Limits...
NK Cells of Kidney Transplant Recipients Display an Activated Phenotype that Is Influenced by Immunosuppression and Pathological Staging.

Hoffmann U, Neudörfl C, Daemen K, Keil J, Stevanovic-Meyer M, Lehner F, Haller H, Blume C, Falk CS - PLoS ONE (2015)

Bottom Line: Upon in vitro stimulation via Ca++-dependent signals, down-modulation of CD16 was associated with induction of interferon (IFN)-γ expression.However, secretion of other cytokines like IL-13, IL-17, IL-22 and IL-31 was significantly reduced compared to healthy donors.Thus, immunosuppressive treatment affects NK cell function at the level of NFAT-dependent gene expression whereby calcineurin inhibitors primarily impair cytokine secretion while mTOR inhibitors have only marginal effects.

View Article: PubMed Central - PubMed

Affiliation: Institute of Transplant Immunology, IFB-Tx, Hannover Medical School Hannover, Hannover, Germany.

ABSTRACT
To explore phenotype and function of NK cells in kidney transplant recipients, we investigated the peripheral NK cell repertoire, capacity to respond to various stimuli and impact of immunosuppressive drugs on NK cell activity in kidney transplant recipients. CD56dim NK cells of kidney transplanted patients displayed an activated phenotype characterized by significantly decreased surface expression of CD16 (p=0.0003), CD226 (p<0.0001), CD161 (p=0.0139) and simultaneously increased expression of activation markers like HLA-DR (p=0.0011) and CD25 (p=0.0015). Upon in vitro stimulation via Ca++-dependent signals, down-modulation of CD16 was associated with induction of interferon (IFN)-γ expression. CD16 modulation and secretion of NFAT-dependent cytokines such as IFN-γ, TNF-α, IL-10 and IL-31 were significantly suppressed by treatment of isolated NK cells with calcineurin inhibitors but not with mTOR inhibitors. In kidney transplant recipients, IFN-γ production was retained in response to HLA class I-negative target cells and to non-specific stimuli, respectively. However, secretion of other cytokines like IL-13, IL-17, IL-22 and IL-31 was significantly reduced compared to healthy donors. In contrast to suppression of cytokine expression at the transcriptional level, cytotoxin release, i.e. perforin, granzyme A/B, was not affected by immunosuppression in vitro and in vivo in patients as well as in healthy donors. Thus, immunosuppressive treatment affects NK cell function at the level of NFAT-dependent gene expression whereby calcineurin inhibitors primarily impair cytokine secretion while mTOR inhibitors have only marginal effects. Taken together, NK cells may serve as indicators for immunosuppression and may facilitate a personalized adjustment of immunosuppressive medication in kidney transplant recipients.

No MeSH data available.


Related in: MedlinePlus

Cytokine response of PBMC derived from KTx patients is partially impaired compared to healthy individuals.PBMC of KTx patients (n = 4, white bars) were stimulated for 24h with P/I or left untreated as described, supernatants were collected, analyzed for cytokine production and compared to P/I stimulated PBMCs of healthy donors (n = 6, grey bars). Data are represented as mean values compared by two-sided One-way ANOVA test with Tukey’s post test (* = p≤0.05, ** = p≤0.01, *** = p≤0.001, only significant values are shown).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492590&req=5

pone.0132484.g005: Cytokine response of PBMC derived from KTx patients is partially impaired compared to healthy individuals.PBMC of KTx patients (n = 4, white bars) were stimulated for 24h with P/I or left untreated as described, supernatants were collected, analyzed for cytokine production and compared to P/I stimulated PBMCs of healthy donors (n = 6, grey bars). Data are represented as mean values compared by two-sided One-way ANOVA test with Tukey’s post test (* = p≤0.05, ** = p≤0.01, *** = p≤0.001, only significant values are shown).

Mentions: The multiplex analyses of supernatants from P/I stimulated PBMC of KTx recipients confirmed our observations of intracellular IFN-γ production (Fig 2C). Unstimulated PBMC of KTx patients showed slightly, though not significantly, elevated cytokine levels. The capacity to respond to P/I stimulation was selectively retained for certain cytokines (Fig 5): while induction of IFN-γ and IL-21 secretion as well as shedding of IL-2Rα was comparable, secretion of other cytokines was reduced in KTx patients compared to healthy individuals. Significantly lower concentrations were detected for IL-13, IL-22, IL-31 (Fig 5) and IL-4 (S5B Fig). Though not reaching statistical significance, secretion of TNF-α, IL-17A, IL-10 and IL-17F was impaired in KTx recipients suggesting that immunosuppressive treatment differentially affects cytokine responses and may, thus, impinge on the Th1/Th2/Th17 balance.


