title: Immunotherapeutic strategies to prevent and treat human herpesvirus 6 reactivation after allogeneic stem cell transplantation.
abstract: Human herpesvirus (HHV) 6 causes substantial morbidity and mortality in the immunocompromised host and has no approved therapy. Adoptive transfer of virus specific T cells has proven safe and apparently effective as prophylaxis and treatment of other virus infections in immunocompromised patients; however, extension to subjects with HHV6 has been hindered by the paucity of information on targets of cellular immunity. We now characterize the cellular immune response from 20 donors against 5 major HHV6B antigens predicted to be immunogenic and define a hierarchy of immunodominance of antigens based on the frequency of responding donors and the magnitude of the T-cell response. We identified specific epitopes within these antigens and expanded the HHV6 reactive T cells using a GMP-compliant protocol. The expanded population comprised both CD4(+) and CD8(+) T cells that were able to produce multiple effector cytokines and kill both peptide-loaded and HHV6B wild-type virus-infected target cells. Thus, we conclude that adoptive T-cell immunotherapy for HHV6 is a practical objective and that the peptide and epitope tools we describe will allow such cells to be prepared, administered, and monitored in human subjects.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Methodist Hospital, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Gerdemann
authors.forename: Laura
authors.initials: L
authors.lastname: Keukens
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Keirnan
authors.forename: Usha L
authors.initials: UL
authors.lastname: Katari
authors.forename: Chinh T Q
authors.initials: CT
authors.lastname: Nguyen
authors.forename: Anne P
authors.initials: AP
authors.lastname: de Pagter
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Ramos
authors.forename: Alana
authors.initials: A
authors.lastname: Kennedy-Nasser
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Gottschalk
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
authors.forename: Ann M
authors.initials: AM
authors.lastname: Leen
mesh_terms: D000956:Antigens, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured / Q000276:immunology; D018920:Coculture Techniques; D003587:Cytomegalovirus / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D051858:Forkhead Transcription Factors / Q000032:analysis; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D015654:Herpesvirus 6, Human / Q000276:immunology* / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D016867:Immunocompromised Host; D016056:Immunodominant Epitopes / Q000276:immunology; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D009000:Monocytes / Q000276:immunology; D019349:Roseolovirus Infections / Q000517:prevention & control / Q000628:therapy*; D037182:T-Cell Antigen Receptor Specificity; D014184:Transplantation, Homologous / Q000009:adverse effects*; D014775:Virus Activation / Q000276:immunology
chemical_list: D000956:Antigens, Viral; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016056:Immunodominant Epitopes