title: HLA mismatch combinations associated with decreased risk of relapse: implications for the molecular mechanism.
abstract: The finding that the risk of relapse in hematologic malignancy decreases after allogeneic hematopoietic stem cell transplantation (HSCT) has lead to the concept of a graft-versus-leukemia (GVL) effect. However, this beneficial effect is considered to be frequently offset by graft-versus-host disease (GVHD). Thus, improving HSCT outcomes by separating GVL from GVHD is a key clinical issue. This cohort study registered 4643 patients with hematologic malignancies who received transplants from unrelated donors. Six major human leukocyte antigen (HLA) loci were retrospectively genotyped. We identified 4 HLA-Cw and 6 HLA-DPB1 mismatch combinations responsible for a decreased risk of relapse; of these, 8 of 10 combinations were different from those responsible for severe acute GVHD, including all 6 of the HLA-DPB1 combinations. Pairs with these combinations of HLA-DPB1 were associated with a significantly better overall survival than were completely matched pairs. Moreover, several amino acid substitutions on specific positions responsible for a decreased risk of relapse were identified in HLA-Cw, but not in HLA-DPB1. These findings might be crucial to elucidating the mechanism of the decreased risk of relapse on the basis of HLA molecule. Donor selection made in consideration of these results might allow the separation of GVL from acute GVHD, especially in HLA-DPB1 mismatch combinations.
authors.affiliation: Division of Epidemiology and Prevention, Aichi Cancer Center, Nagoya, Japan.
authors.forename: Takakazu
authors.initials: T
authors.lastname: Kawase
authors.forename: Keitaro
authors.initials: K
authors.lastname: Matsuo
authors.forename: Koichi
authors.initials: K
authors.lastname: Kashiwase
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Inoko
authors.forename: Hiroh
authors.initials: H
authors.lastname: Saji
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Shunichi
authors.initials: S
authors.lastname: Kato
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kodera
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Morishima
mesh_terms: D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease; D006086:Graft vs Host Disease / Q000453:epidemiology / Q000276:immunology; D020544:Graft vs Leukemia Effect / Q000276:immunology; D015236:HLA-C Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006682:HLA-DP Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D059868:HLA-DP beta-Chains; D018380:Hematopoietic Stem Cell Transplantation; D006648:Histocompatibility; D006801:Humans; D053208:Kaplan-Meier Estimate; D007938:Leukemia / Q000276:immunology / Q000401:mortality / Q000601:surgery*; D008297:Male; D009101:Multiple Myeloma / Q000276:immunology / Q000401:mortality / Q000601:surgery; D016016:Proportional Hazards Models; D012008:Recurrence; D012189:Retrospective Studies; D012306:Risk; D014184:Transplantation, Homologous / Q000276:immunology; D055815:Young Adult
chemical_list: D015236:HLA-C Antigens; D006682:HLA-DP Antigens; D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen