title: Dissection of the CMV specific T-cell response is required for optimized cardiac transplant monitoring.
abstract: Despite the success of antivirals in preventing clinically overt CMV disease in cardiac allograft recipients, sub-clinical active CMV infection remains a major concern because of its association with allograft rejection and vasculopathy. The measurement of CMV specific T-cell responses is a promising approach to assessing this situation. For simplicity, class-I MHC/peptide-multimers staining CD8 T-cells directly are often used but this ignores a much wider range of responses including the whole CD4 T-cell compartment. CD4 T-cells, however, were recently shown to be critical to reducing CMV load early after transplantation. To determine how extensive T-cell responses to CMV are, the responses to two dominant CMV proteins, IE-1 and pp65, were dissected in detail accounting for T-cell lineage, frequencies, epitope recognition and changes over time in more than 25 heart transplant recipients. Cross-sectional results from over 30 healthy CMV-carriers were analyzed for comparison. Responses were unexpectedly complex, with considerable inter-individual variation in terms of dominance, breadth, and recognized epitopes. Whereas the use of MHC/peptide-multimers for clinical CD8 T-cell response monitoring alone can be justified in some situations, short term T-cell activation combined with intracellular cytokine staining was clearly found to be of more general usefulness. The performance of IFN-gamma, TNF-alpha, or IL-2 as single read-outs in identifying activated T-cells was examined and confirmed that the frequently used IFN-gamma was best suited. These results should be used to inform the design of clinically applicable and diagnostically useful approaches to monitoring CMV specific responses in heart transplant recipients.
authors.affiliation: Institut für Medizinische Immunologie, Charité, Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kirchner
authors.forename: Bodo
authors.initials: B
authors.lastname: Hoffmeister
authors.forename: Georgy
authors.initials: G
authors.lastname: Cherepnev-G
authors.forename: Stephan
authors.initials: S
authors.lastname: Fuhrmann
authors.forename: Mathias
authors.initials: M
authors.lastname: Streitz
authors.forename: Raskit
authors.initials: R
authors.lastname: Lachmann
authors.forename: Torsten
authors.initials: T
authors.lastname: Bunde
authors.forename: Pauline
authors.initials: P
authors.lastname: Meij
authors.forename: Constanze
authors.initials: C
authors.lastname: Schönemann
authors.forename: Roland
authors.initials: R
authors.lastname: Hetzer
authors.forename: Hans B
authors.initials: HB
authors.lastname: Lehmkuhl
authors.forename: Rudolf
authors.initials: R
authors.lastname: Volkmer-Engert
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.forename: Jan W
authors.initials: JW
authors.lastname: Gratama
authors.forename: Florian
authors.initials: F
authors.lastname: Kern
mesh_terms: D003430:Cross-Sectional Studies; D016207:Cytokines / Q000096:biosynthesis; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D008137:Longitudinal Studies; D008213:Lymphocyte Activation; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014180:Transplantation; D019737:Transplants; D014764:Viral Proteins / Q000276:immunology
chemical_list: D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D014764:Viral Proteins