title: Combined CD8+ and CD4+ adenovirus hexon-specific T cells associated with viral clearance after stem cell transplantation as treatment for adenovirus infection.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. m.l.zandvliet@lumc.nl
authors.forename: Maarten L
authors.initials: ML
authors.lastname: Zandvliet
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
authors.forename: Ellis
authors.initials: E
authors.lastname: van Liempt
authors.forename: Louise A
authors.initials: LA
authors.lastname: Veltrop-Duits
authors.forename: Arjan C
authors.initials: AC
authors.lastname: Lankester
authors.forename: Jayant S
authors.initials: JS
authors.lastname: Kalpoe
authors.forename: Michel G D
authors.initials: MG
authors.lastname: Kester
authors.forename: Dirk M
authors.initials: DM
authors.lastname: van der Steen
authors.forename: Maarten J
authors.initials: MJ
authors.lastname: van Tol
authors.forename: Roel
authors.initials: R
authors.lastname: Willemze
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.forename: Marco W
authors.initials: MW
authors.lastname: Schilham
authors.forename: Pauline
authors.initials: P
authors.lastname: Meij
mesh_terms: 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
chemical_list: D036022:Capsid Proteins; C018315:hexon capsid protein, Adenovirus