title: Polyfunctional T-Cell Signatures to Predict Protection from Cytomegalovirus after Lung Transplantation.
abstract: BACKGROUND
  Cytomegalovirus (CMV), which is one of the most common infections after lung transplantation, is associated with chronic lung allograft dysfunction and worse post-transplantation survival. Current approaches for at-risk patients include a fixed duration of antiviral prophylaxis despite the associated cost and side effects.
  
  
  OBJECTIVE
  We sought to identify a specific immunologic signature that predicted protection from subsequent CMV.
  
  
  METHODS
  CMV-seropositive lung transplantation recipients were included in the discovery (n = 43) and validation (n = 28) cohorts. Polyfunctional CMV-specific immunity was assessed by stimulating peripheral blood mononuclear cells with CMV pp65 or IE-1 peptide pools and then by measuring T-cell expression of CD107a, IFN-γ, tumor necrosis factor-α (TNF-α), and IL-2. Recipients were prospectively monitored for subsequent viremia. A Cox proportional hazards regression model that considered cytokine responses individually and in combination was used to create a predictive model for protection from CMV reactivation. This model was then applied to the validation cohort.
  
  
  RESULTS
  Using the discovery cohort, we identified a specific combination of polyfunctional T-cell subsets to pp65 that predicted protection from subsequent CMV viremia (concordance index 0.88 [SE, 0.087]). The model included both protective (CD107a(-)/IFN-γ(+)/IL-2(+)/TNF-α(+) CD4(+) T cells, CD107a(-)/IFN-γ(+)/IL-2(+)/TNF-α(+) CD8(+) T cells) and detrimental (CD107a(+)/IFN-γ(+)/IL-2(-)/TNF-α(-) CD8(+) T cells) subsets. The model was robust in the validation cohort (concordance index 0.81 [SE, 0.103]).
  
  
  CONCLUSIONS
  We identified and validated a specific T-cell polyfunctional response to CMV antigen stimulation that provides a clinically useful prediction of subsequent cytomegalovirus risk. This novel diagnostic approach could inform the optimal duration of individual prophylaxis.
authors.affiliation: 1 Department of Medicine.
authors.forename: Laurie D
authors.initials: LD
authors.lastname: Snyder
authors.affiliation: 2 Department of Biostatistics and Bioinformatics.
authors.forename: Cliburn
authors.initials: C
authors.lastname: Chan
authors.affiliation: 2 Department of Biostatistics and Bioinformatics.
authors.forename: Darongsae
authors.initials: D
authors.lastname: Kwon
authors.affiliation: 3 Department of Surgery, and.
authors.forename: John S
authors.initials: JS
authors.lastname: Yi
authors.affiliation: 1 Department of Medicine.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Martissa
authors.affiliation: 1 Department of Medicine.
authors.forename: C Ashley Finlen
authors.initials: CA
authors.lastname: Copeland
authors.affiliation: 3 Department of Surgery, and.
authors.forename: Robyn J
authors.initials: RJ
authors.lastname: Osborne
authors.affiliation: 3 Department of Surgery, and.
authors.forename: Sara D
authors.initials: SD
authors.lastname: Sparks
authors.affiliation: 1 Department of Medicine.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Palmer
authors.affiliation: 3 Department of Surgery, and.|4 Department of Immunology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Kent J
authors.initials: KJ
authors.lastname: Weinhold
mesh_terms: D000368:Aged; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000209:etiology / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006085:Graft Survival / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D016040:Lung Transplantation / Q000009:adverse effects*; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012307:Risk Factors; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014766:Viremia / Q000276:immunology
chemical_list: D007376:Interleukin-2; D052118:Lysosomal-Associated Membrane Protein 1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: cytomegalovirus; immunologic monitoring; lung transplantation