Chronic graft-versus-host disease (cGVHD) occurs in 50-70% of patients following allogeneic hematopoietic stem cell transplantation (HSCT) and is a major cause of morbidity and mortality. The clinical manifestations of cGVHD are diverse and variable, and the diagnosis, staging and assessment of response to therapeutic interventions have been difficult to standardize. There are no signs or symptoms or diagnostic tools that predict the development or severity of cGVHD, or the need for immune suppression therapy. The goal of this proposal is to address these unmet needs by identifying novel biomarkers that are associated with the onset and severity of cGVHD. The initial phase of study will consist of a parallel discovery strategy that employs a genome-wide analysis of transcriptional changes in peripheral blood mononuclear cells (PBMC) together with a high-resolution, high-sensitivity quantitative proteomic analysis to identify informative proteins in plasma that correlate with disease activity. These transcriptional changes and proteins will be prioritized to develop a list of candidates for second phase validation studies to confirm and further define a panel of markers that together provide high sensitivity and specificity for the diagnosis of cGVHD and the prediction of severity and/or treatment response.
Aim 1 of this study is to identify novel biomarkers in peripheral blood for the diagnosis of cGVHD using dual approaches: 1a) analysis of global gene expression and alternate splicing in mononuclear leucocytes;and 1b) quantitative in-depth profiling of circulating proteins in plasma. The transcriptional analysis will be performed on PBMC using the Affymetrix Human Exon 1.0 ST array, and the proteomic analysis will be performed on plasma by mass spectrometry.
Aim 2 will focus on the validation of candidate biomarkers identified in an independent, multicenter cohort study of cGVHD. Candidate genes and alternate splice variants will be validated by PCR-based assays, and candidate proteins will be validated by antibody-based assays. This application is submitted in response to RFA-HL-08-001, titled """"""""Ancillary Studies in Clinical trials (R01)."""""""" We are proposing a biomarker discovery and validation project that is focused on cGVHD occurring after allo HSCT. The subjects for this study, cases and controls, will be enrolled in a separate NIH funded multi-center study titled """"""""Improving outcomes assessment in chronic GVHD"""""""" (R01-CA118953;Dr. Stephanie Lee, PI). Participating Centers include the Dana-Farber Cancer Institute (DFCI), the Seattle Cancer Care Alliance (SCCA)/Fred Hutchinson Cancer Research Center (FHCRC), Stanford University and the University of Minnesota. Total enrollment across the sites will reach 336 incident and 336 prevalent cGVHD cases. Patients will be followed for three years, and systematically evaluated for cGVHD status and response to cGVHD therapy. Chronic graft-versus-host disease (cGVHD) occurs in 50-70% of patients following allogeneic hematopoietic stem cell transplantation (HSCT) and is a major cause of morbidity and mortality. As the utilization of HSCT and number of HSCT survivors increases, the issue of cGVHD becomes a greater concern not only to patients and their families but also to the specialized physicians and health care facilities responsible for their care. The studies proposed here are aimed at improving methods for the diagnosis of cGVHD, monitoring disease activity and the effectiveness of cGVHD therapy. These studies may also yield insights into the underlying disorders responsible for cGVHD and thereby suggest new treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094260-04
Application #
8081764
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M2))
Program Officer
Wagner, Elizabeth
Project Start
2008-07-17
Project End
2012-12-30
Budget Start
2011-07-01
Budget End
2012-12-30
Support Year
4
Fiscal Year
2011
Total Cost
$440,000
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Inamoto, Yoshihiro; Martin, Paul J; Paczesny, Sophie et al. (2017) Association of Plasma CD163 Concentration with De Novo-Onset Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant 23:1250-1256
McDonald, George B; Tabellini, Laura; Storer, Barry E et al. (2017) Predictive Value of Clinical Findings and Plasma Biomarkers after Fourteen Days of Prednisone Treatment for Acute Graft-versus-host Disease. Biol Blood Marrow Transplant 23:1257-1263
Liu, X; Yue, Z; Yu, J et al. (2016) Proteomic Characterization Reveals That MMP-3 Correlates With Bronchiolitis Obliterans Syndrome Following Allogeneic Hematopoietic Cell and Lung Transplantation. Am J Transplant 16:2342-51
McDonald, George B; Tabellini, Laura; Storer, Barry E et al. (2015) Plasma biomarkers of acute GVHD and nonrelapse mortality: predictive value of measurements before GVHD onset and treatment. Blood 126:113-20
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
Hansen, John A; Hanash, Samir M; Tabellini, Laura et al. (2013) A novel soluble form of Tim-3 associated with severe graft-versus-host disease. Biol Blood Marrow Transplant 19:1323-30
Chien, Jason W; Zhang, Xinyi Cindy; Fan, Wenhong et al. (2012) Evaluation of published single nucleotide polymorphisms associated with acute GVHD. Blood 119:5311-9
Warren, Edus H; Zhang, Xinyi Cindy; Li, Shuying et al. (2012) Effect of MHC and non-MHC donor/recipient genetic disparity on the outcome of allogeneic HCT. Blood 120:2796-806
Grogan, Bryan M; Tabellini, Laura; Storer, Barry et al. (2011) Activation and expansion of CD8(+) T effector cells in patients with chronic graft-versus-host disease. Biol Blood Marrow Transplant 17:1121-32
Chronic GVHD Consortium (2011) Rationale and design of the chronic GVHD cohort study: improving outcomes assessment in chronic GVHD. Biol Blood Marrow Transplant 17:1114-20

Showing the most recent 10 out of 16 publications