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Levels of CMV specific CD4 T cells are dynamic and correlate with CMV viremia after allogeneic stem cell transplantation.

Widmann T, Sester U, Gärtner BC, Schubert J, Pfreundschuh M, Köhler H, Sester M - PLoS ONE (2008)

Bottom Line: In contrast, CMV-peptide specific CD8 T cells did not show any association with viremia (p = 0.82).Interestingly, therapeutic dosages of cyclosporine A and corticosteroids led to a dose-dependent reduction of CMV-specific T-cell functions, indicating a causal link between intensified immunosuppressive treatment and CMV reactivation.In conclusion, levels of CMV-specific CD4 T cells inversely correlate with reactivation episodes and may represent a valuable measure to individually guide antiviral therapy after stem cell transplantation.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine I, University Clinics of the Saarland, Homburg, Germany.

ABSTRACT
Cytomegalovirus (CMV) infection is the most frequent viral complication in patients after allogeneic stem cell transplantation. As CMV replication is tightly controlled by the cellular arm of specific immunity, the kinetics of CMV-specific T cells in association with individual reactivation episodes were prospectively analyzed in 40 allogeneic transplant recipients in a routine clinical setting and evaluated as determinant of impaired CMV control. Antigen-specific CD4 and CD8 T cells were quantified directly from whole blood using intracellular cytokine staining after specific stimulation and MHC class I multimers, respectively. Highly dynamic intraindividual changes of CMV-specific CD4 T cells were observed in patients experiencing CMV viremia. Episodes of CMV reactivation were associated with a drop of CMV-specific CD4 T cells that re-increased after viral clearance (p<0.0001). Furthermore, levels of CMV-specific CD4 T cells at the onset of viremia inversely correlated with peak viral load thereafter (p = 0.02). In contrast, CMV-peptide specific CD8 T cells did not show any association with viremia (p = 0.82). Interestingly, therapeutic dosages of cyclosporine A and corticosteroids led to a dose-dependent reduction of CMV-specific T-cell functions, indicating a causal link between intensified immunosuppressive treatment and CMV reactivation. In conclusion, levels of CMV-specific CD4 T cells inversely correlate with reactivation episodes and may represent a valuable measure to individually guide antiviral therapy after stem cell transplantation.

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Combined immunosuppression with cyclosporine A and methylprednisolone contributes to a decrease in CMV specific CD4 T-cell function.CMV specific CD4 T cells reactivity from six immunocompetent CMV seropositive individuals were analyzed directly from whole blood supplemented with or without 180 ng/ml cyclosporine A (CyA) in the absence or presence of increasing dosages of methylprednisolone (MP). A The mean percentage of IFN-γ producing CD4 T cells (including standard error of the mean, SEM) and B the mean percentage of BrdU positive, proliferating CD4 T cells (including SEM) was analyzed after 36 h of stimulation using flow-cytometry.
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pone-0003634-g003: Combined immunosuppression with cyclosporine A and methylprednisolone contributes to a decrease in CMV specific CD4 T-cell function.CMV specific CD4 T cells reactivity from six immunocompetent CMV seropositive individuals were analyzed directly from whole blood supplemented with or without 180 ng/ml cyclosporine A (CyA) in the absence or presence of increasing dosages of methylprednisolone (MP). A The mean percentage of IFN-γ producing CD4 T cells (including standard error of the mean, SEM) and B the mean percentage of BrdU positive, proliferating CD4 T cells (including SEM) was analyzed after 36 h of stimulation using flow-cytometry.

Mentions: Stem cell transplant recipients who experience acute GvHD receive corticosteroids in addition to their established cyclosporine A (CyA) based immunosuppressive drug regimen. As this intensified treatment may favour viral replication, the direct impact of therapeutic levels of these immunosuppressive drugs on antigen-specific effector functions was analyzed in a whole blood test (figure 3, n = 6 healthy CMV seropositive individuals). The suppressive effect of 180 ng/ml cyclosporine A in the presence or absence of 0.4, 2, or 10 ng/ml of methylprednisolone (MP, equivalent to 0.4 mg/kg, 2 mg/kg and 10 mg/kg) was analyzed on CMV specific induction of IFN-γ (figure 3A) and on CMV specific T-cell proliferation (figure 3B) after 36 h of stimulation. Incubation with cyclosporine A reduced the percentage of IFN-γ positive CD4 T cells from 0.87±0.52% to 0.55±0.37%. The addition of methylprednisolone led to a further decrease in a dose dependent manner (0.37±0.27%, 0.28±0.20%, and 0.31±0.25% for 0.4, 2 and 10 ng/ml MP; p = 0.007, figure 3A). Similarly, the percentage of BrdU positive T cells after CMV specific stimulation was reduced upon incubation with CyA and MP, although this reduction did not reach statistical significance (figure 3B). Together these data illustrate that immunosuppressive drugs and drug combinations in clinically relevant concentrations contribute to a direct suppression of T-cell function.


