Skip to main content
Top
Published in: Journal of Clinical Immunology 4/2012

01-08-2012

Simultaneous Monitoring of Cytomegalovirus-Specific Antibody and T-cell levels in Seropositive Heart Transplant Recipients

Authors: Javier Carbone, Nallibe Lanio, Antonio Gallego, Florian Kern, Joaquin Navarro, Patricia Muñoz, Roberto Alonso, Pilar Catalán, Juan Fernández-Yáñez, Jesús Palomo, Manuel Ruiz, Eduardo Fernández-Cruz, Elizabeth Sarmiento

Published in: Journal of Clinical Immunology | Issue 4/2012

Login to get access

Abstract

Purpose

Human cytomegalovirus (CMV) active infection (CMV infection) poses serious risks to CMV-seropositive heart transplant recipients. We evaluated the usefulness of simultaneous assessment of CMV-specific values for parameters of the humoral (antibodies) and cellular (CD4+ and CD8+ T-cells) immune responses in the identification of heart recipients at risk of developing CMV infection after transplantation.

Methods

We prospectively studied 38 CMV-seropositive heart recipients. Anti-CMV antibody titers were assessed using enzyme-linked immunosorbent assays. CD4+ and CD8+ T-cell responses to overlapping peptide pools of the CMV proteins pp65 and immediate early protein-1 (IE1) were evaluated by flow cytometry. Immunological studies were performed before transplantation and at 30 days after transplantation. Patients with CMV infection were compared with heart recipients without CMV infection.

Results

During the 6-month follow-up period, 13 (34.2%) patients developed CMV infection. At baseline, the mean anti-CMV-IgG antibody titer was lower in patients who developed CMV infection. This difference remained at 30 days after transplantation. One month after transplantation, the mean percentage of IE1-specific CD8+ T cells that are IFNg-positive (CD8/IFNg + IE1) was lower in CMV-infected patients. The predictive value of these variables at 30 days was increased when they were combined. Cox regression analysis revealed an association between the risk of developing CMV infection and the combination marker (low anti-CMV titer [<16,100] and low CD8/IFNg + IE1 percentages [<0.40%], relative hazard, 6.07; p = 0.019). The combination marker remained significant after adjustment for clinical variables.

