Interindividual HLA evolutionary divergence in mismatched unrelated donor allo-HCT for malignant hematological disorders
Year: 2026
Type: article
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.
Source: Blood Advances
Authors: Simona Pagliuca, Jarl Eduard Mooyaart, Francis Ayuketang Ayuk, Robert Zeiser, Victoria Potter, Peter Dreger, Wolfgang Andreas Bethge, Inken Hilgendorf, David Michonneau, Alessandro Rambaldi, Henrik Sengeloev, Jakob R Passweg, Deborah Susan Richardson, Tobias Gedde-Dahl, Francesca A. M. Kinsella, Matthias Edinger, Stephan Mielke, Matthias Eder, Marco Andreani, Pietro Crivello, Pietro Merli, Jorinde Desiree Hoogenboom, Liesbeth C. de Wreede, Christian Chabannon, Jürgen Kuball, Carmelo Gurnari, Katharina Fleischhauer, Annalisa Ruggeri, Tobias Lenz
Institutions: Université de Lorraine, European Society for Blood and Marrow Transplantation, University Medical Center Hamburg-Eppendorf, University Medical Center Freiburg, King's College Hospital, University Hospital Heidelberg, University of Tübingen, Jena University Hospital, Assistance Publique – Hôpitaux de Paris, Ospedale Papa Giovanni XXIII, Rigshospitalet, University Hospital of Basel, University Hospital Southampton NHS Foundation Trust, Oslo University Hospital, University of Birmingham, University Hospital Regensburg, Karolinska University Hospital, Karolinska Institutet, Medizinische Hochschule Hannover, Bambino Gesù Children's Hospital, Essen University Hospital, Leiden University Medical Center, Institut Paoli-Calmettes, University Medical Center Utrecht, Cleveland Clinic, IRCCS Ospedale San Raffaele, Universität Hamburg
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
OpenAlex ID: W7204213372
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