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Longitudinal analysis of whole blood transcriptomes to explore molecular signatures associated with acute renal allograft rejection.

Shin H, Günther O, Hollander Z, Wilson-McManus JE, Ng RT, Balshaw R, Keown PA, McMaster R, McManus BM, Isbel NM, Knoll G, Tebbutt SJ - Bioinform Biol Insights (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

No MeSH data available.


Related in: MedlinePlus

A. PCA plot generated by the representative set of the most significant genes from both neutrophil and lymphocyte signatures shows clear separation of ARs from NRs. B. Average gene expression levels in 3 time periods: pretransplant (BL), posttransplant up to rejection (Pre-RJ and RJ), and postrejection (Post-RJ). A representative set of the neutrophil signature genes show upregulation from BL towards rejection and downregulation after rejection treatment in AR samples; these same genes show a more stable level of expression in NR samples. C. A representative set of the lymphocyte signature genes show downregulation from BL towards rejection and upregulation after rejection treatment in AR samples; these same genes show more stable expression in NR samples.
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f3-bbi-8-2014-017: A. PCA plot generated by the representative set of the most significant genes from both neutrophil and lymphocyte signatures shows clear separation of ARs from NRs. B. Average gene expression levels in 3 time periods: pretransplant (BL), posttransplant up to rejection (Pre-RJ and RJ), and postrejection (Post-RJ). A representative set of the neutrophil signature genes show upregulation from BL towards rejection and downregulation after rejection treatment in AR samples; these same genes show a more stable level of expression in NR samples. C. A representative set of the lymphocyte signature genes show downregulation from BL towards rejection and upregulation after rejection treatment in AR samples; these same genes show more stable expression in NR samples.

Mentions: We reasoned that if the differential gene expression signatures we have described were specifically associated with acute allograft rejection, these signatures might be modulated in response to rejection therapies applied after primary confirmation of the rejection episode. To test this hypothesis, we interrogated patient transcriptome data collected after the time that rejection was confirmed and when rejection treatments were initiated. A PCA plot generated using the most significantly differentially expressed genes from both neutrophil and lymphocyte molecular signatures revealed a clear separation of the 8 AR patients and their matched 8 NR counterparts (Fig. 3A). Additionally, the expression levels of these genes were altered in AR patients undergoing treatment for rejection (ie, treated with solumedrol, prednisone, or antithymocyte globulin [ATG]). Specifically, genes upregulated in the neutrophil signature showed a decreased expression after rejection treatment (Fig. 3B). Conversely, downregulated genes associated with the lymphocyte gene signature exhibited a general increase in expression post rejection treatment (Fig. 3C).


Longitudinal analysis of whole blood transcriptomes to explore molecular signatures associated with acute renal allograft rejection.

Shin H, Günther O, Hollander Z, Wilson-McManus JE, Ng RT, Balshaw R, Keown PA, McMaster R, McManus BM, Isbel NM, Knoll G, Tebbutt SJ - Bioinform Biol Insights (2014)

A. PCA plot generated by the representative set of the most significant genes from both neutrophil and lymphocyte signatures shows clear separation of ARs from NRs. B. Average gene expression levels in 3 time periods: pretransplant (BL), posttransplant up to rejection (Pre-RJ and RJ), and postrejection (Post-RJ). A representative set of the neutrophil signature genes show upregulation from BL towards rejection and downregulation after rejection treatment in AR samples; these same genes show a more stable level of expression in NR samples. C. A representative set of the lymphocyte signature genes show downregulation from BL towards rejection and upregulation after rejection treatment in AR samples; these same genes show more stable expression in NR samples.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3921155&req=5

f3-bbi-8-2014-017: A. PCA plot generated by the representative set of the most significant genes from both neutrophil and lymphocyte signatures shows clear separation of ARs from NRs. B. Average gene expression levels in 3 time periods: pretransplant (BL), posttransplant up to rejection (Pre-RJ and RJ), and postrejection (Post-RJ). A representative set of the neutrophil signature genes show upregulation from BL towards rejection and downregulation after rejection treatment in AR samples; these same genes show a more stable level of expression in NR samples. C. A representative set of the lymphocyte signature genes show downregulation from BL towards rejection and upregulation after rejection treatment in AR samples; these same genes show more stable expression in NR samples.
Mentions: We reasoned that if the differential gene expression signatures we have described were specifically associated with acute allograft rejection, these signatures might be modulated in response to rejection therapies applied after primary confirmation of the rejection episode. To test this hypothesis, we interrogated patient transcriptome data collected after the time that rejection was confirmed and when rejection treatments were initiated. A PCA plot generated using the most significantly differentially expressed genes from both neutrophil and lymphocyte molecular signatures revealed a clear separation of the 8 AR patients and their matched 8 NR counterparts (Fig. 3A). Additionally, the expression levels of these genes were altered in AR patients undergoing treatment for rejection (ie, treated with solumedrol, prednisone, or antithymocyte globulin [ATG]). Specifically, genes upregulated in the neutrophil signature showed a decreased expression after rejection treatment (Fig. 3B). Conversely, downregulated genes associated with the lymphocyte gene signature exhibited a general increase in expression post rejection treatment (Fig. 3C).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

No MeSH data available.


Related in: MedlinePlus