Combined CD8+ and CD4+ adenovirus hexon-specific T cells associated with viral clearance after stem cell transplantation as treatment for adenovirus infection.
BACKGROUND
Human adenovirus can cause morbidity and mortality in immunocompromised patients after allogeneic stem cell transplantation. Reconstitution of adenovirus-specific CD4(+) T cells has been reported to be associated with sustained protection from adenovirus disease, but epitope specificity of these responses has not been characterized. Since mainly CD4(+) T cells and no CD8(+) T cells specific for adenovirus have been detected after allogeneic stem cell transplantation, the relative contribution of adenovirus-specific CD4(+) and CD8(+) T cells in protection from adenovirus disease remains to be elucidated.


METHODS
The presence of human adenovirus hexon-specific T cells was investigated in peripheral blood of pediatric and adult allogeneic stem cell transplant recipients, who showed spontaneous resolution of disseminated adenovirus infection. Subsequently, a clinical grade method was developed for rapid generation of adenovirus-specific T-cell lines for adoptive immunotherapy.


RESULTS
Clearance of human adenovirus viremia coincided with emergence of a coordinated CD8(+) and CD4(+) T-cell response against adenovirus hexon epitopes in patients after allogeneic stem cell transplantation. Activation of adenovirus hexon-specific CD8(+) and CD4(+) T cells with a hexon protein-spanning peptide pool followed by interferon-γ-based isolation allowed rapid expansion of highly specific T-cell lines from healthy adults, including donors with very low frequencies of adenovirus hexon-specific T cells. Adenovirus-specific T-cell lines recognized multiple MHC class I and II restricted epitopes, including known and novel epitopes, and efficiently lysed human adenovirus-infected target cells.


CONCLUSIONS
This study provides a rationale and strategy for the adoptive transfer of donor-derived human adenovirus hexon-specific CD8(+) and CD4(+) T cells for the treatment of disseminated adenovirus infection after allogeneic stem cell transplantation.
Zandvliet
Maarten L
ML
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. m.l.zandvliet@lumc.nl
Falkenburg
J H Frederik
JH
van Liempt
Ellis
E
Veltrop-Duits
Louise A
LA
Lankester
Arjan C
AC
Kalpoe
Jayant S
JS
Kester
Michel G D
MG
van der Steen
Dirk M
DM
van Tol
Maarten J
MJ
Willemze
Roel
R
Guchelaar
Henk-Jan
HJ
Schilham
Marco W
MW
Meij
Pauline
P
D000256:Adenoviridae; D000257:Adenoviridae Infections / Q000097:blood / Q000209:etiology / Q000276:immunology / Q000628:therapy*; D019264:Adoptive Transfer / Q000379:methods*; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D036022:Capsid Proteins / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D033581:Stem Cell Transplantation; D014184:Transplantation, Homologous; D014766:Viremia / Q000276:immunology / Q000628:therapy
D036022:Capsid Proteins; C018315:hexon capsid protein, Adenovirus