title: High-risk HLA alleles for severe acute graft-versus-host disease and mortality in unrelated donor bone marrow transplantation.
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.
authors.affiliation: Department of Hematology, Fujita Health University School of Medicine, Toyoake, Aichi, Tokyo, Japan smorishi@fujita-hu.ac.jp.
authors.forename: Satoko
authors.initials: S
authors.lastname: Morishima
authors.affiliation: Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kashiwase
authors.affiliation: Divsion of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Azuma
authors.affiliation: Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Yabe
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato-Otsubo
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Division of Basic Medical Science and Molecular Medicine, Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shiina
authors.affiliation: Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Satake
authors.affiliation: HLA Foundation Laboratory, Kyoto, Japan.
authors.forename: Hiroh
authors.initials: H
authors.lastname: Saji
authors.affiliation: Department of Cell Transplantation and Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Kato
authors.affiliation: Department of Promotion for Blood and Marrow Transplantation, Aichi Medical University School of Medicine, Nagakute, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kodera
authors.affiliation: Institute for Advanced Study, Kyushu University, Fukuoka, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
authors.affiliation: Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Morishima
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000741:Anemia, Aplastic / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D016026:Bone Marrow Transplantation; D002648:Child; D002675:Child, Preschool; D000075202:Contraindications; D005260:Female; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000175:diagnosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology*; D015236:HLA-C Antigens / Q000235:genetics / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007938:Leukemia / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D054342:Receptors, KIR2DL1 / Q000235:genetics / Q000276:immunology; D012189:Retrospective Studies; D012307:Risk Factors; D016019:Survival Analysis; D014184:Transplantation, Homologous; D061349:Unrelated Donors
chemical_list: D015235:HLA-B Antigens; D015236:HLA-C Antigens; D054342:Receptors, KIR2DL1