T-cell suicide gene therapy for organ transplantation: Induction of long-lasting tolerance to allogeneic heart without generalized immunosuppression

被引:8
作者
Braunberger, E
Cohen, JL
Boyer, O
Pegaz-Fiornet, B
Raynal-Raschilas, N
Bruneval, P
Thomas-Vaslin, V
Bellier, B
Carpentier, A
Glotz, D
Klatzmann, D
机构
[1] Hop La Pitie Salpetriere, Biol & Therapeut Pathol Immunitaires CNRS UPMC ES, F-75651 Paris 13, France
[2] INSERM, Immunopathol U430, Paris, France
[3] Hop Broussais, Lab Etud Greffes & Protheses, F-75674 Paris, France
关键词
ganciclovir; allotransplantation; vascularized; graft; HSV1-TK; suicide gene; therapy; transgenic; mice;
D O I
10.1006/mthe.2000.0208
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
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.
引用
收藏
页码:596 / 601
页数:6
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