Immunological defects after suicide gene therapy of experimental graft-versus-host disease.

Donor T cells are beneficial for engraftment, immune reconstitution, and antileukemic effects after allogeneic marrow transplantation, but they also cause graft-versus-host disease. Treatment with ganciclovir can control graft-versus-host disease if donor T cells are genetically engineered to express viral thymidine kinase. Clinical protocols with thymidine kinase-expressing T cells currently prescribe the curative use of ganciclovir for genetic immunosuppression only after clinical manifestations of graft-versus-host disease have appeared. The aim of this work was to compare early/preventive versus delayed/curative treatment of GVHD. Here, we found that ganciclovir administered early after experimental marrow transplantation was highly effective in preventing graft-versus-host disease caused by thymidine kinase-expressing T cells, and surviving recipient mice were able to mount a T cell-dependent B cell response. In contrast, curative ganciclovir administration later after transplantation was much less effective in treating graft-versus-host disease and surviving recipients had markedly impaired immune function. These findings should be considered in the development of future clinical trials using thymidine kinase-expressing T cells; to date, such trials have envisaged the use of GCV to treat only declared graft-versus-host disease. The use of thymidine kinase-expressing T cells for conditional elimination of activated T cells after allogeneic marrow transplantation offers a promising new approach for the control of graft-versus-host disease. The versatility of the thymidine kinase/ganciclovir system offers clinical options depending on whether thymidine kinase-expressing T cells are infused at the time of bone marrow transplantation or in a delayed manner, and depending on whether GCV is administered in an early/preventive or delayed/curative manner. The rationale underlying these options is more complex than it may appear and is likely to have a profound impact on the efficacy of such treatments. In the present work, we analyze the immunological impact when GCV is administered in an early/preventive or delayed/curative manner. Our results demonstrate that the delayed/curative strategy is clearly associated with severe immunological defects. To our knowledge, this is the first report of immunodeficiency subsequent to suicide gene therapy for GVHD.