Conclusions

This novel approach of a simultaneous assessment of specific anti-CMV antibody titers and CD8/IFNg + IE1 percentages might help identify heart transplant recipients with an increased risk of developing CMV infection.
Literature
1.
go back to reference Gurgui M, Munoz P. Infection in heart transplantation. Enferm Infecc Microbiol Clin. 2007;25(9):587–97.PubMedCrossRef Gurgui M, Munoz P. Infection in heart transplantation. Enferm Infecc Microbiol Clin. 2007;25(9):587–97.PubMedCrossRef
2.
go back to reference Pérez-Sola MJ, Castón JJ, Solana R, Rivero A, Torre-Cisneros J. Indirect effects of cytomegalovirus infection in solid organ transplant recipients. Enferm Infecc Microbiol Clin. 2008;26(1):38–47.PubMedCrossRef Pérez-Sola MJ, Castón JJ, Solana R, Rivero A, Torre-Cisneros J. Indirect effects of cytomegalovirus infection in solid organ transplant recipients. Enferm Infecc Microbiol Clin. 2008;26(1):38–47.PubMedCrossRef
3.
go back to reference Avery RK. Prevention and treatment of cytomegalovirus infection and disease in heart transplant recipients. Curr Opin Cardiol. 1998;13(2):122–9.PubMedCrossRef Avery RK. Prevention and treatment of cytomegalovirus infection and disease in heart transplant recipients. Curr Opin Cardiol. 1998;13(2):122–9.PubMedCrossRef
4.
go back to reference Potena L, Holweg CT, Vana ML, et al. Frequent occult infection with Cytomegalovirus in cardiac transplant recipients despite antiviral prophylaxis. J Clin Microbiol. 2007;45(6):1804–10.PubMedCrossRef Potena L, Holweg CT, Vana ML, et al. Frequent occult infection with Cytomegalovirus in cardiac transplant recipients despite antiviral prophylaxis. J Clin Microbiol. 2007;45(6):1804–10.PubMedCrossRef
5.
go back to reference Kijpittayarit-Arthurs S, Eid AJ, Kremers WK, et al. Clinical features and outcomes of delayed-onset primary cytomegalovirus disease in cardiac transplant recipients. J Heart Lung Transplant. 2007;26(10):1019–24.PubMedCrossRef Kijpittayarit-Arthurs S, Eid AJ, Kremers WK, et al. Clinical features and outcomes of delayed-onset primary cytomegalovirus disease in cardiac transplant recipients. J Heart Lung Transplant. 2007;26(10):1019–24.PubMedCrossRef
6.
go back to reference Li F, Kenyon KW, Kirby KA, et al. Incidence and clinical features of ganciclovir-resistant cytomegalovirus disease in heart transplant recipients. Clin Infect Dis. 2007;45(4):439–47.PubMedCrossRef Li F, Kenyon KW, Kirby KA, et al. Incidence and clinical features of ganciclovir-resistant cytomegalovirus disease in heart transplant recipients. Clin Infect Dis. 2007;45(4):439–47.PubMedCrossRef
7.
go back to reference Baldanti F, Lilleri D, Gerna G. Monitoring human cytomegalovirus infection in transplant recipients. J Clin Virol. 2008;41(3):237–41.PubMedCrossRef Baldanti F, Lilleri D, Gerna G. Monitoring human cytomegalovirus infection in transplant recipients. J Clin Virol. 2008;41(3):237–41.PubMedCrossRef
8.
go back to reference Kotton CN, Kumar D, Caliendo AM, et al. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation. 2010;89(7):779–95.PubMedCrossRef Kotton CN, Kumar D, Caliendo AM, et al. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation. 2010;89(7):779–95.PubMedCrossRef
9.
go back to reference Sarmiento E, Rodriguez-Molina JJ, Fernandez-Yañez J, et al. IgG monitoring to identify the risk for development of infection in heart transplant recipients. Transpl Infect Dis. 2006;8(1):49–53.PubMedCrossRef Sarmiento E, Rodriguez-Molina JJ, Fernandez-Yañez J, et al. IgG monitoring to identify the risk for development of infection in heart transplant recipients. Transpl Infect Dis. 2006;8(1):49–53.PubMedCrossRef
10.
go back to reference Sarmiento E, Lanio N, Gallego A, et al. Immune monitoring of anti cytomegalovirus antibodies and risk of cytomegalovirus disease in heart transplantation. Int Immunopharmacol. 2009;9(6):649–52.PubMedCrossRef Sarmiento E, Lanio N, Gallego A, et al. Immune monitoring of anti cytomegalovirus antibodies and risk of cytomegalovirus disease in heart transplantation. Int Immunopharmacol. 2009;9(6):649–52.PubMedCrossRef
11.
