Abstract
Reactivation of CMV is a common complication following allogeneic haematopoietic SCT and is associated with significant morbidity and mortality. The relative importance of the CD4+ and CD8+ components of the CMV-specific immune response in protection from reactivation is unclear. The CMV-specific CD4+ and CD8+ immune response was measured at serial time points in 32 patients following allogeneic HSCT. Intracellular cytokine staining following CMV lysate stimulation and HLA-peptide tetramers were used to determine CMV-specific CD4+ and CD8+ responses, respectively. A deficient CMV-specific CD4+ T-cell immune response within the first 30–50 days post transplant was associated with high risk of viral reactivation. Patients with combined impairment of the CD4+ and CD8+ immune response within the first 100 days were susceptible to late viral reactivation. The frequency of CMV-specific CD4+ T cells correlated with CMV-specific CD8+ T cells, comprising 10% of the whole T-cell repertoire. Early CMV-specific CD4+ T-cell reconstitution was dominated by effector memory cells with normal levels of IL-2 resuming 6 months following transplantation. In summary, both CD4 and CD8 CMV-specific immune reconstitution is required for protection from recurrent activation. Measurement of the magnitude of the CMV-specific CD4+ immune response is useful in managing viral reactivation following HSCT.
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References
Maury S, Mary JY, Rabian C, Schwarzinger M, Toubert A, Scieux C et al. Prolonged immune deficiency following allogeneic stem cell transplantation: risk factors and complications in adult patients. Br J Haematol 2001; 115: 630–641.
Broers AE, van Der Holt R, van Esser JW, Gratama JW, Henzen-Logmans S, Kuenen-Boumeester V et al. Increased transplant-related morbidity and mortality in CMV-seropositive patients despite highly effective prevention of CMV disease after allogeneic T-cell-depleted stem cell transplantation. Blood 2000; 95: 2240–2245.
Kroger N, Zabelina T, Kruger W, Renges H, Stute N, Schrum J et al. Patient cytomegalovirus seropositivity with or without reactivation is the most important prognostic factor for survival and treatment-related mortality in stem cell transplantation from unrelated donors using pretransplant in vivo T-cell depletion with anti-thymocyte globulin. Br J Haematol 2001; 113: 1060–1071.
Goodrich JM, Mori M, Gleaves CA, Du Mond C, Cays M, Ebeling DF et al. Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation. N Engl J Med 1991; 325: 1601–1607.
Li CR, Greenberg PD, Gilbert MJ, Goodrich JM, Riddell SR . Recovery of HLA-restricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis. Blood 1994; 83: 1971–1979.
Cwynarski K, Ainsworth J, Cobbold M, Wagner S, Mahendra P, Apperley J et al. Direct visualization of cytomegalovirus-specific T-cell reconstitution after allogeneic stem cell transplantation. Blood 2001; 97: 1232–1240.
Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS, Thomas ED et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 1995; 333: 1038–1044.
Sester M, Sester U, Gartner B, Heine G, Girndt M, Mueller-Lantzsch N et al. Levels of virus-specific CD4 T cells correlate with cytomegalovirus control and predict virus-induced disease after renal transplantation. Transplantation 2001; 71: 1287–1294.
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: 2686–2692.
Boeckh M, Gooley TA, Myerson D, Cunningham T, Schoch G, Bowden RA . Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. Blood 1996; 88: 4063–4071.
Hakki M, Riddell SR, Storek J, Carter RA, Stevens-Ayers T, Sudour P et al. Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation. Blood 2003; 102: 3060–3067.
Ozdemir E, St John LS, Gillespie G, Rowland-Jones S, Champlin RE, Molldrem JJ et al. Cytomegalovirus reactivation following allogeneic stem cell transplantation is associated with the presence of dysfunctional antigen-specific CD8+ T cells. Blood 2002; 100: 3690–3697.
Avetisyan G, Aschan J, Hagglund H, Ringden O, Ljungman P . Evaluation of intervention strategy based on CMV-specific immune responses after allogeneic SCT. Bone Marrow Transplant 2007; 40: 865–869.
Lilleri D, Gerna G, Fornara C, Lozza L, Maccario R, Locatelli F . Prospective simultaneous quantification of human cytomegalovirus-specific CD4+ and CD8+ T-cell reconstitution in young recipients of allogeneic hematopoietic stem cell transplants. Blood 2006; 108: 1406–1412.
Suni MA, Picker LJ, Maino VC . Detection of antigen-specific T cell cytokine expression in whole blood by flow cytometry. J Immunol Methods 1998; 212: 89–98.
Altman JD, Moss PA, Goulder PJ, Barouch DH, McHeyzer-Williams MG, Bell JI et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 1996; 274: 94–96.
Ozdemir E, Saliba RM, Champlin RE, Couriel DR, Giralt SA, de Lima M et al. Risk factors associated with late cytomegalovirus reactivation after allogeneic stem cell transplantation for hematological malignancies. Bone Marrow Transplant 2007; 40: 125–136.
Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A . Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999; 401: 708–712.
Ljungman P . Risk assessment in haematopoietic stem cell transplantation: viral status. Best Pract Res Clin Haematol 2007; 20: 209–217.
Kalpoe JS, van der Heiden PL, Vaessen N, Claas EC, Barge RM, Kroes AC . Comparable incidence and severity of cytomegalovirus infections following T cell-depleted allogeneic stem cell transplantation preceded by reduced intensity or myeloablative conditioning. Bone Marrow Transplant 2007; 40: 137–143.
