Ganciclovir-mediated elimination of HSV-Tk(+) T cells and cure of graft-vs-host disease in an allogeneic bone marrow transplantation model in the rat

Objective. Suicide gene therapy for leukemia aims to benefit from T cells in the BM graft, by reducing the probability of leukemia relapse (GVL), while severe complications of graft-vs-host disease (GVHD) may be avoided. In an allogeneic rat BMT model we defined the conditions to induce a lethal GVHD with HSV-Tk gene-transduced T cells. We studied the feasibility to rescue the animals by conditional elimination of the T cells with ganciclovir (GCV) treatment.

Methods. Allogeneic T cells transduced with a retroviral vector encoding the HSV-Tk suicide gene were added in varying numbers to a BM graft. Expression of HSV-Tk strongly increases the cytolytic effect of GCV, thereby allowing elimination of overreactive T cells at will. Various experimental conditions were tested in the rat model.

Results. A relation between the number of HSV-Tk(+) T cells added to the BM graft and GVHD development was found. GCV treatment resulted in selective HSV-Tk(+) T-cell elimination in blood and tissues but not in abrogation of GVHD due to persistence of HSV-Tk(-) T cells. T cells in unmanipulated rat BM normally have a low risk to induce GVH but when they are administered in combination with high numbers of HSV-Tk(+) T cells there is an apparent increase in their GVH-inducing potential. When HSV-Tk(+) T cells are added to T cell-depleted BM a consequently developing GVH can be controlled by GCV treatment with 60-70% of the animals surviving.

Conclusions. We show that T cell-mediated suicide gene therapy within the context of allo-BMT can be applied with success. The apparent limitation in the number of transduced as well as nontransduced T cells that can be safely added to the BM graft should be taken into consideration when designing human suicide gene therapy protocols. (C) 2004 International Society for Experimental Hematology. Published by Elsevier Inc.