title: Impaired recovery of Epstein-Barr virus (EBV)--specific CD8+ T lymphocytes after partially T-depleted allogeneic stem cell transplantation may identify patients at very high risk for progressive EBV reactivation and lymphoproliferative disease.
abstract: Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes are considered pivotal to prevent lymphoproliferative disease (LPD) in allogeneic stem cell transplantation (SCT) recipients. We evaluated the recovery of EBV-specific CD8+ T cells after partially T-cell-depleted SCT and studied the interaction between EBV-specific CD8+ T cells, EBV reactivation, and EBV-LPD. EBV-specific CD8+ T cells were enumerated using 12 class I HLA tetramers presenting peptides derived from 7 EBV proteins. Blood samples were taken at regular intervals after SCT in 61 patients, and EBV DNA levels were assessed by real-time polymerase chain reaction. Forty-five patients showed EBV reactivation, including 25 with high-level reactivation (ie, more than 1000 genome equivalents [geq] per milliliter). Nine of these 25 patients progressed to EBV-LPD. CD8+ T cells specific for latent or lytic EBV epitopes repopulated the peripheral blood at largely similar rates. In most patients, EBV-specific CD8+ T-cell counts had returned to normal levels within 6 months after SCT. Concurrently, the incidence of EBV reactivations clearly decreased. Patients with insufficient EBV-specific CD8+ T-cell recovery were at high risk for EBV reactivation in the first 6 months after SCT. Failure to detect EBV-specific CD8+ T cells in patients with high-level reactivation was associated with the subsequent development of EBV-LPD (P =.048). Consequently, the earlier defined positive predictive value of approximately 40%, based on high-level EBV reactivation only, increased to 100% in patients without detectable EBV-specific CD8+ T cells. Thus, impaired recovery of EBV-specific CD8+ T cells in patients with high-level EBV reactivation may identify a subgroup at very high risk for EBV-LPD and supports that EBV-specific CD8+ T cells protect SCT recipients from progressive EBV reactivation and EBV-LPD.
authors.affiliation: Department of Internal Oncology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Pauline
authors.initials: P
authors.lastname: Meij
authors.forename: Joost W J
authors.initials: JW
authors.lastname: van Esser
authors.forename: Hubert G M
authors.initials: HG
authors.lastname: Niesters
authors.forename: Debbie
authors.initials: D
authors.lastname: van Baarle
authors.forename: Frank
authors.initials: F
authors.lastname: Miedema
authors.forename: Neil
authors.initials: N
authors.lastname: Blake
authors.forename: Alan B
authors.initials: AB
authors.lastname: Rickinson
authors.forename: Ingrid
authors.initials: I
authors.lastname: Leiner
authors.forename: Eric
authors.initials: E
authors.lastname: Pamer
authors.forename: Bob
authors.initials: B
authors.lastname: Lowenberg
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Cornelissen
authors.forename: Jan W
authors.initials: JW
authors.lastname: Gratama
mesh_terms: D000293:Adolescent; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D005260:Female; D019337:Hematologic Neoplasms / Q000150:complications / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects* / Q000379:methods; D004854:Herpesvirus 4, Human / Q000276:immunology* / Q000502:physiology; D006801:Humans; D015994:Incidence; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D008232:Lymphoproliferative Disorders / Q000209:etiology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012306:Risk; D014184:Transplantation, Homologous; D014775:Virus Activation