title: Tetramer monitoring to assess risk factors for recurrent cytomegalovirus reactivation and reconstitution of antiviral immunity post allogeneic hematopoietic stem cell transplantation.
abstract: BACKGROUND
  Reactivation of cytomegalovirus (CMV) is a major cause of morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). In healthy individuals, virus-specific T cells (CMV-CTL) control the reactivation of latent CMV. The monitoring of virus-epitope-binding CD8(+) T cells using major histocompatibility complex-I-peptide complexes (tetramers) has recently been established, allowing assessment of the reconstitution of CMV-CTL post HSCT.
  
  
  METHODS
  In order to study immune reconstitution and reactivation control through CMV-CTL, we regularly monitored all patients undergoing allogeneic HSCT in our department for 2 years, who matched at least 1 of 6 commercially available tetramers for common human leukocyte antigen (HLA) types. To verify risk factors for CMV reactivations in our cohorts, clinical characteristics of all patients transplanted within the last 10 years were included in statistical analyses determining the relative risk for single and recurrent CMV reactivations.
  
  
  RESULTS
  As expected, CMV serostatus, HLA match, and donor source significantly influenced the risk of recurrent CMV reactivation. Applying CMV-CTL tetramer monitoring for 2 years allowed the monitoring of 114 (85%) of 134 patients, by testing a set of tetramers representing 6 epitopes from 3 different CMV proteins. The presence of CMV-CTL before day + 50 and their expansion post reactivation seem to protect against recurrent CMV reactivations. The mean number of CMV-CTL by day +100 was >5-fold higher in the recipient CMV-positive/donor-positive (R +/D +) group (91/μL) compared with the R +/ D- (13/μL) and the R -/D +(2/μL) group. Seventy-nine percent of patients from the R +/D + setting recovered >10 CMV-CTL per μL by day + 100, while almost 50% of the other groups failed to mount a CMV-specific response by that time (R +/D -: 58%; R -/D +: 43%).
  
  
  CONCLUSIONS
  Tetramer monitoring can help to predict (recurrent) CMV reactivation and is a useful approach to monitor individual patients with increased risk for recurrent reactivation post HSCT; thus, it could help to identify patients in need of adoptive transfer of CMV-CTL or to optimize the use of antiviral drugs.
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Borchers
authors.forename: S
authors.initials: S
authors.lastname: Luther
authors.forename: U
authors.initials: U
authors.lastname: Lips
authors.forename: N
authors.initials: N
authors.lastname: Hahn
authors.forename: J
authors.initials: J
authors.lastname: Kontsendorn
authors.forename: M
authors.initials: M
authors.lastname: Stadler
authors.forename: S
authors.initials: S
authors.lastname: Buchholz
authors.forename: H
authors.initials: H
authors.lastname: Diedrich
authors.forename: M
authors.initials: M
authors.lastname: Eder
authors.forename: U
authors.initials: U
authors.lastname: Koehl
authors.forename: A
authors.initials: A
authors.lastname: Ganser
authors.forename: E
authors.initials: E
authors.lastname: Mischak-Weissinger
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015331:Cohort Studies; D003587:Cytomegalovirus / Q000276:immunology / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000175:diagnosis / Q000276:immunology / Q000821:virology; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000276:immunology*; D010455:Peptides / Q000276:immunology*; D012008:Recurrence; D012307:Risk Factors; D014184:Transplantation, Homologous / Q000009:adverse effects; D014775:Virus Activation / Q000502:physiology*
chemical_list: D015395:Histocompatibility Antigens Class I; D046912:Multiprotein Complexes; D010455:Peptides