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Blood, 15 May 2002, Vol. 99, No. 10, pp. 3830-3837
TRANSPLANTATION
Sensitive detection of human cytomegalovirus peptide-specific
cytotoxic T-lymphocyte responses by interferon- -enzyme-linked
immunospot assay and flow cytometry in healthy individuals and
in patients after allogeneic stem cell transplantation
Holger Hebart,
Senay Daginik,
Stefan Stevanovic,
Ulrich Grigoleit,
Andrea Dobler,
Manuela Baur,
Georg Rauser,
Christian Sinzger,
Gerhard Jahn,
Juergen Loeffler,
Lothar Kanz,
Hans-Georg Rammensee, and
Hermann Einsele
From Medizinische Klinik II, Institut für
Zellbiologie, and Medizinische Virologie,
Eberhard-Karls-Universität Tübingen, Germany.
Reconstitution of human cytomegalovirus (HCMV)-specific cytotoxic
T lymphocytes (CTLs), predominantly directed against pp65, provides
protective immunity for the development of HCMV disease after
allogeneic stem cell transplantation (SCT). To define pp65-derived CTL
epitopes that would allow sensitive detection of HCMV-specific immune
reconstitution, a computer-based epitope prediction was performed.
Peptide-specific CTL responses were assessed by interferon- release.
With this approach, pp65-derived epitopes presented by the HLA alleles
A*0101, A*0201, A*1101, and B*0702 were identified. The frequency of
CTLs in healthy HCMV-seropositive individuals ranged from about 0.1%
to 3.3% of all CD8+ T cells. In patients at risk of HCMV
infection after allogeneic SCT, HCMV-peptide-specific CTLs were found
in 14 of 19 patients at a median of 90 days after SCT (range, 35-234 days) and HCMV-antigen-specific CD4+ T lymphocytes in 11 of 18 patients at a median of 90 days after SCT (range, 35->180
days). Peak counts of peptide-specific CD8+ T cells ranged
from 0.14 to 60.6 cells/µL; those of protein-specific CD4+ T cells ranged from 0.64 to 18.97 cells/µL.
Reconstitution of HCMV-peptide-specific CD8+ T cells and
protein-specific CD4+ T cells was associated with clearance
of HCMV infection (r2 = 0.89, P < .0001
and r2 = 0.61, P = .0045, respectively).
HCMV infection recurred after documentation of HCMV-specific T-cell
reconstitution (n = 4) when immunosuppression was intensified.
Patients in whom late-onset HCMV disease developed lacked
HCMV-protein-specific T cells at 3 months after SCT. In conclusion,
prospective monitoring of HCMV-specific CD4+ and
CD8+ T-cell reconstitution can be performed rapidly by
using flow cytometry after specific stimulation with HCMV peptides and
proteins and might help to further improve clinical management of HCMV infection after allogeneic SCT.
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