Prolonged allograft survival through conditional and specific ablation of alloreactive T cells expressing a suicide gene.

Biologie et Thérapeutique des Pathologies Immunitaires, UPMC/CNRS ESA 7087, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Transplantation (Impact Factor: 3.83). 06/2000; 69(10):2154-61.
Source: PubMed

ABSTRACT Control of antidonor activated T cells involved in allograft rejection while preserving immunocompetence is a challenging goal in transplantation. Engineered T cells expressing a viral thymidine kinase (TK) suicide gene metabolize the nontoxic prodrug ganciclovir (GCV) into a metabolite toxic only to dividing cells. We evaluated this suicide gene strategy for inducing transplantation tolerance in mice.
Transgenic mice expressing TK in mature T cells were analyzed for (i) specific T-cell depletion under GCV treatment upon various stimulations; (ii) outcome of allogeneic nonvascularized skin or heart allografts under a short 14-day GCV treatment initiated at the time of transplantation; and (iii) the capacities of T cells from such allotransplanted mice to proliferate in mixed lymphocyte reactions and to induce graft-versus-host disease in irradiated recipients with the genetic background of the donor allograft.
Upon in vitro or in vivo GCV treatment, only activated dividing TK T cells but not B cells were efficiently depleted. Acute rejection of allogeneic grafts was prevented and a significant prolongation of graft survival was obtained, although associated with signs of chronic rejection. Prolonged skin graft survival correlated with decreased in vitro and in vivo T-cell reactivities against donor alloantigens, whereas overall immunocompetence was preserved.
Efficient and specific depletion of alloreactive TK T cells can be achieved by administrating GCV. These results open new perspectives for the control of allogeneic graft rejection using suicide gene therapy.

12 Reads
  • Transplantation 06/2000; 69(10):2002-3. DOI:10.1097/00007890-200005270-00004 · 3.83 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Molecular Therapy 01/2001; 2(6):596-601. DOI:10.1006/mthe.2000.0208 · 6.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In transplantation, gene therapy strategies to prolong graft survival involve gene transfer and expression of immunomodulatory or graft-protecting molecules. The local production of immunosuppressive molecules has the potential to reduce their systemic side effects, and to increase their bioavailability and hence their therapeutic efficiency. Ex vivo gene transfer enables manipulation prior to engraftment. Vectors have now been developed that can optimally transfer the relevant genes to various cells, tissues and organs. The elimination of genetically modified cells can even be time-controlled by prodrug administration in suicide gene therapy systems. Gene transfer to stem cells may eventually lead to accelerated tissue repair and regeneration. In addition, xenotransplantation and organ cloning techniques have the potential to resolve the current shortage of donor organs.
    Current opinion in molecular therapeutics 09/2001; 3(4):390-8. · 3.42 Impact Factor
Show more