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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100019-09
Application #
8024567
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Wu, Roy S
Project Start
2008-03-04
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
9
Fiscal Year
2011
Total Cost
$334,184
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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
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
Petersdorf, Effie W; Gooley, Theodore A; Malkki, Mari et al. (2014) HLA-C expression levels define permissible mismatches in hematopoietic cell transplantation. Blood 124:3996-4003
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
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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