Prevention of graft-versus-host disease in mice using a suicide gene expressed in T lymphocytes.
Alloreactive T cells present in a bone marrow transplant are responsible for graft-versus-host disease (GVHD), but their depletion is associated with impaired engraftment, immunosuppression, and loss of the graft-versus-leukemia effect. We developed a therapeutic strategy against GVHD based on the selective destruction of these alloreactive T cells, while preserving a competent T-cell pool of donor origin. We generated transgenic mice expressing in their T lymphocytes the Herpes simplex type 1 thymidine kinase (TK) suicide gene that allows the destruction of dividing T cells by a ganciclovir treatment. T cells expressing the TK transgene were used to generate GVHD in irradiated bone marrow grafted mice. We show that a short 7-day ganciclovir treatment, initiated at the time of bone marrow transplantation, efficiently prevented GVHD in mice receiving TK-expressing T cells. These mice were healthy and had a normal survival. They maintained a T-cell pool of donor origin that responded normally to in vitro stimulation with mitogens or third party alloantigens, but were tolerant to recipient alloantigens. Our experimental system provides the proof of concept for a therapeutic strategy of GVHD prevention using genetically engineered T cells.
Cohen
J L
JL
CNRS ERS 107 Laboratoire de Biologie et Therapeutique des Pathologies Immunitaires, Groupe Hospitalier Pitié-Salpêtrière, Paris France.
Boyer
O
O
Salomon
B
B
Onclercq
R
R
Charlotte
F
F
Bruel
S
S
Boisserie
G
G
Klatzmann
D
D
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology / Q000627:therapeutic use*; D006086:Graft vs Host Disease / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D011828:Radiation Chimera; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000201:enzymology; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics; D019076:Transgenes; D014184:Transplantation, Homologous / Q000009:adverse effects
D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D013937:Thymidine Kinase; D015774:Ganciclovir