Tolerance induced without immunosuppression in a T-lymphocyte suicide-genetherapy cardiac allograft model in mice

Background: Life-long immunosuppression is a major cause of mortality and m orbidity in transplant recipients. Gene therapy could provide new ways to o btain tolerance and avoid indefinite immunosuppression. EpTK mice are deriv ed from the FVB/V strain (H2q) and express the thymidine kinase gene of her pesvirus in all mature T cells. Thus any mature dividing T cell can be kill ed in the presence of ganciclovir. We investigated the survival of alloinco mpatible C57B1/6 (H2b) hearts heterotopically transplanted into EpTK mice g iven only ganciclovir from day 0 to day 7 or 14. Methods: Abdominal cardiac transplantations were performed in 22 control mice (untreated FVB [n = 15] , ganciclovir-treated FVB [n = 5], and untreated EpTK mice [n = 2]) and in 28 EpTK mice given ganciclovir from day 0 to day 7 (n = 15) or day 14 (n = 13), Rejection was defined as complete cessation of cardiac beat. Histologi c examination of the grafts was performed at rejection, at day 7, or at day 100, Lymphocyte proliferation assays (concanavalin A stimulation or mixed lymphocyte reaction) were performed at day 7 and at day 100, Results: All c ontrol animals rejected transplants in 7 days (range, 5-9 days), whereas in definite survival (>100 days) was observed in 89% of the ganciclovir-treate d EpTK group, irrespective of the duration of ganciclovir treatment. Graft histology showed extensive cellular infiltrates with myocyte necrosis and a rteritis in the control animals but only a mild infiltrate without necrosis or arteritis in the ganciclovir-treated EpTK group. The proliferative resp onses of the tolerant mice at day 100 were identical to those of naive mice , including a preserved proliferation against the donor's lymphocytes in mi xed lymphocyte reaction. Conclusion: Functional transplantation tolerance o f a fully incompatible heart can be achieved without immunosuppressive drug s in this model of suicide gene therapy.