title: Transplantation of IL-2-transduced murine bone marrow is associated with dose-dependent toxicity.
abstract: OBJECTIVE
  The purpose of this study was to investigate the effects of interleukin-2 (IL-2) gene-transduced hematopoietic progenitor cells or cytotoxic function and systemic toxicity following syngeneic bone marrow transplantation.
  
  
  METHODS
  Marrow of 5-fluorouracil pretreated donor mice were transfected with a retroviral vector containing the murine IL-2 gene and transplanted into lethally irradiated syngeneic hosts.
  
  
  RESULTS
  Productive insertion of the IL-2 gene could be demonstrated at various intervals post-transplant without impairment of hematopoietic engraftment. Endogenously augmented IL-2 release resulted in a selective increase in CD4(+), CD8(+), and NK1.1(+) population in spleen and bone marrow, as well as significant cytolytic activity against syngeneic leukemia cells in vitro. Our results also illustrate the interdependence among the magnitude of systemic IL-2 levels, the number of IL-2-transduced cells in the transplant inoculum, and the appearance of systemic toxicity. Infusion of marrow transduced with high-titer, high-expressing IL-2 retrovirus resulted in significant morbidity and mortality in the recipients. Our studies demonstrate that mortality was secondary to severe lymphocytic infiltration of liver and lung, which was associated with increased expression of intercellular adhesion molecule-1 and vascular adhesion molecule-1. Reducing the number of IL-2-transduced cells in the bone marrow inoculum, however, resulted in significantly improved survival with no adverse events being evident during the post-transplant period.
  
  
  CONCLUSIONS
  Delivery of IL-2 to the bone marrow can be achieved by transplantation of genetically modified hematopoietic cells, however, the overall feasibility is strongly influenced by the number of transduced cells in the bone marrow inocolum and/or the expression pattern of IL-2 in vivo.
authors.affiliation: Department of Internal Medicine, University of Innsbruck, Innsbruck, Austria. thomas.kuehr@uibk.ac.at
authors.forename: T
authors.initials: T
authors.lastname: Kühr
authors.forename: O
authors.initials: O
authors.lastname: Bechter
authors.forename: S
authors.initials: S
authors.lastname: Dirnhofer
authors.forename: S
authors.initials: S
authors.lastname: Geley
authors.forename: A
authors.initials: A
authors.lastname: Gächter
authors.forename: G
authors.initials: G
authors.lastname: Pall
authors.forename: M
authors.initials: M
authors.lastname: Url
authors.forename: H
authors.initials: H
authors.lastname: Dietrich
authors.forename: P
authors.initials: P
authors.lastname: Oberaigner
authors.forename: G
authors.initials: G
authors.lastname: Klima
authors.forename: W
authors.initials: W
authors.lastname: Eisterer
authors.forename: W
authors.initials: W
authors.lastname: Hilbe
authors.forename: P
authors.initials: P
authors.lastname: Lukas
authors.forename: J
authors.initials: J
authors.lastname: Thaler
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D016026:Bone Marrow Transplantation; D002452:Cell Count; D002455:Cell Division; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression; D005822:Genetic Vectors; D020544:Graft vs Leukemia Effect; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007376:Interleukin-2 / Q000235:genetics* / Q000276:immunology / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D007700:Kinetics; D051379:Mice; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis
chemical_list: D007376:Interleukin-2; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1