title: Longitudinal analysis of whole blood transcriptomes to explore molecular signatures associated with acute renal allograft rejection.
abstract: In this study, we explored a time course of peripheral whole blood transcriptomes from kidney transplantation patients who either experienced an acute rejection episode or did not in order to better delineate the immunological and biological processes measureable in blood leukocytes that are associated with acute renal allograft rejection. Using microarrays, we generated gene expression data from 24 acute rejectors and 24 nonrejectors. We filtered the data to obtain the most unambiguous and robustly expressing probe sets and selected a subset of patients with the clearest phenotype. We then performed a data-driven exploratory analysis using data reduction and differential gene expression analysis tools in order to reveal gene expression signatures associated with acute allograft rejection. Using a template-matching algorithm, we then expanded our analysis to include time course data, identifying genes whose expression is modulated leading up to acute rejection. We have identified molecular phenotypes associated with acute renal allograft rejection, including a significantly upregulated signature of neutrophil activation and accumulation following transplant surgery that is common to both acute rejectors and nonrejectors. Our analysis shows that this expression signature appears to stabilize over time in nonrejectors but persists in patients who go on to reject the transplanted organ. In addition, we describe an expression signature characteristic of lymphocyte activity and proliferation. This lymphocyte signature is significantly downregulated in both acute rejectors and nonrejectors following surgery; however, patients who go on to reject the organ show a persistent downregulation of this signature relative to the neutrophil signature.
authors: NCE CECR PROOF Centre of Excellence, Vancouver, BC. ; University of British Columbia (UBC) Department of Medicine, Vancouver, BC. ; Institute for HEART + LUNG Health, Vancouver, BC.
authors: Heesun
authors: H
authors: Shin
authors: NCE CECR PROOF Centre of Excellence, Vancouver, BC.
authors: Oliver
authors: O
authors: Günther
authors: NCE CECR PROOF Centre of Excellence, Vancouver, BC. ; UBC Department of Pathology and Laboratory Medicine, Vancouver, BC. ; Institute for HEART + LUNG Health, Vancouver, BC.
authors: Zsuzsanna
authors: Z
authors: Hollander
authors: NCE CECR PROOF Centre of Excellence, Vancouver, BC.
authors: Janet E
authors: JE
authors: Wilson-McManus
authors: NCE CECR PROOF Centre of Excellence, Vancouver, BC. ; UBC Department of Computer Science, Vancouver, BC.
authors: Raymond T
authors: RT
authors: Ng
authors: NCE CECR PROOF Centre of Excellence, Vancouver, BC. ; UBC Department of Statistics, Vancouver, BC.
authors: Robert
authors: R
authors: Balshaw
authors: NCE CECR PROOF Centre of Excellence, Vancouver, BC. ; University of British Columbia (UBC) Department of Medicine, Vancouver, BC.
authors: Paul A
authors: PA
authors: Keown
authors: NCE CECR PROOF Centre of Excellence, Vancouver, BC. ; UBC Department of Medical Genetics, Vancouver, BC.
authors: Robert
authors: R
authors: McMaster
authors: NCE CECR PROOF Centre of Excellence, Vancouver, BC. ; UBC Department of Pathology and Laboratory Medicine, Vancouver, BC. ; Institute for HEART + LUNG Health, Vancouver, BC.
authors: Bruce M
authors: BM
authors: McManus
authors: Department of Nephrology, Princess Alexandra Hospital, and University of Queensland, Brisbane Australia.
authors: Nicole M
authors: NM
authors: Isbel
authors: The Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors: Greg
authors: G
authors: Knoll
authors: NCE CECR PROOF Centre of Excellence, Vancouver, BC. ; University of British Columbia (UBC) Department of Medicine, Vancouver, BC. ; Institute for HEART + LUNG Health, Vancouver, BC.
authors: Scott J
authors: SJ
authors: Tebbutt
keywords: blood transcriptomics; kidney transplant rejection; microarray; neutrophil to lymphocyte ratio; peripheral whole blood