Lamba R, Carrum G, Myers GD, Bollard CM, Krance RA, Heslop HE et al. Cytomegalovirus (CMV) infections and CMV-specific cellular immune reconstitution following reduced intensity conditioning allogeneic stem cell transplantation with Alemtuzumab. Bone Marrow Transplant 2005; 36: 797–802.
Walker CM, van Burik JA, De For TE, Weisdorf DJ . Cytomegalovirus infection after allogeneic transplantation: comparison of cord blood with peripheral blood and marrow graft sources. Biol Blood Marrow Transplant 2007; 13: 1106–1115.
Reusser P, Riddell SR, Meyers JD, Greenberg PD . Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease. Blood 1991; 78: 1373–1380.
Gratama JW, van Esser JW, Lamers CH, Tournay C, Lowenberg B, Bolhuis RL et al. Tetramer-based quantification of cytomegalovirus (CMV)-specific CD8+ T lymphocytes in T-cell-depleted stem cell grafts and after transplantation may identify patients at risk for progressive CMV infection. Blood 2001; 98: 1358–1364.
Bitmansour AD, Waldrop SL, Pitcher CJ, Khatamzas E, Kern F, Maino VC et al. Clonotypic structure of the human CD4+ memory T cell response to cytomegalovirus. J Immunol 2001; 167: 1151–1163.
Gamadia LE, Rentenaar RJ, van Lier RA, ten Berge IJ . Properties of CD4(+) T cells in human cytomegalovirus infection. Hum Immunol 2004; 65: 486–492.
Foster AE, Gottlieb DJ, Sartor M, Hertzberg MS, Bradstock KF . Cytomegalovirus-specific CD4+ and CD8+ T-cells follow a similar reconstitution pattern after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2002; 8: 501–511.
Hebart H, Daginik S, Stevanovic S, Grigoleit U, Dobler A, Baur M et al. Sensitive detection of human cytomegalovirus peptide-specific cytotoxic T-lymphocyte responses by interferon-gamma-enzyme-linked immunospot assay and flow cytometry in healthy individuals and in patients after allogeneic stem cell transplantation. Blood 2002; 99: 3830–3837.
Komanduri KV, Viswanathan MN, Wieder ED, Schmidt DK, Bredt BM, Jacobson MA et al. Restoration of cytomegalovirus-specific CD4(+) T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1. Nat Med 1998; 4: 953–956.
Wursch AM, Gratama JW, Middeldorp JM, Nissen C, Gratwohl A, Speck B et al. The effect of cytomegalo-virus infection on lymphocytes-T after allogeneic bone-marrow transplantation. Clin Exp Immunol 1985; 62: 278–287.
Einsele H, Ehninger G, Steidle M, Fischer I, Bihler S, Gerneth F et al. Lymphocytopenia as an unfavorable prognostic factor in patients with cytomegalovirus infection after bone marrow transplantation. Blood 1993; 82: 1672–1678.
Reeves MB, MacAry PA, Lehner PJ, Sissons JGP, Sinclair JH . Latency, chromatin remodeling, and reactivation of human cytomegalovirus in the dendritic cells of healthy carriers. Proc Natl Acad Sci USA 2005; 102: 4140–4145.
Pourgheysari B, Khan N, Best D, Bruton R, Nayak L, Moss PA . The cytomegalovirus-specific CD4+ T-cell response expands with age and markedly alters the CD4+ T-cell repertoire. J Virol 2007; 81: 7759–7765.
Gallez-Hawkins G, Thao L, Lacey SF, Martinez J, Li X, Franck AE et al. Cytomegalovirus immune reconstitution occurs in recipients of allogeneic hematopoietic cell transplants irrespective of detectable cytomegalovirus infection. Biol Blood Marrow Transplant 2005; 11: 890–902.
Wills MR, Carmichael AJ, Mynard K, Jin X, Weekes MP, Plachter B et al. The human cytotoxic T-lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp65: frequency, specificity, and T-cell receptor usage of pp65-specific CTL. J Virol 1996; 70: 7569–7579.
Bunde T, Kirchner A, Hoffmeister B, Habedank D, Hetzer R, Cherepnev G et al. Protection from cytomegalovirus after transplantation is correlated with immediate early 1-specific CD8 T cells. J Exp Med 2005; 201: 1031–1036.
Lacey SF, La Rosa C, Zhou W, Sharma MC, Martinez J, Krishnan A et al. Functional comparison of T cells recognizing cytomegalovirus pp65 and intermediate-early antigen polypeptides in hematopoietic stem-cell transplant and solid organ transplant recipients. J Infect Dis 2006; 194: 1410–1421.
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: 633–644.
Lilleri D, Zelini P, Fornara C, Comolli G, Gerna G . Inconsistent responses of cytomegalovirus-specific T cells to pp65 and IE-1 versus infected dendritic cells in organ transplant recipients. Am J Transplant 2007; 7: 1997–2005.
Acknowledgements
We thank the Leukemia Research Fund for financial support (Grant 9904). BP was supported by a scholarship from the Government of Iran.
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Pourgheysari, B., Piper, K., McLarnon, A. et al. Early reconstitution of effector memory CD4+ CMV-specific T cells protects against CMV reactivation following allogeneic SCT. Bone Marrow Transplant 43, 853–861 (2009). https://doi.org/10.1038/bmt.2008.403
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DOI: https://doi.org/10.1038/bmt.2008.403
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