Project 2: Immunogenetics of Graft-versus-Host Disease (GVHD) The long-term goals of Project 2 are to improve the outcome of unrelated donor (URD) hematopoietic cell transplantation (HCT) for the treatment of hematopoietic malignancies and other blood disorders and broaden the availability of mismatched URD HCT through a better understanding of the immunogenetic basis of GVHD. We propose to re-define the transplantation barrier by introducing a novel DMAmicroarray technique to determine the physical linkage of HLA genes in unrelated donors and recipients. Project 2 will perform HLA haplotyping of donors and recipients to address the following aims: define the probability of identifying HLA allele-matched, haplotype-matched unrelated donors (Specific Aim 1); determine the extent to which matching for donor haplotypes can.reduce severe acute GVHD and improve survival after unrelated donor HCT (Specific Aim 2), and define locus- and haplotype-specific risks in unrelated HCT (Specific Aim 3). The risks conferred by single HLA-A, B, C, DRB1 or DQB1 mismatches will be determined in patients transplanted from donors matched for one haplotype. Single locus mismatches that are not associated with increased GVHD or lower survival may permit donor selection criteria to be relaxed and thereby enable more patients to benefit from transplantation. Among HLA allele-matched, haplotype-matched transplants, the risk of GVHD associated with the presence or absence of ancestral HLA haplotypes will be defined. Identification of GVHD-risk haplotypes will provide clinicians with a proxy for GVHD risk and will permit a focused strategy for laboratory-based GVHD mapping studies. The implications of this work to the overall theme of the Adult Leukemia Center Program Project are three-fold: 1) improve the safety of unrelated HCT by understanding the genetic basis of GVHD for donor selection; 2) increase the availability of unrelated HCT by broadening the use of mismatched donors; and 3) increase the efficacy of unrelated HCT by understanding the genetic basis of graft-versus-leukemia.
The aims outlined in this project will provide new information as to the influence of the MHC region in transplantation that will enable us to re-define the optimal alternative donor. Relevance to Public Health: We have developed a novel way to select unrelated donors for hematopoietic cell transplantation. In this project, we will test the effectiveness of this new selection technique in reducing the incidence and severity of graft-versus-host disease and other transplant complications, and in increasing the odds of finding an appropriate donor for patients in need.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA018029-33
Application #
7617974
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
33
Fiscal Year
2008
Total Cost
$349,382
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Lee, Stephanie J; Onstad, Lynn; Chow, Eric J et al. (2018) Patient-reported outcomes and health status associated with chronic graft-versus-host disease. Haematologica 103:1535-1541
McCune, Jeannine S; Storer, Barry; Thomas, Sushma et al. (2018) Inosine Monophosphate Dehydrogenase Pharmacogenetics in Hematopoietic Cell Transplantation Patients. Biol Blood Marrow Transplant 24:1802-1807
Deegan, Anthony J; Talebi-Liasi, Faezeh; Song, Shaozhen et al. (2018) Optical coherence tomography angiography of normal skin and inflammatory dermatologic conditions. Lasers Surg Med 50:183-193
Leger, Kasey J; Baker, K Scott; Cushing-Haugen, Kara L et al. (2018) Lifestyle factors and subsequent ischemic heart disease risk after hematopoietic cell transplantation. Cancer 124:1507-1515
Schmitt, Michael W; Pritchard, Justin R; Leighow, Scott M et al. (2018) Single-Molecule Sequencing Reveals Patterns of Preexisting Drug Resistance That Suggest Treatment Strategies in Philadelphia-Positive Leukemias. Clin Cancer Res 24:5321-5334
Shaw, Bronwen E; Syrjala, Karen L; Onstad, Lynn E et al. (2018) PROMIS measures can be used to assess symptoms and function in long-term hematopoietic cell transplantation survivors. Cancer 124:841-849
Jamani, Kareem; Onstad, Lynn E; Bar, Merav et al. (2018) Quality of Life of Caregivers of Hematopoietic Cell Transplant Recipients. Biol Blood Marrow Transplant 24:2271-2276
Ogimi, Chikara; Xie, Hu; Leisenring, Wendy M et al. (2018) Initial High Viral Load Is Associated with Prolonged Shedding of Human Rhinovirus in Allogeneic Hematopoietic Cell Transplant Recipients. Biol Blood Marrow Transplant 24:2160-2163
Salter, Alexander I; Pont, Margot J; Riddell, Stanley R (2018) Chimeric antigen receptor-modified T cells: CD19 and the road beyond. Blood 131:2621-2629
Lee, Stephanie J; Nguyen, Tam D; Onstad, Lynn et al. (2018) Success of Immunosuppressive Treatments in Patients with Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant 24:555-562

Showing the most recent 10 out of 1845 publications