go back to reference Bunde T, Kirchner A, Hoffmeister B, et al. Protection from cytomegalovirus after transplantation is correlated with immediate early 1-specific CD8 T cells. J Exp Med. 2005;201(7):1031–6.PubMedCrossRef Bunde T, Kirchner A, Hoffmeister B, et al. Protection from cytomegalovirus after transplantation is correlated with immediate early 1-specific CD8 T cells. J Exp Med. 2005;201(7):1031–6.PubMedCrossRef
12.
go back to reference Sester U, Gärtner BC, Wilkens H, et al. Differences in CMV-specific T-cell levels and long-term susceptibility to CMV infection after kidney, heart and lung transplantation. Am J Transplant. 2005;5(6):1483–9.PubMedCrossRef Sester U, Gärtner BC, Wilkens H, et al. Differences in CMV-specific T-cell levels and long-term susceptibility to CMV infection after kidney, heart and lung transplantation. Am J Transplant. 2005;5(6):1483–9.PubMedCrossRef
13.
go back to reference Gerna G, Lilleri D, Fornara C, et al. Monitoring of human cytomegalovirus-specific CD4 and CD8 T-cell immunity in patients receiving solid organ transplantation. Am J Transplant. 2006;6(10):2356–64.PubMedCrossRef Gerna G, Lilleri D, Fornara C, et al. Monitoring of human cytomegalovirus-specific CD4 and CD8 T-cell immunity in patients receiving solid organ transplantation. Am J Transplant. 2006;6(10):2356–64.PubMedCrossRef
14.
go back to reference Egli A, Binet I, Binggeli S, et al. Cytomegalovirus-specific T-cell responses and viral replication in kidney transplant recipients. J Transl Med. 2008;6:29.PubMedCrossRef Egli A, Binet I, Binggeli S, et al. Cytomegalovirus-specific T-cell responses and viral replication in kidney transplant recipients. J Transl Med. 2008;6:29.PubMedCrossRef
15.
go back to reference Mattes FM, Vargas A, Kopycinski J, et al. Functional impairment of cytomegalovirus specific CD8 T cells predicts high-level replication after renal transplantation. Am J Transplant. 2008;8(5):990–9.PubMedCrossRef Mattes FM, Vargas A, Kopycinski J, et al. Functional impairment of cytomegalovirus specific CD8 T cells predicts high-level replication after renal transplantation. Am J Transplant. 2008;8(5):990–9.PubMedCrossRef
16.
go back to reference Gamadia LE, Remmerswaal EB, Weel JF, Bemelman F, van Lier RA, Ten Berge IJ. Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease. Blood. 2003;101(7):2686–92.PubMedCrossRef Gamadia LE, Remmerswaal EB, Weel JF, Bemelman F, van Lier RA, Ten Berge IJ. Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease. Blood. 2003;101(7):2686–92.PubMedCrossRef
17.
go back to reference La Rosa C, Limaye AP, Krishnan A, Longmate J, Diamond DJ. Longitudinal assessment of cytomegalovirus (CMV)-specific immune responses in liver transplant recipients at high risk for late CMV disease. J Infect Dis. 2007;195(5):633–44.PubMedCrossRef La Rosa C, Limaye AP, Krishnan A, Longmate J, Diamond DJ. Longitudinal assessment of cytomegalovirus (CMV)-specific immune responses in liver transplant recipients at high risk for late CMV disease. J Infect Dis. 2007;195(5):633–44.PubMedCrossRef
18.
go back to reference Opelz G, Döhler B, Ruhenstroth A. Cytomegalovirus prophylaxis and graft outcome in solid organ transplantation: a collaborative transplant study report. Am J Transplant. 2004;4(6):928–36.PubMedCrossRef Opelz G, Döhler B, Ruhenstroth A. Cytomegalovirus prophylaxis and graft outcome in solid organ transplantation: a collaborative transplant study report. Am J Transplant. 2004;4(6):928–36.PubMedCrossRef
19.
go back to reference Gerna G, Lilleri D, Chiesa A, et al. Virologic and immunologic monitoring of cytomegalovirus to guide preemptive therapy in solid-organ transplantation. Am J Transplant. 2011;11(11):2463–71.PubMedCrossRef Gerna G, Lilleri D, Chiesa A, et al. Virologic and immunologic monitoring of cytomegalovirus to guide preemptive therapy in solid-organ transplantation. Am J Transplant. 2011;11(11):2463–71.PubMedCrossRef
20.
go back to reference Bunk S, Schaffert H, Schmid B, et al. Chlamydia pneumoniae-induced memory CD4+ T-cell activation in human peripheral blood correlates with distinct antibody response patterns. Clin Vaccine Immunol. 2010;17(5):705–12.PubMedCrossRef Bunk S, Schaffert H, Schmid B, et al. Chlamydia pneumoniae-induced memory CD4+ T-cell activation in human peripheral blood correlates with distinct antibody response patterns. Clin Vaccine Immunol. 2010;17(5):705–12.PubMedCrossRef
21.
