T-Cell suicide gene therapy for organ transplantation: induction of long-lasting tolerance to allogeneic heart without generalized immunosuppression.
Standard immunosuppressive drugs used for allogeneic organ transplantation do not specifically target alloreactive T cells and must be given for the lifetime of the patient, resulting in significant morbidity and mortality. We aimed to induce experimental immune tolerance to vascularized heart allograft using a suicide gene allowing selective elimination of dividing T cells expressing Herpes simplex virus type 1 thymidine kinase upon ganciclovir administration. We show that without ganciclovir, transgenic mice selectively expressing thymidine kinase in T cells rejected a vascularized cardiac allograft in 7 days. In contrast, allograft was definitively accepted after a 7-day course of ganciclovir initiated at the time of allotransplantation. Interestingly, T cells from both rejecting and tolerant mice proliferated in response to donor or third-party allogeneic stimulation. This state of tolerance was challenged through a second vascularized cardiac allotransplantation. Third-party allografts were rejected while those syngeneic to the first allograft were accepted without any additional treatment. These results show that short-term pharmacogenetic immunosuppression can induce long-lasting, robust, and specific tolerance to solid vascularized allograft without generalized continuous immunosuppression.
Braunberger
E
E
Immunopathologie INSERM U 430, Paris, France.
Cohen
J L
JL
Boyer
O
O
Pegaz-Fiornet
B
B
Raynal-Raschilas
N
N
Bruneval
P
P
Thomas-Vaslin
V
V
Bellier
B
B
Carpentier
A
A
Glotz
D
D
Klatzmann
D
D
D000222:Adaptation, Physiological / Q000276:immunology*; D000818:Animals; D015774:Ganciclovir / Q000008:administration & dosage; D015316:Genetic Therapy; D016027:Heart Transplantation / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013937:Thymidine Kinase / Q000235:genetics; D014184:Transplantation, Homologous
D013937:Thymidine Kinase; D015774:Ganciclovir