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Apoptotic effects of antilymphocyte globulins on human pro-inflammatory CD4+CD28- T-cells.

Duftner C, Dejaco C, Hengster P, Bijuklic K, Joannidis M, Margreiter R, Schirmer M - PLoS ONE (2012)

Bottom Line: In vivo, peripheral levels of CD3(+)CD4(+)CD28(-) T-cells decreased from 3.7 ± 7.1% before to 0 ± 0% six hours after ATG-F application (P = 0.043) in 5 ATG-F treated but not in 11 control patients (2.9 ± 2.9% vs. 3.9 ± 3.0%).In summary, in vivo depletion of peripheral CD3(+)CD4(+)CD28(-) T-cells by ATG-F in transplant recipients was paralleled in vitro by ATG-F induced apoptosis.CD25 expression and chemokine receptor down-regulation in CD4(+)CD28(-) T-cells only partly explain the underlying mechanism.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Clinic of Internal Medicine I, Innsbruck Medical University, Innsbruck, Austria.

ABSTRACT

Background: Pro-inflammatory, cytotoxic CD4(+)CD28(-) T-cells with known defects in apoptosis have been investigated as markers of premature immuno-senescence in various immune-mediated diseases. In this study we evaluated the influence of polyclonal antilymphocyte globulins (ATG-Fresenius, ATG-F) on CD4(+)CD28(-) T-cells in vivo and in vitro.

Principal findings: Surface and intracellular three colour fluorescence activated cell sorting analyses of peripheral blood mononuclear cells from 16 consecutive transplant recipients and short-term cell lines were performed. In vivo, peripheral levels of CD3(+)CD4(+)CD28(-) T-cells decreased from 3.7 ± 7.1% before to 0 ± 0% six hours after ATG-F application (P = 0.043) in 5 ATG-F treated but not in 11 control patients (2.9 ± 2.9% vs. 3.9 ± 3.0%). In vitro, ATG-F induced apoptosis even in CD4(+)CD28(-) T-cells, which was 4.3-times higher than in CD4(+)CD28(+) T-cells. ATG-F evoked apoptosis was partially reversed by the broad-spectrum caspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk) and prednisolon-21-hydrogensuccinate. ATG-F triggered CD25 expression and production of pro-inflammatory cytokines, and induced down-regulation of the type 1 chemokine receptors CXCR-3, CCR-5, CX3CR-1 and the central memory adhesion molecule CD62L predominately in CD4(+)CD28(-) T-cells.

Conclusion: In summary, in vivo depletion of peripheral CD3(+)CD4(+)CD28(-) T-cells by ATG-F in transplant recipients was paralleled in vitro by ATG-F induced apoptosis. CD25 expression and chemokine receptor down-regulation in CD4(+)CD28(-) T-cells only partly explain the underlying mechanism.

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Treatment with polyclonal antilymphocyte globulins induces depletion of circulating CD3+CD4+CD28− T-cells in transplant recipients.Prevalences of peripheral circulating CD3+CD4+CD28− T-cells in 16 age- and sex-matched healthy controls, 5 allograft recipients before and 6 hours after the application of ATG-F and 11 control patients before and 6 hours after organ transplantation. Data are given as mean±standard error of the mean (SEM).
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pone-0033939-g001: Treatment with polyclonal antilymphocyte globulins induces depletion of circulating CD3+CD4+CD28− T-cells in transplant recipients.Prevalences of peripheral circulating CD3+CD4+CD28− T-cells in 16 age- and sex-matched healthy controls, 5 allograft recipients before and 6 hours after the application of ATG-F and 11 control patients before and 6 hours after organ transplantation. Data are given as mean±standard error of the mean (SEM).

Mentions: In this small pilot study the prevalence of peripheral circulating CD3+CD4+CD28− T-cells was tested before and 6 hours after organ transplantation with and without application of ATG-F. Results of a blinded laboratory investigator showed that ATG-F treatment resulted in a total decrement of peripheral T-cells. Peripheral levels of circulating CD3+CD4+CD28− T-cells decreased from 3.7±7.1% to 0±0% (P = 0.043) in ATG-F treated patients, but did not decrease in control patients (2.9±2.9% and 3.9±3.0% before and after organ transplantation, respectively, Figure 1).


