The long-term goals of CA100019 are to improve the outcome of unrelated donor (URD) hematopoietic cell transplantation (HCT) and broaden the application of mismatched HCT through a better understanding of the immunogenetics of the transplantation barrier. We hypothesize that undetected variation within the gene- dense MHC could contribute to risks after HLA-matched and HLA-mismatched URD HCT. We developed a novel long-range phasing method to link HLA alleles in unrelated individuals and demonstrated that haplotype mismatching is associated with higher risk of clinically severe acute graft-versus-host disease (GVHD) after HLA matched and HLA mismatched HCT. Patients mismatched for both HLA alleles and haplotypes had significantly lower survival. Haplotype-mismatched donors and recipients had a greater degree of disparity for MHC-resident variation compared to haplotype-matched pairs, and undetected disparity was associated with increased post-transplant risks. These data demonstrate that the haplotype is a proxy for transplant risk. To define the risks of GVHD, relapse, TRM and mortality in a larger independent clinical transplant population, we will refine our long-range phasing method and develop short-range phasing methods to map variation (Specific Aim 1). We will determine the extent to which haplotype matching can lower risks of GVHD and TRM, while preserving graft-versus-leukemia effects (Specific Aim 2). We will identify novel MHC-resident variation associated with transplant risks (Specific Aim 3). CA100019 will provide a powerful practical immunogenetic approach for optimizing URD HCT and for broadening the use of HLA mismatched URDs. Finally, CA100019 will contribute novel genetic data needed for hypothesis-driven and exploratory gene mapping.
We developed a tool for studying human chromosomes and genes, and discovered ways to improve the results of unrelated transplantation for the treatment of blood disorders. We will use the tool to find the genes that are important to transplant success.
|Petersdorf, E W (2017) In celebration of Ruggero Ceppellini: HLA in transplantation. HLA 89:71-76|
|Petersdorf, Effie W (2016) Mismatched unrelated donor transplantation. Semin Hematol 53:230-236|
|Boyiadzis, Michael; Arora, Mukta; Klein, John P et al. (2015) Impact of Chronic Graft-versus-Host Disease on Late Relapse and Survival on 7,489 Patients after Myeloablative Allogeneic Hematopoietic Cell Transplantation for Leukemia. Clin Cancer Res 21:2020-8|
|Petersdorf, Effie W; Malkki, Mari; O'hUigin, Colm et al. (2015) High HLA-DP Expression and Graft-versus-Host Disease. N Engl J Med 373:599-609|
|Petersdorf, Effie W (2015) HLA mismatching in transplantation. Blood 125:1058-9|
|Israeli, Moshe; Roelen, Dave L; Carrington, Mary et al. (2014) Association between CTL Precursor Frequency to HLA-C Mismatches and HLA-C Antigen Cell Surface Expression. Front Immunol 5:547|
|Pidala, Joseph; Lee, Stephanie J; Ahn, Kwang Woo et al. (2014) Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation. Blood 124:2596-606|
|Fernandez-Viña, Marcelo A; Wang, Tao; Lee, Stephanie J et al. (2014) Identification of a permissible HLA mismatch in hematopoietic stem cell transplantation. Blood 123:1270-8|
|Inamoto, Yoshihiro; Storer, Barry E; Petersdorf, Effie W et al. (2013) Incidence, risk factors, and outcomes of sclerosis in patients with chronic graft-versus-host disease. Blood 121:5098-103|
|Fernández-Viña, Marcelo A; Klein, John P; Haagenson, Michael et al. (2013) Multiple mismatches at the low expression HLA loci DP, DQ, and DRB3/4/5 associate with adverse outcomes in hematopoietic stem cell transplantation. Blood 121:4603-10|
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