TY - JOUR
T1 - 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
AU - Rettig, Michael P.
AU - Ritchey, Julie K.
AU - Prior, Julie L.
AU - Haug, Jeffrey S.
AU - Piwnica-Worms, David
AU - DiPersio, John F.
PY - 2004/9/15
Y1 - 2004/9/15
N2 - 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 (ACD34-tk). ACD34-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 ΔCD34-tk suicide gene in the absence of extended ex vivo manipulation by generating transgenic animals that express ΔCD34-tk in the peripheral and thymic T cell compartments using the CD2 locus control region. We found that ΔCD34-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 ΔCD34-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 ΔCD34-tk-expressing T cells. This murine model demonstrates the potential usefulness of ΔCD34-tk-expressing T cells to control GVHD, promote alloengraftment, and provide a graft-vs-leukemia effect in man.
AB - 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 (ACD34-tk). ACD34-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 ΔCD34-tk suicide gene in the absence of extended ex vivo manipulation by generating transgenic animals that express ΔCD34-tk in the peripheral and thymic T cell compartments using the CD2 locus control region. We found that ΔCD34-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 ΔCD34-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 ΔCD34-tk-expressing T cells. This murine model demonstrates the potential usefulness of ΔCD34-tk-expressing T cells to control GVHD, promote alloengraftment, and provide a graft-vs-leukemia effect in man.
UR - http://www.scopus.com/inward/record.url?scp=4644285690&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.173.6.3620
DO - 10.4049/jimmunol.173.6.3620
M3 - Article
C2 - 15356106
AN - SCOPUS:4644285690
SN - 0022-1767
VL - 173
SP - 3620
EP - 3630
JO - Journal of Immunology
JF - Journal of Immunology
IS - 6
ER -