Deep functional immunophenotyping predicts risk of cytomegalovirus reactivation after hematopoietic cell transplantation

Jose Camargo Galvis, Eric Wieder, Erik Kimble, Cara Benjamin, Despina S. Kolonias, Deukwoo Kwon, Xi Chen, Krishna V Komanduri

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Cytomegalovirus (CMV) is the most common viral infection in hematopoietic cell transplantation (HCT) recipients. We performed deep phenotyping of CMV-specific T cells to predict CMV outcomes following allogeneic HCT. By using 13-color flow cytometry, we studied ex vivo CD8 1 T-cell cytokine production in response to CMV-pp65 peptides in 3 clinically distinct subgroups of CMV-seropositive HCT patients: (1) Elite Controllers (n 5 19): did not have evidence of CMV DNAemia on surveillance testing; (2) Spontaneous Controllers (n 5 16): spontaneously resolved low-grade CMV DNAemia without antiviral therapy; and (3) Noncontrollers (NC; n 5 21): experienced clinically significant CMV. Two CMV-specific CD8 1 T-cell functional subsets were strongly associated with risk of CMV: (i) the nonprotective signature (NPS; IL-22IFN-g 1 TNF-a 2 MIP-1b 1 ), found at increased levels among NC; and (ii) the protective signature (PS; IL-2 1 IFN-g 1 TNF-a 1 MIP-1b 1 ) found at low levels among NC. High levels of the NPS and low levels of PS were associated with an increased 100-day cumulative incidence of clinically significant CMV infection (35% vs 5%; P 5 .02; and 40% vs 12%; P 5 .05, respectively). The highest predictive value was observed when these signatures were combined into a composite biomarker consisting of low levels of the PS and high levels of the NPS (67% vs 10%; P < .001). After adjusting for steroid use or donor type, this composite biomarker remained associated with a fivefold increase in the risk of clinically significant CMV infection. CMV-specific CD8 1 T-cell cytokine signatures with robust predictive value for risk of CMV reactivation should prove useful in guiding clinical decision making in HCT recipients.

Original languageEnglish (US)
Pages (from-to)867-877
Number of pages11
JournalBlood
Volume133
Issue number8
DOIs
StatePublished - Feb 21 2019

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Immunophenotyping
T-cells
Cell Transplantation
Cytomegalovirus
Biomarkers
Cytokines
Controllers
Flow cytometry
Composite materials
Set theory
Interleukin-2
Antiviral Agents
Decision making
Steroids
Cytomegalovirus Infections
Color
T-Lymphocytes
Peptides
Testing
T-Lymphocyte Subsets

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Deep functional immunophenotyping predicts risk of cytomegalovirus reactivation after hematopoietic cell transplantation. / Camargo Galvis, Jose; Wieder, Eric; Kimble, Erik; Benjamin, Cara; Kolonias, Despina S.; Kwon, Deukwoo; Chen, Xi; Komanduri, Krishna V.

In: Blood, Vol. 133, No. 8, 21.02.2019, p. 867-877.

Research output: Contribution to journalArticle

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title = "Deep functional immunophenotyping predicts risk of cytomegalovirus reactivation after hematopoietic cell transplantation",
abstract = "Cytomegalovirus (CMV) is the most common viral infection in hematopoietic cell transplantation (HCT) recipients. We performed deep phenotyping of CMV-specific T cells to predict CMV outcomes following allogeneic HCT. By using 13-color flow cytometry, we studied ex vivo CD8 1 T-cell cytokine production in response to CMV-pp65 peptides in 3 clinically distinct subgroups of CMV-seropositive HCT patients: (1) Elite Controllers (n 5 19): did not have evidence of CMV DNAemia on surveillance testing; (2) Spontaneous Controllers (n 5 16): spontaneously resolved low-grade CMV DNAemia without antiviral therapy; and (3) Noncontrollers (NC; n 5 21): experienced clinically significant CMV. Two CMV-specific CD8 1 T-cell functional subsets were strongly associated with risk of CMV: (i) the nonprotective signature (NPS; IL-22IFN-g 1 TNF-a 2 MIP-1b 1 ), found at increased levels among NC; and (ii) the protective signature (PS; IL-2 1 IFN-g 1 TNF-a 1 MIP-1b 1 ) found at low levels among NC. High levels of the NPS and low levels of PS were associated with an increased 100-day cumulative incidence of clinically significant CMV infection (35{\%} vs 5{\%}; P 5 .02; and 40{\%} vs 12{\%}; P 5 .05, respectively). The highest predictive value was observed when these signatures were combined into a composite biomarker consisting of low levels of the PS and high levels of the NPS (67{\%} vs 10{\%}; P < .001). After adjusting for steroid use or donor type, this composite biomarker remained associated with a fivefold increase in the risk of clinically significant CMV infection. CMV-specific CD8 1 T-cell cytokine signatures with robust predictive value for risk of CMV reactivation should prove useful in guiding clinical decision making in HCT recipients.",
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T1 - Deep functional immunophenotyping predicts risk of cytomegalovirus reactivation after hematopoietic cell transplantation

