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Impact of HLA-DPB1 haplotypes on outcome of 10/10 matched unrelated hematopoietic stem cell donor transplants depends on MHC-linked microsatellite polymorphisms


Bettens, F; Passweg, J; Schanz, U; Chalandon, Y; Heim, D; Güngör, T; Stussi, G; Nicoloso, G; Baldomero, H; Gratwohl, A; Tiercy, J M (2012). Impact of HLA-DPB1 haplotypes on outcome of 10/10 matched unrelated hematopoietic stem cell donor transplants depends on MHC-linked microsatellite polymorphisms. Biology of Blood and Marrow Transplantation, 18(4):608-616.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Hematology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2012
Deposited On:01 Dec 2011 08:35
Last Modified:26 Jan 2017 08:50
Publisher:Elsevier
ISSN:1083-8791
Publisher DOI:https://doi.org/10.1016/j.bbmt.2011.09.011
PubMed ID:21963878

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