Dissection of the CMV specific T-cell response is required for optimized cardiac transplant monitoring.
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.
Kirchner
Alexander
A
Institut für Medizinische Immunologie, Charité, Berlin, Germany.
Hoffmeister
Bodo
B
Cherepnev-G
Georgy
G
Fuhrmann
Stephan
S
Streitz
Mathias
M
Lachmann
Raskit
R
Bunde
Torsten
T
Meij
Pauline
P
Schönemann
Constanze
C
Hetzer
Roland
R
Lehmkuhl
Hans B
HB
Volkmer-Engert
Rudolf
R
Volk
Hans-Dieter
HD
Gratama
Jan W
JW
Kern
Florian
F
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
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D014764:Viral Proteins