Suicide gene therapy of graft-versus-host disease: immune reconstitution with transplanted mature T cells.
After allogeneic hematopoietic stem cell transplantation (HSCT), mature transplanted T cells play a major role in restoration of the immune system. However, they can also induce a life-threatening complication: graft-versus-host disease (GVHD). Suicide gene therapy of GVHD aims to selectively eliminate alloreactive T cells mediating GVHD while sparing nonalloreactive T cells that should contribute to immune reconstitution. It was demonstrated previously that treatment with ganciclovir (GCV) can control GVHD in mice by killing donor T cells engineered to express the thymidine kinase (TK) suicide gene. TK allows phosphorylation of nontoxic GCV into triphosphate GCV, which is selectively toxic for dividing cells. Thus, in the TK-GCV system, the specificity of cell killing depends on the cycling status of TK T cells rather than allogeneic recognition. This is a potential drawback because in recipients of lymphopenic allogeneic HSCT, alloreactive and homeostatic signals drive the proliferation of donor T cells. It is shown here that the onset of alloreactive T-cell division occurs earlier than that of nonalloreactive T cells, thus establishing a time frame for GCV administration. A 7-day GCV treatment initiated at the time of HSCT allowed efficient prevention of GVHD, while sparing a pool of nondividing donor TK T cells. These cells later expanded and contributed to the replenishment of the recipient immune system with a diversified T-cell receptor repertoire. These results provide a rationale for designing the therapeutic scheme when using TK-GCV suicide gene therapy in allogeneic HSCT.
Cohen
J L
JL
Laboratoire de Biologie et Thérapeutique des Pathologies Immunitaires CNRS/UPMC ESA 7087, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Boyer
O
O
Klatzmann
D
D
D000818:Animals; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D015774:Ganciclovir / Q000008:administration & dosage; D015316:Genetic Therapy / Q000379:methods*; D006086:Graft vs Host Disease / Q000628:therapy*; D006801:Humans; D007107:Immune System / Q000166:cytology / Q000187:drug effects; D016130:Immunophenotyping; D018655:Lymphocyte Count; D051379:Mice; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000637:transplantation; D013937:Thymidine Kinase / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors
D016693:Receptors, Antigen, T-Cell, alpha-beta; D013937:Thymidine Kinase; D015774:Ganciclovir