NK Cells of Kidney Transplant Recipients Display an Activated Phenotype that Is Influenced by Immunosuppression and Pathological Staging.

Hoffmann U, Neudörfl C, Daemen K, Keil J, Stevanovic-Meyer M, Lehner F, Haller H, Blume C, Falk CS - PLoS ONE (2015)

Cytokine response of PBMC derived from KTx patients is partially impaired compared to healthy individuals.PBMC of KTx patients (n = 4, white bars) were stimulated for 24h with P/I or left untreated as described, supernatants were collected, analyzed for cytokine production and compared to P/I stimulated PBMCs of healthy donors (n = 6, grey bars). Data are represented as mean values compared by two-sided One-way ANOVA test with Tukey’s post test (* = p≤0.05, ** = p≤0.01, *** = p≤0.001, only significant values are shown).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492590&req=5

pone.0132484.g005: Cytokine response of PBMC derived from KTx patients is partially impaired compared to healthy individuals.PBMC of KTx patients (n = 4, white bars) were stimulated for 24h with P/I or left untreated as described, supernatants were collected, analyzed for cytokine production and compared to P/I stimulated PBMCs of healthy donors (n = 6, grey bars). Data are represented as mean values compared by two-sided One-way ANOVA test with Tukey’s post test (* = p≤0.05, ** = p≤0.01, *** = p≤0.001, only significant values are shown).
Mentions: The multiplex analyses of supernatants from P/I stimulated PBMC of KTx recipients confirmed our observations of intracellular IFN-γ production (Fig 2C). Unstimulated PBMC of KTx patients showed slightly, though not significantly, elevated cytokine levels. The capacity to respond to P/I stimulation was selectively retained for certain cytokines (Fig 5): while induction of IFN-γ and IL-21 secretion as well as shedding of IL-2Rα was comparable, secretion of other cytokines was reduced in KTx patients compared to healthy individuals. Significantly lower concentrations were detected for IL-13, IL-22, IL-31 (Fig 5) and IL-4 (S5B Fig). Though not reaching statistical significance, secretion of TNF-α, IL-17A, IL-10 and IL-17F was impaired in KTx recipients suggesting that immunosuppressive treatment differentially affects cytokine responses and may, thus, impinge on the Th1/Th2/Th17 balance.

Bottom Line: Upon in vitro stimulation via Ca++-dependent signals, down-modulation of CD16 was associated with induction of interferon (IFN)-γ expression.However, secretion of other cytokines like IL-13, IL-17, IL-22 and IL-31 was significantly reduced compared to healthy donors.Thus, immunosuppressive treatment affects NK cell function at the level of NFAT-dependent gene expression whereby calcineurin inhibitors primarily impair cytokine secretion while mTOR inhibitors have only marginal effects.

View Article: PubMed Central - PubMed

Affiliation: Institute of Transplant Immunology, IFB-Tx, Hannover Medical School Hannover, Hannover, Germany.

ABSTRACT
To explore phenotype and function of NK cells in kidney transplant recipients, we investigated the peripheral NK cell repertoire, capacity to respond to various stimuli and impact of immunosuppressive drugs on NK cell activity in kidney transplant recipients. CD56dim NK cells of kidney transplanted patients displayed an activated phenotype characterized by significantly decreased surface expression of CD16 (p=0.0003), CD226 (p<0.0001), CD161 (p=0.0139) and simultaneously increased expression of activation markers like HLA-DR (p=0.0011) and CD25 (p=0.0015). Upon in vitro stimulation via Ca++-dependent signals, down-modulation of CD16 was associated with induction of interferon (IFN)-γ expression. CD16 modulation and secretion of NFAT-dependent cytokines such as IFN-γ, TNF-α, IL-10 and IL-31 were significantly suppressed by treatment of isolated NK cells with calcineurin inhibitors but not with mTOR inhibitors. In kidney transplant recipients, IFN-γ production was retained in response to HLA class I-negative target cells and to non-specific stimuli, respectively. However, secretion of other cytokines like IL-13, IL-17, IL-22 and IL-31 was significantly reduced compared to healthy donors. In contrast to suppression of cytokine expression at the transcriptional level, cytotoxin release, i.e. perforin, granzyme A/B, was not affected by immunosuppression in vitro and in vivo in patients as well as in healthy donors. Thus, immunosuppressive treatment affects NK cell function at the level of NFAT-dependent gene expression whereby calcineurin inhibitors primarily impair cytokine secretion while mTOR inhibitors have only marginal effects. Taken together, NK cells may serve as indicators for immunosuppression and may facilitate a personalized adjustment of immunosuppressive medication in kidney transplant recipients.

No MeSH data available.


Related in: MedlinePlus