High-risk HLA alleles for severe acute graft-versus-host disease and mortality in unrelated donor bone marrow transplantation

Haematologica. 2016 Apr;101(4):491-8. doi: 10.3324/haematol.2015.136903. Epub 2016 Jan 14.

Abstract

HLA molecules play an important role for immunoreactivity in allogeneic hematopoietic stem cell transplantation. To elucidate the effect of specific HLA alleles on acute graft-versus-host disease, we conducted a retrospective analysis using 6967 Japanese patients transplanted with T-cell-replete marrow from an unrelated donor. Using unbiased searches of patient and donor HLA alleles, patient and/or donor HLA-B*51:01 (patient: HR, 1.37,P<0.001; donor: HR, 1.35,P<0.001) and patient HLA-C*14:02 (HR, 1.35,P<0.001) were significantly associated with an increased risk of severe acute graft-versus-host disease. The finding that donor HLA-C*14:02 was not associated with severe acute graft-versus-host disease prompted us to elucidate the relation of these high-risk HLA alleles with patient and donor HLA-C allele mismatches. In comparison to HLA-C allele match, patient mismatched HLA-C*14:02 showed the highest risk of severe acute graft-versus-host disease (HR, 3.61,P<0.001) and transplant-related mortality (HR, 2.53,P<0.001) among all patient mismatched HLA-C alleles. Although patient HLA-C*14:02 and donor HLA-C*15:02 mismatch was usually KIR2DL-ligand mismatch in the graft-versus-host direction, the risk of patient mismatched HLA-C*14:02 for severe acute graft-versus-host disease was obvious regardless of KIR2DL-ligand matching. The effect of patient and/or donor HLA-B*51:01 on acute graft-versus-host disease was attributed not only to strong linkage disequilibrium of HLA-C*14:02 and -B*51:01, but also to the effect of HLA-B*51:01 itself. With regard to clinical implications, patient mismatched HLA-C*14:02 proved to be a potent risk factor for severe acute graft-versus-host disease and mortality, and should be considered a non-permissive HLA-C mismatch in donor selection for unrelated donor hematopoietic stem cell transplantation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Alleles
  • Anemia, Aplastic / genetics
  • Anemia, Aplastic / immunology
  • Anemia, Aplastic / mortality
  • Anemia, Aplastic / therapy*
  • Bone Marrow Transplantation*
  • Child
  • Child, Preschool
  • Contraindications
  • Female
  • Gene Expression
  • Graft vs Host Disease / diagnosis
  • Graft vs Host Disease / genetics
  • Graft vs Host Disease / immunology*
  • Graft vs Host Disease / pathology
  • HLA-B Antigens / genetics
  • HLA-B Antigens / immunology*
  • HLA-C Antigens / genetics
  • HLA-C Antigens / immunology*
  • Histocompatibility Testing
  • Humans
  • Infant
  • Infant, Newborn
  • Leukemia / genetics
  • Leukemia / immunology
  • Leukemia / mortality
  • Leukemia / therapy*
  • Linkage Disequilibrium
  • Male
  • Middle Aged
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / immunology
  • Myelodysplastic Syndromes / mortality
  • Myelodysplastic Syndromes / therapy*
  • Receptors, KIR2DL1 / genetics
  • Receptors, KIR2DL1 / immunology
  • Retrospective Studies
  • Risk Factors
  • Survival Analysis
  • Transplantation, Homologous
  • Unrelated Donors

Substances

  • HLA-B Antigens
  • HLA-C Antigens
  • Receptors, KIR2DL1