Patients with life-threatening hematologic disorders can be cured by blood, marrow and cord blood transplantation, but face major impediments. Life-threatening post-transplant complications can still occur despite HLA matching; when matched stem cell sources are not available, the criteria for selecting the least risky mismatched allograft are not known. Patients who tolerate the transplant procedure remain at risk for disease recurrence. As the global transplant experience matures, patient/donor ethnicity has been recognized as an important determinant of post-transplant outcomes. We hypothesized that the MHC and KIR genetic regions harbor functional variants that are not currently tested in routine clinical practice. We have identified SNP variants within the MHC that influence the success of HLA matched and mismatched transplantation, and have elucidated the importance of KIR diversity and KIR-HLA interactions on outcomes. We now propose to examine the underlying mechanisms of these genotype associations with transplant outcomes. We will leverage large, ethnically diverse transplant populations to 1) validate SNPs and determine the mechanisms for SNP-associated mortality; 2) determine the role of expression in defining permissible HLA-A mismatches; 3) determine how expression and specificity of KIR3DL1/HLA-Bw4 interactions influence NK function and outcomes; 4) determine how allotype interactions between HLA-C specific KIR and HLA-C ligands impact outcomes, and 5) determine the rank order of immunogenetic factors that most strongly predict survival. These research questions will address the current roadblocks in alternative donor transplantation and provide novel information that can be translated to clinical practice for patients of diverse racial background.

Public Health Relevance

Even though life-threatening blood disorders can be cured through transplantation of healthy stem cells, patients suffer from life-threatening complications caused by variation in the genetic code between the patient and the stem cells. We will find the genes that are causing the complications, and understand how they function. This information may be used to select unrelated donors and cord blood stem cells that lower risks and help patients live longer healthier lives.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI069197-14
Application #
9521346
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Rice, Jeffrey S
Project Start
2005-09-30
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
14
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Boudreau, Jeanette E; Hsu, Katharine C (2018) Natural Killer Cell Education and the Response to Infection and Cancer Therapy: Stay Tuned. Trends Immunol 39:222-239
Boudreau, Jeanette E; Hsu, Katharine C (2018) Natural killer cell education in human health and disease. Curr Opin Immunol 50:102-111
Luduec, Jean-Benoît Le; Kudva, Anupa; Boudreau, Jeanette E et al. (2018) Novel multiplex PCR-SSP method for centromeric KIR allele discrimination. Sci Rep 8:14853
Eaton, Keith D; Romine, Perrin E; Goodman, Gary E et al. (2018) Inflammatory Gene Polymorphisms in Lung Cancer Susceptibility. J Thorac Oncol 13:649-659
Schöne, Bianca; Bergmann, Sabine; Lang, Kathrin et al. (2018) Predicting an HLA-DPB1 expression marker based on standard DPB1 genotyping: Linkage analysis of over 32,000 samples. Hum Immunol 79:20-27
El-Jawahri, Areej; LeBlanc, Thomas W; Burns, Linda J et al. (2018) What do transplant physicians think about palliative care? A national survey study. Cancer 124:4556-4566
Petersdorf, Effie W; O'hUigin, Colm (2018) The MHC in the Era of Next-Generation Sequencing: Implications for Bridging Structure with Function. Hum Immunol :
Petersdorf, Effie W; Stevenson, Philip; Malkki, Mari et al. (2018) Patient HLA Germline Variation and Transplant Survivorship. J Clin Oncol 36:2524-2531
Boudreau, Jeanette E; Giglio, Fabio; Gooley, Ted A et al. (2017) KIR3DL1/ HL A-B Subtypes Govern Acute Myelogenous Leukemia Relapse After Hematopoietic Cell Transplantation. J Clin Oncol 35:2268-2278
Petersdorf, Effie W (2017) Which factors influence the development of GVHD in HLA-matched or mismatched transplants? Best Pract Res Clin Haematol 30:333-335

Showing the most recent 10 out of 45 publications