go back to reference Dasari V, Smith C, Zhong J, Scott G, Rawlinson W, Khanna R. Recombinant glycoprotein B vaccine formulation with Toll-like receptor 9 agonist and immune-stimulating complex induces specific immunity against multiple strains of cytomegalovirus. J Gen Virol. 2011;92:1021–31.PubMedCrossRef Dasari V, Smith C, Zhong J, Scott G, Rawlinson W, Khanna R. Recombinant glycoprotein B vaccine formulation with Toll-like receptor 9 agonist and immune-stimulating complex induces specific immunity against multiple strains of cytomegalovirus. J Gen Virol. 2011;92:1021–31.PubMedCrossRef
22.
go back to reference Sabbaj S, Pass RF, Goepfert PA, Pichon S. Glycoprotein B vaccine is capable of boosting both antibody and CD4 T-cell responses to cytomegalovirus in chronically infected women. J Infect Dis. 2011;203(11):1534–41.PubMedCrossRef Sabbaj S, Pass RF, Goepfert PA, Pichon S. Glycoprotein B vaccine is capable of boosting both antibody and CD4 T-cell responses to cytomegalovirus in chronically infected women. J Infect Dis. 2011;203(11):1534–41.PubMedCrossRef
23.
go back to reference Bonaros N, Mayer B, Schachner T, et al. CMV-hyperimmune globulin for preventing cytomegalovirus infection and disease in solid organ transplant recipients: a meta-analysis. Clin Transplant. 2008;22:89–97.PubMed Bonaros N, Mayer B, Schachner T, et al. CMV-hyperimmune globulin for preventing cytomegalovirus infection and disease in solid organ transplant recipients: a meta-analysis. Clin Transplant. 2008;22:89–97.PubMed
24.
go back to reference Peggs KS, Thomson K, Samuel E, et al. Directly selected cytomegalovirus-reactive donor T cells confer rapid and safe systemic reconstitution of virus-specific immunity following stem cell transplantation. Clin Infect Dis. 2011;52:49–57.PubMedCrossRef Peggs KS, Thomson K, Samuel E, et al. Directly selected cytomegalovirus-reactive donor T cells confer rapid and safe systemic reconstitution of virus-specific immunity following stem cell transplantation. Clin Infect Dis. 2011;52:49–57.PubMedCrossRef
25.
go back to reference Engstrand M, Lidehall AK, Totterman TH, Herrman B, Eriksson BM, Korsgren O. Cellular responses to cytomegalovirus in immunosuppressed patients: circulating CD8+ T cells recognizing CMVpp 65 are present but display functional impairment. Clin Exp Immunol. 2003;132(1):96–104.PubMedCrossRef Engstrand M, Lidehall AK, Totterman TH, Herrman B, Eriksson BM, Korsgren O. Cellular responses to cytomegalovirus in immunosuppressed patients: circulating CD8+ T cells recognizing CMVpp 65 are present but display functional impairment. Clin Exp Immunol. 2003;132(1):96–104.PubMedCrossRef
26.
go back to reference Sester M, Sester U, Gärtner B, et al. Levels of virus-specific CD4 T cells correlate with cytomegalovirus control and predict virus-induced disease after renal transplantation. Transplantation. 2001;71(9):1287–94.PubMedCrossRef Sester M, Sester U, Gärtner B, et al. Levels of virus-specific CD4 T cells correlate with cytomegalovirus control and predict virus-induced disease after renal transplantation. Transplantation. 2001;71(9):1287–94.PubMedCrossRef
27.
go back to reference Gratama JW, Brooimans RA, van der Holt B, et al. Monitoring cytomegalovirus IE-1 and pp 65-specific CD4+ and CD8+ T-cell responses after allogeneic stem cell transplantation may identify patients at risk for recurrent CMV reactivations. Cytometry B Clin Cytom. 2008;74(4):211–20.PubMed Gratama JW, Brooimans RA, van der Holt B, et al. Monitoring cytomegalovirus IE-1 and pp 65-specific CD4+ and CD8+ T-cell responses after allogeneic stem cell transplantation may identify patients at risk for recurrent CMV reactivations. Cytometry B Clin Cytom. 2008;74(4):211–20.PubMed
28.
go back to reference Kichner A, Hoffmeister B, Cherepnev-G G, et al. Dissection of the CMV specific T-cell response is required for optimized cardiac transplant monitoring. J Med Virol. 2008;80(9):1604–14.CrossRef Kichner A, Hoffmeister B, Cherepnev-G G, et al. Dissection of the CMV specific T-cell response is required for optimized cardiac transplant monitoring. J Med Virol. 2008;80(9):1604–14.CrossRef
29.
