recipient HLA loci shapes these responses. To this end, we evaluated the effect of HLA evolutionary divergence (HED), a metric quantifying amino acid variability at HLA peptide-binding sites, on selected hematological malignancies in 4,695 patients undergoing allo-HCT from a 9/10 mismatched unrelated donor (MMUD), reported to the EBMT database. We examined (i) locus-specific recipient HED (HED-R) and (ii) "HED-mismatch" (HED-MM), capturing immunopeptidome divergence at the mismatched locus. While dichotomous mismatch status explained differences in survival and acute GvHD risk (with overall greater detriment for class I loci), HED metrics uncovered substantial within-mismatch heterogeneity. In DRB1 mismatched subgroup, HED-MM at this locus, independently predicted inferior relapse-free survival (RFS) with an attenuating time-dependent association, further modulated by cross-locus HED-R. In this subgroup, higher HED-R at HLA-A and HLA-C associated with increased risks of acute GvHD and non-relapse mortality, respectively. Among HLA-B-mismatched pairs, higher DRB1 HED-R associated with worse overall survival (OS) and RFS and higher relapse risk. In the HLA-A-mismatched subgroup, higher HED-R at HLA-A increased chronic GvHD risk. Collectively, HED-derived metrics complement conventional mismatch classification by capturing qualitative differences in donor-recipient immunopeptidome interactions and reveal a complex, non-linear interplay among alleles across mismatch subgroups that modulates the clinical impact of mismatching.

Blood Advances
Oslo University Hospital (NO), Cleveland Clinic (US), Karolinska University Hospital (SE), Universität Hamburg (DE), Heidelberg University (DE), Southampton Hospital (US), Leiden University Medical Center (NL), University Medical Center Freiburg (DE), Southampton General Hospital (GB), University Hospital Heidelberg (DE), University Hospital of Basel (CH), Rigshospitalet (DK), Karolinska Institutet (SE), San Raffaele University of Rome (IT), University Medical Center Utrecht (NL), University Hospital Regensburg (DE), Medizinische Hochschule Hannover (DE), Assistance Publique – Hôpitaux de Paris (FR), European Society for Blood and Marrow Transplantation (NL), Ospedale Papa Giovanni XXIII (IT), University Medical Center Hamburg-Eppendorf (DE), Essen University Hospital (DE), Bambino Gesù Children's Hospital (IT), Jena University Hospital (DE), Institut Paoli-Calmettes (FR), Istituti di Ricovero e Cura a Carattere Scientifico (IT), King's College Hospital (GB), University of Birmingham (GB), University of Tübingen (DE), Université de Lorraine (FR)
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vaccines and immunoinformatics approaches
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