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

Background Control of antidonor activated T cells involved in allograft rej ection while preserving: immunocompetence is a challenging goal in transpla ntation, Engineered T cells expressing a viral thymidine kinase (TR) suicid e gene metabolize the nontoxic prodrug ganciclovir (GCV) into a metabolite toxic only to dividing cells. We evaluated this suicide gene strategy for i nducing transplantation tolerance in mice. Methods. 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 prolife rate in mixed lymphocyte reactions and to induce graft-versus-host disease in irradiated recipients with the genetic background of the donor allograft , Results. Upon in vitro or in vivo GCV treatment, only activated dividing TK T cells but not B cells were efficiently depleted. Acute rejection of allo geneic grafts was prevented and a significant prolongation of graft surviva l was obtained, although associated with signs of chronic rejection. Prolon ged skin graft survival correlated with decreased in vitro and in vivo T-ce ll reactivities against donor alloantigens, whereas overall immunocompetenc e was preserved. Conclusions. Efficient and specific depletion of alloreactive TK T cells ca n be achieved by administrating GCV. These results open new perspectives fo r the control of allogeneic graft rejection using suicide gene therapy.