go back to reference Zhu J, Shearer GM, Marincola FM, et al. Discordant cellular and humoral immune responses to cytomegalovirus infection in healthy blood donors: existence of a Th1-type dominant response. Int Immunol. 2001;13(6):785–90.PubMedCrossRef Zhu J, Shearer GM, Marincola FM, et al. Discordant cellular and humoral immune responses to cytomegalovirus infection in healthy blood donors: existence of a Th1-type dominant response. Int Immunol. 2001;13(6):785–90.PubMedCrossRef
30.
go back to reference Manuel O, Pang XL, Humar A, et al. An assessment of donor-to-recipient transmission patterns of human cytomegalovirus by analysis of viral genomic variants. J Infect Dis. 2009;199(11):1621–28.PubMedCrossRef Manuel O, Pang XL, Humar A, et al. An assessment of donor-to-recipient transmission patterns of human cytomegalovirus by analysis of viral genomic variants. J Infect Dis. 2009;199(11):1621–28.PubMedCrossRef
31.
go back to reference Manuel O, Asberg A, Pang X, et al. Impact of genetic polymorphisms in cytomegalovirus glycoprotein B on outcomes in solid-organ transplant recipients with cytomegalovirus disease. Clin Infect Dis. 2009;49(8):1160–6.PubMedCrossRef Manuel O, Asberg A, Pang X, et al. Impact of genetic polymorphisms in cytomegalovirus glycoprotein B on outcomes in solid-organ transplant recipients with cytomegalovirus disease. Clin Infect Dis. 2009;49(8):1160–6.PubMedCrossRef
32.
go back to reference Tu W, Potena L, Stepick-Biek P, et al. T-cell immunity to subclinical cytomegalovirus infection reduces cardiac allograft disease. Circulation. 2006;114(15):1608–15.PubMedCrossRef Tu W, Potena L, Stepick-Biek P, et al. T-cell immunity to subclinical cytomegalovirus infection reduces cardiac allograft disease. Circulation. 2006;114(15):1608–15.PubMedCrossRef
33.
go back to reference Nickel P, Bold G, Presber F, et al. High levels of CMV-IE-1-specific memory T cells are associated with less alloimmunity and improved renal allograft function. Transpl Immunol. 2009;20(4):238–42.PubMedCrossRef Nickel P, Bold G, Presber F, et al. High levels of CMV-IE-1-specific memory T cells are associated with less alloimmunity and improved renal allograft function. Transpl Immunol. 2009;20(4):238–42.PubMedCrossRef
34.
go back to reference Amir AL, D'Orsogna LJ, Roelen DL, et al. Allo-HLA reactivity of virus-specific memory T cells is common. Blood. 2010;115(15):3146–57.PubMedCrossRef Amir AL, D'Orsogna LJ, Roelen DL, et al. Allo-HLA reactivity of virus-specific memory T cells is common. Blood. 2010;115(15):3146–57.PubMedCrossRef
35.
go back to reference Ouwehand AJ, Balk AH, Baan CC, Vaessen LM, Jutte NH, Bos E, Claas FH, Weimar W, et al. Cytomegalovirus infection and allospecific cytotoxic activity of graft-infiltrating cells after heart transplantation. J Med Virol. 1994;42(2):175–81.PubMedCrossRef Ouwehand AJ, Balk AH, Baan CC, Vaessen LM, Jutte NH, Bos E, Claas FH, Weimar W, et al. Cytomegalovirus infection and allospecific cytotoxic activity of graft-infiltrating cells after heart transplantation. J Med Virol. 1994;42(2):175–81.PubMedCrossRef
36.
go back to reference Ishibashi K, Tokumoto T, Shirakawa H, et al. Lack of antibodies against the antigen domain 2 epitope of cytomegalovirus (CMV) glycoprotein B is associated with CMV disease after renal transplantation in recipients having the same glycoprotein H serotypes as their donors. Transpl Infect Dis. 2011;13(3):318–23.PubMedCrossRef Ishibashi K, Tokumoto T, Shirakawa H, et al. Lack of antibodies against the antigen domain 2 epitope of cytomegalovirus (CMV) glycoprotein B is associated with CMV disease after renal transplantation in recipients having the same glycoprotein H serotypes as their donors. Transpl Infect Dis. 2011;13(3):318–23.PubMedCrossRef
Metadata
Title
Simultaneous Monitoring of Cytomegalovirus-Specific Antibody and T-cell levels in Seropositive Heart Transplant Recipients
Authors
Javier Carbone
Nallibe Lanio
Antonio Gallego
Florian Kern
Joaquin Navarro
Patricia Muñoz
Roberto Alonso
Pilar Catalán
Juan Fernández-Yáñez
Jesús Palomo
Manuel Ruiz
Eduardo Fernández-Cruz
Elizabeth Sarmiento
Publication date
01-08-2012
Publisher
Springer US
Published in
Journal of Clinical Immunology / Issue 4/2012
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-012-9670-7

Other articles of this Issue 4/2012

Journal of Clinical Immunology 4/2012 Go to the issue