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J Thorac Cardiovasc Surg 2000;119:46-052
© 2000 Mosby, Inc.

CARDIOTHORACIC TRANSPLANTATION

TOLERANCE INDUCED WITHOUT IMMUNOSUPPRESSION IN A T-LYMPHOCYTE SUICIDE-GENE THERAPY CARDIAC ALLOGRAFT MODEL IN MICE

From the Laboratoire d’etude des greffes et protheses cardiaques, Hopital Broussais, Paris, France.

Address for reprints: Professor Denis Glotz, INSERM U430, Hopital Broussais, 96 rue Didot, 75014, Paris, France, and Dr Eric Braunberger, Laboratoire d’etude des greffes et protheses cardiaques, Hopital Broussais, 96 rue Didot, 75014, Paris, France.

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