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.
Cohen
J L
JL
Génopoïétic, Paris, France.
Lacroix-Desmazes
S
S
Charlotte
F
F
Lejeune
L
L
Martin
P J
PJ
Klatzmann
D
D
Boyer
O
O
D000818:Animals; D016026:Bone Marrow Transplantation; D004247:DNA / Q000378:metabolism; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology*; D015316:Genetic Therapy / Q000379:methods*; D006086:Graft vs Host Disease / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000378:metabolism; D008099:Liver / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D013154:Spleen / Q000473:pathology; D015996:Survival Rate; D013937:Thymidine Kinase / Q000187:drug effects / Q000235:genetics
D007074:Immunoglobulin G; D007075:Immunoglobulin M; D004247:DNA; D013937:Thymidine Kinase; D015774:Ganciclovir