Limits...
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.

Show MeSH

Related in: MedlinePlus

Dynamic changes of CMV specific CD4 T-cell frequencies in viremic patients.A Dotplots showing CMV specific CD4 T cells of a stem-cell transplant recipient, that were quantified by the induction of CD69 and IFN-γ after specific stimulation with CMV antigen (lysate derived from infected fibroblasts). Lysates from non-infected fibroblasts (control antigen) or Staphylococcus aureus enterotoxin B (SEB) served as negative and positive controls, respectively. B There was a significant correlation between the numbers of CMV specific CD4 T cells producing IFN-γ and TNF-α. Representative examples of CMV specific CD4 T cells (white circles), viral load (stars), and CMV specific CD8 T cells (black circles) over time in patients being C viremic and D non-viremic after initial CMV specific T-cell immunoreconstitution. The number of CMV specific CD8 T cells was calculated by adding T-cell levels towards individual MHC class I pentamers (between 1 and 4 per patient). E Higher standard deviations of normalized mean CMV specific CD4 T cell numbers over time in viremic patients (left panel) as compared to non-viremic patients (right panel, p<0.0001). Normalization was performed using the logarithmic values of CMV specific CD4 T cells/µl. Each symbol represents the variation in CMV specific CD4 T cells of one patient over time. Shown are all individuals where at least four samples were available over time (4-41 in viremic and 4-49 in non-viremic patients, respectively).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2572846&req=5

pone-0003634-g001: Dynamic changes of CMV specific CD4 T-cell frequencies in viremic patients.A Dotplots showing CMV specific CD4 T cells of a stem-cell transplant recipient, that were quantified by the induction of CD69 and IFN-γ after specific stimulation with CMV antigen (lysate derived from infected fibroblasts). Lysates from non-infected fibroblasts (control antigen) or Staphylococcus aureus enterotoxin B (SEB) served as negative and positive controls, respectively. B There was a significant correlation between the numbers of CMV specific CD4 T cells producing IFN-γ and TNF-α. Representative examples of CMV specific CD4 T cells (white circles), viral load (stars), and CMV specific CD8 T cells (black circles) over time in patients being C viremic and D non-viremic after initial CMV specific T-cell immunoreconstitution. The number of CMV specific CD8 T cells was calculated by adding T-cell levels towards individual MHC class I pentamers (between 1 and 4 per patient). E Higher standard deviations of normalized mean CMV specific CD4 T cell numbers over time in viremic patients (left panel) as compared to non-viremic patients (right panel, p<0.0001). Normalization was performed using the logarithmic values of CMV specific CD4 T cells/µl. Each symbol represents the variation in CMV specific CD4 T cells of one patient over time. Shown are all individuals where at least four samples were available over time (4-41 in viremic and 4-49 in non-viremic patients, respectively).

Mentions: CMV specific CD4 T cells of stem cell transplant recipients were prospectively analyzed and correlated to CMV-DNA. CMV specific CD4 T cells were identified by upregulation of CD69 and induction of IFN-γ after stimulation with a whole CMV lysate. Stimulation with control antigen or SEB served as negative or positive controls, respectively (figure 1A). A strong correlation was found between the induction of IFN-γ and TNF-α after stimulation with CMV antigen (figure 1B, r = 0.96, p<0.0001) and SEB (r = 0.91, p<0.0001, data not shown), thus indicating a simultaneous induction of Th1 cytokines after specific stimulation.


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)

Dynamic changes of CMV specific CD4 T-cell frequencies in viremic patients.A Dotplots showing CMV specific CD4 T cells of a stem-cell transplant recipient, that were quantified by the induction of CD69 and IFN-γ after specific stimulation with CMV antigen (lysate derived from infected fibroblasts). Lysates from non-infected fibroblasts (control antigen) or Staphylococcus aureus enterotoxin B (SEB) served as negative and positive controls, respectively. B There was a significant correlation between the numbers of CMV specific CD4 T cells producing IFN-γ and TNF-α. Representative examples of CMV specific CD4 T cells (white circles), viral load (stars), and CMV specific CD8 T cells (black circles) over time in patients being C viremic and D non-viremic after initial CMV specific T-cell immunoreconstitution. The number of CMV specific CD8 T cells was calculated by adding T-cell levels towards individual MHC class I pentamers (between 1 and 4 per patient). E Higher standard deviations of normalized mean CMV specific CD4 T cell numbers over time in viremic patients (left panel) as compared to non-viremic patients (right panel, p<0.0001). Normalization was performed using the logarithmic values of CMV specific CD4 T cells/µl. Each symbol represents the variation in CMV specific CD4 T cells of one patient over time. Shown are all individuals where at least four samples were available over time (4-41 in viremic and 4-49 in non-viremic patients, respectively).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2572846&req=5

pone-0003634-g001: Dynamic changes of CMV specific CD4 T-cell frequencies in viremic patients.A Dotplots showing CMV specific CD4 T cells of a stem-cell transplant recipient, that were quantified by the induction of CD69 and IFN-γ after specific stimulation with CMV antigen (lysate derived from infected fibroblasts). Lysates from non-infected fibroblasts (control antigen) or Staphylococcus aureus enterotoxin B (SEB) served as negative and positive controls, respectively. B There was a significant correlation between the numbers of CMV specific CD4 T cells producing IFN-γ and TNF-α. Representative examples of CMV specific CD4 T cells (white circles), viral load (stars), and CMV specific CD8 T cells (black circles) over time in patients being C viremic and D non-viremic after initial CMV specific T-cell immunoreconstitution. The number of CMV specific CD8 T cells was calculated by adding T-cell levels towards individual MHC class I pentamers (between 1 and 4 per patient). E Higher standard deviations of normalized mean CMV specific CD4 T cell numbers over time in viremic patients (left panel) as compared to non-viremic patients (right panel, p<0.0001). Normalization was performed using the logarithmic values of CMV specific CD4 T cells/µl. Each symbol represents the variation in CMV specific CD4 T cells of one patient over time. Shown are all individuals where at least four samples were available over time (4-41 in viremic and 4-49 in non-viremic patients, respectively).
Mentions: CMV specific CD4 T cells of stem cell transplant recipients were prospectively analyzed and correlated to CMV-DNA. CMV specific CD4 T cells were identified by upregulation of CD69 and induction of IFN-γ after stimulation with a whole CMV lysate. Stimulation with control antigen or SEB served as negative or positive controls, respectively (figure 1A). A strong correlation was found between the induction of IFN-γ and TNF-α after stimulation with CMV antigen (figure 1B, r = 0.96, p<0.0001) and SEB (r = 0.91, p<0.0001, data not shown), thus indicating a simultaneous induction of Th1 cytokines after specific stimulation.

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