Levels of CMV specific CD4 T cells are dynamic and correlate with CMV viremia after allogeneic stem cell transplantation.

Widmann T, Sester U, Gärtner BC, Schubert J, Pfreundschuh M, Köhler H, Sester M - PLoS ONE (2008)

Combined immunosuppression with cyclosporine A and methylprednisolone contributes to a decrease in CMV specific CD4 T-cell function.CMV specific CD4 T cells reactivity from six immunocompetent CMV seropositive individuals were analyzed directly from whole blood supplemented with or without 180 ng/ml cyclosporine A (CyA) in the absence or presence of increasing dosages of methylprednisolone (MP). A The mean percentage of IFN-γ producing CD4 T cells (including standard error of the mean, SEM) and B the mean percentage of BrdU positive, proliferating CD4 T cells (including SEM) was analyzed after 36 h of stimulation using flow-cytometry.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2572846&req=5

pone-0003634-g003: Combined immunosuppression with cyclosporine A and methylprednisolone contributes to a decrease in CMV specific CD4 T-cell function.CMV specific CD4 T cells reactivity from six immunocompetent CMV seropositive individuals were analyzed directly from whole blood supplemented with or without 180 ng/ml cyclosporine A (CyA) in the absence or presence of increasing dosages of methylprednisolone (MP). A The mean percentage of IFN-γ producing CD4 T cells (including standard error of the mean, SEM) and B the mean percentage of BrdU positive, proliferating CD4 T cells (including SEM) was analyzed after 36 h of stimulation using flow-cytometry.
Mentions: Stem cell transplant recipients who experience acute GvHD receive corticosteroids in addition to their established cyclosporine A (CyA) based immunosuppressive drug regimen. As this intensified treatment may favour viral replication, the direct impact of therapeutic levels of these immunosuppressive drugs on antigen-specific effector functions was analyzed in a whole blood test (figure 3, n = 6 healthy CMV seropositive individuals). The suppressive effect of 180 ng/ml cyclosporine A in the presence or absence of 0.4, 2, or 10 ng/ml of methylprednisolone (MP, equivalent to 0.4 mg/kg, 2 mg/kg and 10 mg/kg) was analyzed on CMV specific induction of IFN-γ (figure 3A) and on CMV specific T-cell proliferation (figure 3B) after 36 h of stimulation. Incubation with cyclosporine A reduced the percentage of IFN-γ positive CD4 T cells from 0.87±0.52% to 0.55±0.37%. The addition of methylprednisolone led to a further decrease in a dose dependent manner (0.37±0.27%, 0.28±0.20%, and 0.31±0.25% for 0.4, 2 and 10 ng/ml MP; p = 0.007, figure 3A). Similarly, the percentage of BrdU positive T cells after CMV specific stimulation was reduced upon incubation with CyA and MP, although this reduction did not reach statistical significance (figure 3B). Together these data illustrate that immunosuppressive drugs and drug combinations in clinically relevant concentrations contribute to a direct suppression of T-cell function.

Bottom Line: In contrast, CMV-peptide specific CD8 T cells did not show any association with viremia (p = 0.82).Interestingly, therapeutic dosages of cyclosporine A and corticosteroids led to a dose-dependent reduction of CMV-specific T-cell functions, indicating a causal link between intensified immunosuppressive treatment and CMV reactivation.In conclusion, levels of CMV-specific CD4 T cells inversely correlate with reactivation episodes and may represent a valuable measure to individually guide antiviral therapy after stem cell transplantation.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine I, University Clinics of the Saarland, Homburg, Germany.

ABSTRACT
Cytomegalovirus (CMV) infection is the most frequent viral complication in patients after allogeneic stem cell transplantation. As CMV replication is tightly controlled by the cellular arm of specific immunity, the kinetics of CMV-specific T cells in association with individual reactivation episodes were prospectively analyzed in 40 allogeneic transplant recipients in a routine clinical setting and evaluated as determinant of impaired CMV control. Antigen-specific CD4 and CD8 T cells were quantified directly from whole blood using intracellular cytokine staining after specific stimulation and MHC class I multimers, respectively. Highly dynamic intraindividual changes of CMV-specific CD4 T cells were observed in patients experiencing CMV viremia. Episodes of CMV reactivation were associated with a drop of CMV-specific CD4 T cells that re-increased after viral clearance (p<0.0001). Furthermore, levels of CMV-specific CD4 T cells at the onset of viremia inversely correlated with peak viral load thereafter (p = 0.02). In contrast, CMV-peptide specific CD8 T cells did not show any association with viremia (p = 0.82). Interestingly, therapeutic dosages of cyclosporine A and corticosteroids led to a dose-dependent reduction of CMV-specific T-cell functions, indicating a causal link between intensified immunosuppressive treatment and CMV reactivation. In conclusion, levels of CMV-specific CD4 T cells inversely correlate with reactivation episodes and may represent a valuable measure to individually guide antiviral therapy after stem cell transplantation.

Show MeSH
Related in: MedlinePlus