Preservation of graft-versus-infection effects after suicide gene therapy for prevention of graft-versus-host disease.
The main complications following allogeneic hematopoietic stem cell transplantation are graft-versus-host disease and poor immune reconstitution leading to severe infections. Mature donor T cells present in the transplant facilitate T cell reconstitution in adults, but also induce graft-versus-host disease, which itself impairs immune reconstitution. Thus, infusing a large number of donor T cells with a diverse repertoire should accelerate functional immune reconstitution after transplantation, only if graft-versus-host disease can be controlled. We previously demonstrated that preventive treatment with ganciclovir could control graft-versus-host disease in mice if donor T cells are made to express viral thymidine kinase as a "suicide" gene. Here we evaluated the recovery of functional antiviral immune responses in such mice. Irradiated mice received an allogeneic hematopoietic stem cell transplantation with thymidine kinase-expressing T cells and were protected from graft-versus-host disease by ganciclovir treatment, and then challenged with lymphocytic choriomeningitis virus. Grafted mice could mount efficient antilymphocytic choriomeningitis virus immune responses leading to viral elimination. Furthermore, when transplanted cells were obtained from mice previously immunized against lymphocytic choriomeningitis virus, grafted mice developed memory-type accelerated responses against the virus. We conclude that efficient graft-versus-infection effects can be mediated by naive T cells and memory donor T cells that persist after suicide gene therapy for prevention of graft-versus-host disease.
Cohen
J L
JL
Laboratoire de Biologie et Thérapeutique des Pathologies Immunitaires, CNRS/UPMC ESA 7087, Groupe Hospitalier Pitié-Salpêtrière, F-75651 Paris Cedex 13, France.
Saron
M F
MF
Boyer
O
O
Thomas-Vaslin
V
V
Bellier
B
B
Lejeune
L
L
Charlotte
F
F
Klatzmann
D
D
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001402:B-Lymphocytes / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015774:Ganciclovir / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D006086:Graft vs Host Disease / Q000235:genetics* / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D007150:Immunohistochemistry; D008217:Lymphocytic choriomeningitis virus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000201:enzymology / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics; D013997:Time Factors
D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir