title: In vivo T-cell dynamics during immune reconstitution after hematopoietic stem cell gene therapy in adenosine deaminase severe combined immune deficiency.
abstract: BACKGROUND
  Gene therapy (GT) with hematopoietic stem cells is a promising treatment for inherited immunodeficiencies.
  
  
  OBJECTIVE
  Limited information is available on the relative contribution of de novo thymopoiesis and peripheral expansion to T-cell reconstitution after GT as well as on the potential effects of gene transfer on hematopoietic stem cells and lymphocyte replicative lifespan. We studied these issues in patients affected by adenosine deaminase severe combined immune deficiency after low-intensity conditioning and reinfusion of retrovirally transduced autologous CD34(+) cells.
  
  
  METHODS
  Immunophenotype, proliferative status, telomere length, and T-cell receptor excision circles were investigated at early and late time points (up to 9 years) after GT treatment. Control groups consisted of pediatric healthy donors and patients undergoing allogeneic bone marrow transplantation (BMT).
  
  
  RESULTS
  We observed no telomere shortening in the bone marrow compartment and in granulocytes, whereas peripheral blood naive T cells from both GT and BMT patients showed a significant reduction in telomere length compared with healthy controls. This was in agreement with the presence of a high fraction of actively cycling naive and memory T cells and lower T-cell receptor excision circles.
  
  
  CONCLUSIONS
  These data indicate that T-cell homeostatic expansion contributes substantially to immune reconstitution, like BMT, and is not associated with senescence in the stem cell compartment.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Selleri
authors.forename: Immacolata
authors.initials: I
authors.lastname: Brigida
authors.forename: Miriam
authors.initials: M
authors.lastname: Casiraghi
authors.forename: Samantha
authors.initials: S
authors.lastname: Scaramuzza
authors.forename: Barbara
authors.initials: B
authors.lastname: Cappelli
authors.forename: Barbara
authors.initials: B
authors.lastname: Cassani
authors.forename: Francesca
authors.initials: F
authors.lastname: Ferrua
authors.forename: Memet
authors.initials: M
authors.lastname: Aker
authors.forename: Shimon
authors.initials: S
authors.lastname: Slavin
authors.forename: Alessia
authors.initials: A
authors.lastname: Scarselli
authors.forename: Caterina
authors.initials: C
authors.lastname: Cancrini
authors.forename: Sarah
authors.initials: S
authors.lastname: Marktel
authors.forename: Maria
authors.initials: M
authors.lastname: Grazia Roncarolo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D000328:Adult; D000361:Agammaglobulinemia / Q000235:genetics / Q000276:immunology / Q000628:therapy; D016026:Bone Marrow Transplantation; D016022:Case-Control Studies; D002453:Cell Cycle; D016922:Cellular Senescence / Q000235:genetics; D002648:Child; D015316:Genetic Therapy / Q000379:methods*; D006098:Granulocytes / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007156:Immunologic Memory; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000628:therapy; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D016615:Telomere / Q000235:genetics; D014182:Transplantation, Autologous; D014184:Transplantation, Homologous
chemical_list: D016692:Receptors, Antigen, T-Cell, gamma-delta; D000243:Adenosine Deaminase