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

Life-long immunosuppression is a major cause of mortality and morbidity in transplant recipients. Gene therapy could provide new ways to obtain tolerance and avoid indefinite immunosuppression. EpTK mice are derived from the FVB/N strain (H2q) and express the thymidine kinase gene of herpesvirus in all mature T cells. Thus any mature dividing T cell can be killed in the presence of ganciclovir. We investigated the survival of alloincompatible C57B1/6 (H2b) hearts heterotopically transplanted into EpTK mice given only ganciclovir from day 0 to day 7 or 14.

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. Histologic 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.

All control animals rejected transplants in 7 days (range, 5-9 days), whereas indefinite survival (>100 days) was observed in 89% of the ganciclovir-treated EpTK group, irrespective of the duration of ganciclovir treatment. Graft histology showed extensive cellular infiltrates with myocyte necrosis and arteritis in the control animals but only a mild infiltrate without necrosis or arteritis in the ganciclovir-treated EpTK group. The proliferative responses of the tolerant mice at day 100 were identical to those of naive mice, including a preserved proliferation against the donor's lymphocytes in mixed lymphocyte reaction.

Functional transplantation tolerance of a fully incompatible heart can be achieved without immunosuppressive drugs in this model of suicide gene therapy.