title: Kinetics of in vivo elimination of suicide gene-expressing T cells affects engraftment, graft-versus-host disease, and graft-versus-leukemia after allogeneic bone marrow transplantation.
abstract: Suicide gene therapy is one approach being evaluated for the control of graft-vs-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). We recently constructed a novel chimeric suicide gene in which the entire coding region of HSV thymidine kinase (HSV-tk) was fused in-frame to the extracellular and transmembrane domains of human CD34 (DeltaCD34-tk). DeltaCD34-tk is an attractive candidate as a suicide gene in man because of the ensured expression of HSV-tk in all selected cells and the ability to rapidly and efficiently purify gene-modified cells using clinically approved CD34 immunoselection techniques. In this study we assessed the efficacy of the DeltaCD34-tk suicide gene in the absence of extended ex vivo manipulation by generating transgenic animals that express DeltaCD34-tk in the peripheral and thymic T cell compartments using the CD2 locus control region. We found that DeltaCD34-tk-expressing T cells could be purified to near homogeneity by CD34 immunoselection and selectively eliminated ex vivo and in vivo when exposed to low concentrations of GCV. The optimal time to administer GCV after allogeneic BMT with DeltaCD34-tk-expressing transgenic T cells was dependent on the intensity of the conditioning regimen, the leukemic status of the recipient, and the dose and timing of T cell infusion. Importantly, we used a controlled graft-vs-host reaction to promote alloengraftment in sublethally irradiated mice and provide a graft-vs-leukemia effect in recipients administered a delayed infusion of DeltaCD34-tk-expressing T cells. This murine model demonstrates the potential usefulness of DeltaCD34-tk-expressing T cells to control GVHD, promote alloengraftment, and provide a graft-vs-leukemia effect in man.
authors.affiliation: Division of Oncology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Rettig
authors.forename: Julie K
authors.initials: JK
authors.lastname: Ritchey
authors.forename: Julie L
authors.initials: JL
authors.lastname: Prior
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Haug
authors.forename: David
authors.initials: D
authors.lastname: Piwnica-Worms
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000473:pathology; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D015774:Ganciclovir / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D041722:Genes, Transgenic, Suicide / Q000276:immunology*; D006085:Graft Survival / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control; D020544:Graft vs Leukemia Effect / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007700:Kinetics; D017710:Lymphocyte Transfusion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011828:Radiation Chimera / Q000276:immunology; D018139:Simplexvirus / Q000201:enzymology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000637:transplantation*; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D019172:Transplantation Conditioning / Q000009:adverse effects
chemical_list: D018952:Antigens, CD34; D013937:Thymidine Kinase; D015774:Ganciclovir