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Inherent transcriptional signatures of NK cells are associated with response to IFNα + rivabirin therapy in patients with Hepatitis C Virus.

Ascierto ML, Bozzano F, Bedognetti D, Marras F, Schechterly C, Matsuura K, Picciotto A, Marenco S, Zhao Y, DeGiorgi V, Sommariva M, Moretta L, Wang E, Alter HJ, Marincola FM, De Maria A - J Transl Med (2015)

Bottom Line: In addition, treatment outcome was associated with differences in surface expression of NKp30 and NKG2D.A complex relationship was observed that suggested for extensive post-transcriptional editing.Collectively, inherent/genetic modulation of NK cell transcription is involved in setting the path to divergent treatment outcomes and could become useful to therapeutic advantage.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Differences in the expression of Natural Killer cell receptors have been reported to reflect divergent clinical courses in patients with chronic infections or tumors. However, extensive molecular characterization at the transcriptional level to support this view is lacking. The aim of this work was to characterize baseline differences in purified NK cell transcriptional activity stratified by response to treatment with PEG-IFNα/RBV in patients chronically infected with HCV.

Methods: To this end we here studied by flow cytometer and gene expression profile, phenotypic and transcriptional characteristics of purified NK cells in patients chronically infected with HCV genotype-1 virus who were subsequently treated with PEG-IFNα/RBV. Results were further correlated with divergent clinical response obtained after treatment.

Results: The pre-treatment transcriptional patterns of purified NK cells from patients subsequently undergoing a sustained virologic response (SVR) clearly segregated from those of non-responder (NR) patients. A set of 476 transcripts, including molecules involved in RNA processing, ubiquitination pathways as well as HLA class II signalling were differently expressed among divergent patients. In addition, treatment outcome was associated with differences in surface expression of NKp30 and NKG2D. A complex relationship was observed that suggested for extensive post-transcriptional editing. Only a small number of the NK cell transcripts identified were correlated with chronic HCV infection/replication indicating that inherent transcriptional activity prevails over environment effects such as viral infection.

Conclusions: Collectively, inherent/genetic modulation of NK cell transcription is involved in setting the path to divergent treatment outcomes and could become useful to therapeutic advantage.

No MeSH data available.


Related in: MedlinePlus

Trascriptional profile of NK cells derived from HCV infected patients with diverging treatment response. A) PCA analysis conducted on whole gene dataset expressed by NK cells of Healthy Individuals (HD), baseline responders (SVR) and non-responders (NR) HCV-1 patients. B) Supervised cluster based on 476 genes derived from Student’s t Test (cut off p2 value ≤ 0.005, FC >1.5) SVR vs. NR.
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Fig1: Trascriptional profile of NK cells derived from HCV infected patients with diverging treatment response. A) PCA analysis conducted on whole gene dataset expressed by NK cells of Healthy Individuals (HD), baseline responders (SVR) and non-responders (NR) HCV-1 patients. B) Supervised cluster based on 476 genes derived from Student’s t Test (cut off p2 value ≤ 0.005, FC >1.5) SVR vs. NR.

Mentions: Principal Component Analysis (PCA), a method that identifies gene-expression patterns (principal components) that best explain variance across a data set, was performed on the whole dataset (33,304 transcripts) revealing that pre-treatment transcriptional patterns of purified NK cells were clearly heterogeneous. In particular, transcriptional profiles from patients with subsequent SVR on treatment clearly segregated apart from those of NR patients. Surprisingly, despite the presence of chronic HCV replication, a similar NK transcriptional pattern was found for SVR and HD (Figure 1A).Figure 1


Inherent transcriptional signatures of NK cells are associated with response to IFNα + rivabirin therapy in patients with Hepatitis C Virus.

Ascierto ML, Bozzano F, Bedognetti D, Marras F, Schechterly C, Matsuura K, Picciotto A, Marenco S, Zhao Y, DeGiorgi V, Sommariva M, Moretta L, Wang E, Alter HJ, Marincola FM, De Maria A - J Transl Med (2015)

Trascriptional profile of NK cells derived from HCV infected patients with diverging treatment response. A) PCA analysis conducted on whole gene dataset expressed by NK cells of Healthy Individuals (HD), baseline responders (SVR) and non-responders (NR) HCV-1 patients. B) Supervised cluster based on 476 genes derived from Student’s t Test (cut off p2 value ≤ 0.005, FC >1.5) SVR vs. NR.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4353456&req=5

Fig1: Trascriptional profile of NK cells derived from HCV infected patients with diverging treatment response. A) PCA analysis conducted on whole gene dataset expressed by NK cells of Healthy Individuals (HD), baseline responders (SVR) and non-responders (NR) HCV-1 patients. B) Supervised cluster based on 476 genes derived from Student’s t Test (cut off p2 value ≤ 0.005, FC >1.5) SVR vs. NR.
Mentions: Principal Component Analysis (PCA), a method that identifies gene-expression patterns (principal components) that best explain variance across a data set, was performed on the whole dataset (33,304 transcripts) revealing that pre-treatment transcriptional patterns of purified NK cells were clearly heterogeneous. In particular, transcriptional profiles from patients with subsequent SVR on treatment clearly segregated apart from those of NR patients. Surprisingly, despite the presence of chronic HCV replication, a similar NK transcriptional pattern was found for SVR and HD (Figure 1A).Figure 1

Bottom Line: In addition, treatment outcome was associated with differences in surface expression of NKp30 and NKG2D.A complex relationship was observed that suggested for extensive post-transcriptional editing.Collectively, inherent/genetic modulation of NK cell transcription is involved in setting the path to divergent treatment outcomes and could become useful to therapeutic advantage.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Differences in the expression of Natural Killer cell receptors have been reported to reflect divergent clinical courses in patients with chronic infections or tumors. However, extensive molecular characterization at the transcriptional level to support this view is lacking. The aim of this work was to characterize baseline differences in purified NK cell transcriptional activity stratified by response to treatment with PEG-IFNα/RBV in patients chronically infected with HCV.

Methods: To this end we here studied by flow cytometer and gene expression profile, phenotypic and transcriptional characteristics of purified NK cells in patients chronically infected with HCV genotype-1 virus who were subsequently treated with PEG-IFNα/RBV. Results were further correlated with divergent clinical response obtained after treatment.

Results: The pre-treatment transcriptional patterns of purified NK cells from patients subsequently undergoing a sustained virologic response (SVR) clearly segregated from those of non-responder (NR) patients. A set of 476 transcripts, including molecules involved in RNA processing, ubiquitination pathways as well as HLA class II signalling were differently expressed among divergent patients. In addition, treatment outcome was associated with differences in surface expression of NKp30 and NKG2D. A complex relationship was observed that suggested for extensive post-transcriptional editing. Only a small number of the NK cell transcripts identified were correlated with chronic HCV infection/replication indicating that inherent transcriptional activity prevails over environment effects such as viral infection.

Conclusions: Collectively, inherent/genetic modulation of NK cell transcription is involved in setting the path to divergent treatment outcomes and could become useful to therapeutic advantage.

No MeSH data available.


Related in: MedlinePlus