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.
Exp Hematol
; 32(10): 962-9, 2004 Oct.
Article
en En
| MEDLINE
| ID: mdl-15504552
ABSTRACT
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.
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Banco de datos:
MEDLINE
Asunto principal:
Linfocitos T
/
Terapia Genética
/
Ganciclovir
/
Trasplante de Médula Ósea
/
Genes Transgénicos Suicidas
/
Enfermedad Injerto contra Huésped
Tipo de estudio:
Etiology_studies
/
Guideline
Límite:
Animals
Idioma:
En
Revista:
Exp Hematol
Año:
2004
Tipo del documento:
Article
País de afiliación:
Países Bajos