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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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Lowest levels of CMV specific CD4 T cells at the onset of and during viremia.A CMV specific or B total CD4 T cells were quantified in non-viremic individuals and compared to patients >14 days, <14 days, at the onset of, during, or after viremia. Bars indicate median numbers of cells/µl whole blood. Each patient is depicted once in a given time period. If more than one data set existed, mean values were calculated for each patient. The level of significance in the post-test (p<0.05, p<0.01, p<0.001) is depicted by one, two or three stars, respectively. C Inverse correlation between the levels of CMV specific CD4 T cells at onset of viremia and peak viral load thereafter (r = −0.45, p = 0.02).
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pone-0003634-g002: Lowest levels of CMV specific CD4 T cells at the onset of and during viremia.A CMV specific or B total CD4 T cells were quantified in non-viremic individuals and compared to patients >14 days, <14 days, at the onset of, during, or after viremia. Bars indicate median numbers of cells/µl whole blood. Each patient is depicted once in a given time period. If more than one data set existed, mean values were calculated for each patient. The level of significance in the post-test (p<0.05, p<0.01, p<0.001) is depicted by one, two or three stars, respectively. C Inverse correlation between the levels of CMV specific CD4 T cells at onset of viremia and peak viral load thereafter (r = −0.45, p = 0.02).

Mentions: To more closely address the changes in CMV specific T-cell immunity in relation to viral load over time, CMV specific CD4 T-cell numbers were analyzed in patients at various stages before, during and after viremia. The group of transplant recipients who were never viremic served as a control population (figure 2A, white circles). Median CMV specific CD4 T-cell numbers in non-viremic patients reached 10.49 cells/µl (range 1.35–69.73 cells/µl). In contrast, CMV specific CD4 T-cell levels at the onset and during viremia were significantly lower (1.07 cells/µl, range 0.13–39.31 cells/µl and 0.85 cells/µl, range 0.13–36.33 cells/µl, respectively) and re-increased after resolution of viremia (4.40 cells/µl, range 0.48–74.81 cells/µl). Interestingly, CMV specific T-cell levels already started decreasing before detection of viral load (>14 days before viremia: 5.87 cells/µl, range 0.55–71.91 cells/µl; <14 days before viremia: 2.64 cells/µl; range 0.13–31.78 cells/µl). This indicates that CMV specific CD4 T-cell levels closely correlate with viral replication and may even serve as a measure to predict viremia well before its onset. Interestingly, similar kinetics were observed when the time course of viral load was related to the median number of total CD4 T cells irrespective of specificity (figure 2B). While these findings may indicate some diagnostic value of total CD4 T-cell levels as a rough surrogate parameter to judge the individual immunocompetence towards CMV, the decrease upon viremia, however, was far less pronounced as compared to that observed for CD4 T cells specific for CMV (3.0fold decrease in median CD4 T cells vs. 12.4fold decrease in median CMV specific CD4 T cells between non-viremic patients and patients during viremia).


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)

Lowest levels of CMV specific CD4 T cells at the onset of and during viremia.A CMV specific or B total CD4 T cells were quantified in non-viremic individuals and compared to patients >14 days, <14 days, at the onset of, during, or after viremia. Bars indicate median numbers of cells/µl whole blood. Each patient is depicted once in a given time period. If more than one data set existed, mean values were calculated for each patient. The level of significance in the post-test (p<0.05, p<0.01, p<0.001) is depicted by one, two or three stars, respectively. C Inverse correlation between the levels of CMV specific CD4 T cells at onset of viremia and peak viral load thereafter (r = −0.45, p = 0.02).
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Related In: Results  -  Collection

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pone-0003634-g002: Lowest levels of CMV specific CD4 T cells at the onset of and during viremia.A CMV specific or B total CD4 T cells were quantified in non-viremic individuals and compared to patients >14 days, <14 days, at the onset of, during, or after viremia. Bars indicate median numbers of cells/µl whole blood. Each patient is depicted once in a given time period. If more than one data set existed, mean values were calculated for each patient. The level of significance in the post-test (p<0.05, p<0.01, p<0.001) is depicted by one, two or three stars, respectively. C Inverse correlation between the levels of CMV specific CD4 T cells at onset of viremia and peak viral load thereafter (r = −0.45, p = 0.02).
Mentions: To more closely address the changes in CMV specific T-cell immunity in relation to viral load over time, CMV specific CD4 T-cell numbers were analyzed in patients at various stages before, during and after viremia. The group of transplant recipients who were never viremic served as a control population (figure 2A, white circles). Median CMV specific CD4 T-cell numbers in non-viremic patients reached 10.49 cells/µl (range 1.35–69.73 cells/µl). In contrast, CMV specific CD4 T-cell levels at the onset and during viremia were significantly lower (1.07 cells/µl, range 0.13–39.31 cells/µl and 0.85 cells/µl, range 0.13–36.33 cells/µl, respectively) and re-increased after resolution of viremia (4.40 cells/µl, range 0.48–74.81 cells/µl). Interestingly, CMV specific T-cell levels already started decreasing before detection of viral load (>14 days before viremia: 5.87 cells/µl, range 0.55–71.91 cells/µl; <14 days before viremia: 2.64 cells/µl; range 0.13–31.78 cells/µl). This indicates that CMV specific CD4 T-cell levels closely correlate with viral replication and may even serve as a measure to predict viremia well before its onset. Interestingly, similar kinetics were observed when the time course of viral load was related to the median number of total CD4 T cells irrespective of specificity (figure 2B). While these findings may indicate some diagnostic value of total CD4 T-cell levels as a rough surrogate parameter to judge the individual immunocompetence towards CMV, the decrease upon viremia, however, was far less pronounced as compared to that observed for CD4 T cells specific for CMV (3.0fold decrease in median CD4 T cells vs. 12.4fold decrease in median CMV specific CD4 T cells between non-viremic patients and patients during viremia).

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