AU - Camargo Galvis, Jose

AU - Wieder, Eric

AU - Kimble, Erik

AU - Benjamin, Cara

AU - Kolonias, Despina S.

AU - Kwon, Deukwoo

AU - Chen, Xi

AU - Komanduri, Krishna V

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N2 - Cytomegalovirus (CMV) is the most common viral infection in hematopoietic cell transplantation (HCT) recipients. We performed deep phenotyping of CMV-specific T cells to predict CMV outcomes following allogeneic HCT. By using 13-color flow cytometry, we studied ex vivo CD8 1 T-cell cytokine production in response to CMV-pp65 peptides in 3 clinically distinct subgroups of CMV-seropositive HCT patients: (1) Elite Controllers (n 5 19): did not have evidence of CMV DNAemia on surveillance testing; (2) Spontaneous Controllers (n 5 16): spontaneously resolved low-grade CMV DNAemia without antiviral therapy; and (3) Noncontrollers (NC; n 5 21): experienced clinically significant CMV. Two CMV-specific CD8 1 T-cell functional subsets were strongly associated with risk of CMV: (i) the nonprotective signature (NPS; IL-22IFN-g 1 TNF-a 2 MIP-1b 1 ), found at increased levels among NC; and (ii) the protective signature (PS; IL-2 1 IFN-g 1 TNF-a 1 MIP-1b 1 ) found at low levels among NC. High levels of the NPS and low levels of PS were associated with an increased 100-day cumulative incidence of clinically significant CMV infection (35% vs 5%; P 5 .02; and 40% vs 12%; P 5 .05, respectively). The highest predictive value was observed when these signatures were combined into a composite biomarker consisting of low levels of the PS and high levels of the NPS (67% vs 10%; P < .001). After adjusting for steroid use or donor type, this composite biomarker remained associated with a fivefold increase in the risk of clinically significant CMV infection. CMV-specific CD8 1 T-cell cytokine signatures with robust predictive value for risk of CMV reactivation should prove useful in guiding clinical decision making in HCT recipients.

AB - Cytomegalovirus (CMV) is the most common viral infection in hematopoietic cell transplantation (HCT) recipients. We performed deep phenotyping of CMV-specific T cells to predict CMV outcomes following allogeneic HCT. By using 13-color flow cytometry, we studied ex vivo CD8 1 T-cell cytokine production in response to CMV-pp65 peptides in 3 clinically distinct subgroups of CMV-seropositive HCT patients: (1) Elite Controllers (n 5 19): did not have evidence of CMV DNAemia on surveillance testing; (2) Spontaneous Controllers (n 5 16): spontaneously resolved low-grade CMV DNAemia without antiviral therapy; and (3) Noncontrollers (NC; n 5 21): experienced clinically significant CMV. Two CMV-specific CD8 1 T-cell functional subsets were strongly associated with risk of CMV: (i) the nonprotective signature (NPS; IL-22IFN-g 1 TNF-a 2 MIP-1b 1 ), found at increased levels among NC; and (ii) the protective signature (PS; IL-2 1 IFN-g 1 TNF-a 1 MIP-1b 1 ) found at low levels among NC. High levels of the NPS and low levels of PS were associated with an increased 100-day cumulative incidence of clinically significant CMV infection (35% vs 5%; P 5 .02; and 40% vs 12%; P 5 .05, respectively). The highest predictive value was observed when these signatures were combined into a composite biomarker consisting of low levels of the PS and high levels of the NPS (67% vs 10%; P < .001). After adjusting for steroid use or donor type, this composite biomarker remained associated with a fivefold increase in the risk of clinically significant CMV infection. CMV-specific CD8 1 T-cell cytokine signatures with robust predictive value for risk of CMV reactivation should prove useful in guiding clinical decision making in HCT recipients.

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