Haematologica
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Haematologica, Vol 93, Issue 2, 248-256 doi:10.3324/haematol.11912
Copyright © 2008 by Ferrata Storti Foundation
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Stem Cell Transplantation

Human cytomegalovirus-specific CD4+ and CD8+ T-cell reconstitution in adult allogeneic hematopoietic stem cell transplant recipients and immune control of viral infection

Daniele Lilleri1, Chiara Fornara1, Antonella Chiesa1, Daniela Caldera2, Emilio Paolo Alessandrino2, Giuseppe Gerna1,

1 Servizio di Virologia and
2 Divisione di Ematologia, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy

Correspondence: Giuseppe Gerna, Servizio di Virologia, Fondazione IRCCS Policlinico San, Matteo, 27100 Pavia, Italy., E-mail: g.gerna{at}smatteo.pv.it

Background: Human cytomegalovirus infection is the most frequent viral complication in patients undergoing hematopoietic stem cell transplantation. We investigated the development of human cytomegalovirus-specific T cells in adult recipients of hematopoietic stem cell transplants.

Design and Methods: From May 2003 through October 2006 a total of 45 patients were monitored for human cytomegalovirus-specific T-cell reconstitution. Human cytomegalovirus-infected autologous dendritic cells were used as a stimulus to detect interferon-{gamma}-producing human cytomegalovirus-specific CD8+ and CD4+ T cells during the first year after transplantation. Interleukin-2 production by specific T cells was also determined.


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  		Figure 1. Probability of HCMV infection development and HCMV-specific CD4+ and CD8+ T-cell immunity reconstitution. A: cumulative incidence curves of HCMV infection according to donor (D) and recipient (R) HCMV-serostatus. B: cumulative incidence curves of HCMV infection and HCMV-specific CD8+ and CD4+ T-cell reconstitution (i.e. corresponding to a specific T-cell number greater than 0.4 cells/µL blood). C: cumulative incidence curves of HCMV-specific CD8+ T-cell reconstitution according to D/R HCMV-serostatus. D: cumulative incidence curves of HCMV-specific CD4+ T-cell reconstitution according to D/R HCMV-serostatus.

 
Results: Human cytomegalovirus infection was detected in the blood of 39/45 patients at a median of 29 days after transplantation. Human cytomegalovirus-specific T-cell reconstitution followed reactivation of latent human cytomegalovirus infection at a median time of about 2 months after transplantation. Only donor human cytomegalovirus-seronegativity and bone marrow as a stem cell source were found to delay specific T-cell reconstitution significantly. Levels of three CD8+ and one CD4+ human cytomegalovirus-specific T-cells/µL blood had a positive predictive value of around 80% for identifying patients able to control human cytomegalovirus infection spontaneously. Five patients who received high doses of steroids for treatment of graft-versus-host disease developed human cytomegalovirus infection requiring pre-emptive treatment despite high levels of interferon-{gamma}-producing T cells in response to human cytomegalovirus. Specific interleukin-2 production was not detected in patients with human cytomegalovirus infection requiring treatment, while 90% of patients who spontaneously controlled human cytomegalovirus infection had T cells that produced interleukin-2 and interferon-{gamma}.

Conclusions: Pre-transplant human cytomegalovirus infection of the recipient is a major factor driving human cytomegalovirus-specific immune reconstitution. Control of human cytomegalovirus infection likely requires the presence of both interferon-{gamma} and interleukin-2 producing T cells. Corticosteroid treatment may favor active viral replication even in patients with specific T cells.

Key words: human cytomegalovirus, specific T cells, stem cell transplantation.






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