title: Impact of HLA-DPB1 haplotypes on outcome of 10/10 matched unrelated hematopoietic stem cell donor transplants depends on MHC-linked microsatellite polymorphisms.
abstract: Hematopoietic stem cell transplantation (HSCT) with HLA-A, -B, -C, -DRB1, -DQB1 allele matched (10 of 10) unrelated donors is still associated with a significant rate of posttransplantation complications. In order to disclose additional immunogenetic factors, we analyzed the impact of HLA-DPB1 disparities and major histocompatibility complex (MHC)-resident microsatellite polymorphisms in 246 HLA 10 of 10 matched HSCT patients. First we showed that patients with more frequent/conserved HLA haplotypes had a higher 5-year survival (55% ± 18% versus 39% ± 18%, P = .021). In addition, DPB1 incompatibilities and 3 microsatellite alleles were associated with outcome. In a Cox regression model adjusting for European Blood and Marrow Transplant (EBMT) risk score, T cell depletion, and year of treatment, HSCT with a tumor necrosis factor d (TNFd) 4/d5-positive donor was associated with increased mortality (hazard ratio [HR] = 2.03; confidence interval [CI] 1.25-3.31; P = .004), whereas the D6S510-184 allele was protective (HR = 0.44; CI 0.22-0.87; P = .018). The 2 MHC-linked genetic donor factors, DPB1 mismatch (MM), and TNFd4/d5-positivity, acted in synergy with the EBMT risk score with an always lower survival (HR = 2.97; CI 1.27-6.92; P = .012). These data show that multiple MHC-linked genetic donor factors impact on outcome after unrelated donor HSCT. Their additive and potentially divergent effects could explain previous discrepant results, particularly with respect to the role of HLA-DPB1 disparities. We conclude that HLA-DPB1 typing combined with a simple TNFd microsatellite genotyping assay may significantly help in pretransplantation risk assessment for graft-versus-host disease and mortality, particularly for patients with several potential 10 of 10 matched donors.
authors.affiliation: National Reference Laboratory for Histocompatibility, Department of the Medical Specialties, University Hospital Geneva, Geneva, Switzerland.
authors.forename: Florence
authors.initials: F
authors.lastname: Bettens
authors.forename: Jakob
authors.initials: J
authors.lastname: Passweg
authors.forename: Urs
authors.initials: U
authors.lastname: Schanz
authors.forename: Yves
authors.initials: Y
authors.lastname: Chalandon
authors.forename: Dominik
authors.initials: D
authors.lastname: Heim
authors.forename: Tayfun
authors.initials: T
authors.lastname: Güngör
authors.forename: Georg
authors.initials: G
authors.lastname: Stussi
authors.forename: Grazia
authors.initials: G
authors.lastname: Nicoloso
authors.forename: Helen
authors.initials: H
authors.lastname: Baldomero
authors.forename: Alois
authors.initials: A
authors.lastname: Gratwohl
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Tiercy
mesh_terms: D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D059868:HLA-DP beta-Chains / Q000235:genetics / Q000276:immunology*; D006239:Haplotypes / Q000235:genetics / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D007223:Infant; D008232:Lymphoproliferative Disorders / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics / Q000276:immunology; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D012306:Risk; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*; D061349:Unrelated Donors; D055815:Young Adult
chemical_list: D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; D014409:Tumor Necrosis Factor-alpha