Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2008 Jun 9:6:29.
doi: 10.1186/1479-5876-6-29.

Cytomegalovirus-specific T-cell responses and viral replication in kidney transplant recipients

Adrian Egli  1 , Isabelle Binet, Simone Binggeli, Clemens Jäger, Alexis Dumoulin, Stefan Schaub, Juerg Steiger, Urban Sester, Martina Sester, Hans H Hirsch
Affiliations

Cytomegalovirus-specific T-cell responses and viral replication in kidney transplant recipients

Adrian Egli et al. J Transl Med. .

Abstract

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).

Conclusion: 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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Study flow chart. We enrolled patients undergoing testing for CMV replication as part of the preemptive management strategy. CMV-PCR testing was performed together with the measurement of CMV-specific T-cell responses. According to the initial CMV PCR results, the patients were divided into the 2 groups of CMV replication positive and negative. Further viral testing was done and patients were then newly assigned to a CMV PCR positive or negative. The corresponding numbers of D(+)R(-) and R(+) are shown.
Figure 2
Figure 2
CMV-specific IFNγ positive T-cell response in KT patients. CMV-lysate-specific interferon-γ responses in CMV-seropositive R(+) patients and CMV-seronegative D(+)R(-) KT patients. Black bars indicate median, whiskers indicate interquartile range. P-values were calculated using Mann-Whitney U test. Note: The median was below the analytical cut-off of 0.01% in the CMV-seronegative D(+)R(-) KT patients.
Figure 3
Figure 3
CMV-specific IFNγ positive T-cell response in KT patients. CMV-lysate and CMV-pp65 peptide-induced interferon-γ responses in R(+) KT patients with and without concurrent CMV replication. Note: The median was below the analytical cut-off of 0.01% in for the pp65-induced CD 4+ and CD8+ responses in patients with concurrent CMV replication.
Figure 4
Figure 4
Receiver operating characteristic (ROC) analysis – CMV-specific T-cells protecting from concurrent CMV replication ROC analysis shows thresholds of protection from concurrent CMV replication for the different CMV antigens tested. AUC, Area under the curve; p-value by Fisher exact test; PPV, positive predictive value; NPV, negative predictive value.
Figure 5
Figure 5
CMV pp65-specific CD4+ T-cell responses and CMV replication in the following 8 weeks. X-axis indicates KT R(+) patients without CMV replication in the following 8 weeks versus KT R(+) patients with CMV replication in the following 8 weeks. Y-axis shows frequency of IFNγ positive T-cells in % after specific stimulation with CMV-pp65 peptides. Black bars indicate median, whiskers indicate interquartile range. P-values by Mann-Whitney U test.
Figure 6
Figure 6
CMV UL97 mutant variants. Boxes indicate mutation clusters in CMV UL97 phosphokinase gene. Characters indicate amino acids; changed amino acids are underlined. Ganciclovir (GCV)-inhibitory concentrations 50% (IC50) associated with mutations are listed as μM and -fold increase over wild type AD 169 (1) or Towne (2) strain.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Dharnidharka VR, Stablein DM, Harmon WE. Post-transplant infections now exceed acute rejection as cause for hospitalization: a report of the NAPRTCS. Am J Transplant. 2004;4:384–389. doi: 10.1111/j.1600-6143.2004.00350.x. - DOI - PubMed
    1. Meier-Kriesche HU, Li S, Gruessner RW, Fung JJ, Bustami RT, Barr ML, Leichtman AB. Immunosuppression: evolution in practice and trends, 1994–2004. Am J Transplant. 2006;6:1111–1131. doi: 10.1111/j.1600-6143.2006.01270.x. - DOI - PubMed
    1. Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med. 1998;338:1741–1751. doi: 10.1056/NEJM199806113382407. - DOI - PubMed
    1. Opelz G, Naujokat C, Daniel V, Terness P, Dohler B. Disassociation between risk of graft loss and risk of non-Hodgkin lymphoma with induction agents in renal transplant recipients. Transplantation. 2006;81:1227–1233. doi: 10.1097/01.tp.0000219817.18049.36. - DOI - PubMed
    1. Reinke P, Prosch S, Kern F, Volk HD. Mechanisms of human cytomegalovirus (HCMV) (re)activation and its impact on organ transplant patients. Transpl Infect Dis. 1999;1:157–164. doi: 10.1034/j.1399-3062.1999.010304.x. - DOI - PubMed

Publication types

MeSH terms

Substances