Cytomegalovirus-specific T-cell responses and viral replication in kidney transplant recipients.
BACKGROUND
Cytomegalovirus (CMV) seronegative recipients (R-) of kidney transplants (KT) from seropositive donors (D+) are at higher risk for CMV replication and ganciclovir(GCV)-resistance than CMV R(+). We hypothesized that low CMV-specific T-cell responses are associated with increased risk of CMV replication in R(+)-patients with D(+) or D(-) donors.


METHODS
We prospectively evaluated 73 consecutive KT-patients [48 R(+), 25 D(+)R(-)] undergoing routine testing for CMV replication as part of a preemptive strategy. We compared CMV-specific interferon-gamma (IFN-gamma) responses of CD4+CD3+ lymphocytes in peripheral blood mononuclear cells (PBMC) using three different antigen preparation (CMV-lysate, pp72- and pp65-overlapping peptide pools) using intracellular cytokine staining and flow cytometry.


RESULTS
Median CD4+ and CD8+T-cell responses to CMV-lysate, pp72- and pp65-overlapping peptide pools were lower in D(+)R(-) than in R(+)patients or in non-immunosuppressed donors. Comparing subpopulations we found that CMV-lysate favored CD4+- over CD8+-responses, whereas the reverse was observed for pp72, while pp65-CD4+- and -CD8+-responses were similar. Concurrent CMV replication in R(+)-patients was associated with significantly lower T-cell responses (pp65 median CD4+ 0.00% vs. 0.03%, p = 0.001; CD8+ 0.01% vs. 0.03%; p = 0.033). Receiver operated curve analysis associated CMV-pp65 CD4+ responses of > 0.03% in R(+)-patients with absence of concurrent (p = 0.003) and future CMV replication in the following 8 weeks (p = 0.036). GCV-resistant CMV replication occurred in 3 R(+)-patients (6.3%) with pp65- CD4+ frequencies < 0.03% (p = 0.041).


CONCLUSIONS
The data suggest that pp65-specific CD4+ T-cells might be useful to identify R(+)-patients at increased risk of CMV replication. Provided further corroborating evidence, CMV-pp65 CD4+ responses above 0.03% in PBMCs of KT patients under stable immunosuppression are associated with lower risk of concurrent and future CMV replication during the following 8 weeks.
Transplantation Virology, Institute for Medical Microbiology, University of Basel, Petersplatz 10, 4003 Basel, Switzerland. adrian.egli@unibas.ch
Adrian
A
Egli
Isabelle
I
Binet
Simone
S
Binggeli
Clemens
C
Jäger
Alexis
A
Dumoulin
Stefan
S
Schaub
Juerg
J
Steiger
Urban
U
Sester
Martina
M
Sester
Hans H
HH
Hirsch
D000293:Adolescent; D000328:Adult; D000368:Aged; D000465:Algorithms; D003587:Cytomegalovirus / Q000276:immunology* / Q000502:physiology; D003586:Cytomegalovirus Infections / Q000209:etiology / Q000276:immunology*; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects; D007371:Interferon-gamma / Q000378:metabolism; D016030:Kidney Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000502:physiology*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014180:Transplantation; D014181:Transplantation Immunology; D014779:Virus Replication / Q000502:physiology*
D007371:Interferon-gamma