Apoptotic effects of antilymphocyte globulins on human pro-inflammatory CD4+CD28- T-cells.

Duftner C, Dejaco C, Hengster P, Bijuklic K, Joannidis M, Margreiter R, Schirmer M - PLoS ONE (2012)

Treatment with polyclonal antilymphocyte globulins induces depletion of circulating CD3+CD4+CD28− T-cells in transplant recipients.Prevalences of peripheral circulating CD3+CD4+CD28− T-cells in 16 age- and sex-matched healthy controls, 5 allograft recipients before and 6 hours after the application of ATG-F and 11 control patients before and 6 hours after organ transplantation. Data are given as mean±standard error of the mean (SEM).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3316508&req=5

pone-0033939-g001: Treatment with polyclonal antilymphocyte globulins induces depletion of circulating CD3+CD4+CD28− T-cells in transplant recipients.Prevalences of peripheral circulating CD3+CD4+CD28− T-cells in 16 age- and sex-matched healthy controls, 5 allograft recipients before and 6 hours after the application of ATG-F and 11 control patients before and 6 hours after organ transplantation. Data are given as mean±standard error of the mean (SEM).
Mentions: In this small pilot study the prevalence of peripheral circulating CD3+CD4+CD28− T-cells was tested before and 6 hours after organ transplantation with and without application of ATG-F. Results of a blinded laboratory investigator showed that ATG-F treatment resulted in a total decrement of peripheral T-cells. Peripheral levels of circulating CD3+CD4+CD28− T-cells decreased from 3.7±7.1% to 0±0% (P = 0.043) in ATG-F treated patients, but did not decrease in control patients (2.9±2.9% and 3.9±3.0% before and after organ transplantation, respectively, Figure 1).

Bottom Line: In vivo, peripheral levels of CD3(+)CD4(+)CD28(-) T-cells decreased from 3.7 ± 7.1% before to 0 ± 0% six hours after ATG-F application (P = 0.043) in 5 ATG-F treated but not in 11 control patients (2.9 ± 2.9% vs. 3.9 ± 3.0%).In summary, in vivo depletion of peripheral CD3(+)CD4(+)CD28(-) T-cells by ATG-F in transplant recipients was paralleled in vitro by ATG-F induced apoptosis.CD25 expression and chemokine receptor down-regulation in CD4(+)CD28(-) T-cells only partly explain the underlying mechanism.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Clinic of Internal Medicine I, Innsbruck Medical University, Innsbruck, Austria.

ABSTRACT

Background: Pro-inflammatory, cytotoxic CD4(+)CD28(-) T-cells with known defects in apoptosis have been investigated as markers of premature immuno-senescence in various immune-mediated diseases. In this study we evaluated the influence of polyclonal antilymphocyte globulins (ATG-Fresenius, ATG-F) on CD4(+)CD28(-) T-cells in vivo and in vitro.

Principal findings: Surface and intracellular three colour fluorescence activated cell sorting analyses of peripheral blood mononuclear cells from 16 consecutive transplant recipients and short-term cell lines were performed. In vivo, peripheral levels of CD3(+)CD4(+)CD28(-) T-cells decreased from 3.7 ± 7.1% before to 0 ± 0% six hours after ATG-F application (P = 0.043) in 5 ATG-F treated but not in 11 control patients (2.9 ± 2.9% vs. 3.9 ± 3.0%). In vitro, ATG-F induced apoptosis even in CD4(+)CD28(-) T-cells, which was 4.3-times higher than in CD4(+)CD28(+) T-cells. ATG-F evoked apoptosis was partially reversed by the broad-spectrum caspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk) and prednisolon-21-hydrogensuccinate. ATG-F triggered CD25 expression and production of pro-inflammatory cytokines, and induced down-regulation of the type 1 chemokine receptors CXCR-3, CCR-5, CX3CR-1 and the central memory adhesion molecule CD62L predominately in CD4(+)CD28(-) T-cells.

Conclusion: In summary, in vivo depletion of peripheral CD3(+)CD4(+)CD28(-) T-cells by ATG-F in transplant recipients was paralleled in vitro by ATG-F induced apoptosis. CD25 expression and chemokine receptor down-regulation in CD4(+)CD28(-) T-cells only partly explain the underlying mechanism.

Show MeSH
Related in: MedlinePlus