Effect of combined cytostatic cyclosporin A and cytolytic suicide gene therapy on the prevention of experimental graft-versus-host disease
| Autor: | David Klatzmann, Sébastien Maury, Olivier Boyer, Elena Litvinova, Sylvie Bruel, José L. Cohen, Laurent Benard |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
T-Lymphocytes
viruses medicine.medical_treatment Genetic enhancement T cell Genetic Vectors Graft vs Host Disease Mice Transgenic Herpesvirus 1 Human Hematopoietic stem cell transplantation Biology Antiviral Agents Thymidine Kinase Mice Immune system Cyclosporin a Genetics medicine Animals Transplantation Homologous Ganciclovir Molecular Biology Hematopoietic Stem Cell Transplantation Genetic Therapy Suicide gene medicine.disease Combined Modality Therapy surgical procedures operative Graft-versus-host disease Immunosuppressive drug medicine.anatomical_structure Models Animal Immunology Cyclosporine Cancer research Molecular Medicine Female Cell Division Immunosuppressive Agents |
| Zdroj: | Gene Therapy. 9:201-207 |
| ISSN: | 1476-5462 0969-7128 |
| DOI: | 10.1038/sj.gt.3301637 |
| Popis: | The immunosuppressive drug cyclosporin A (CsA) represents the standard preventive treatment of graft-versus-host disease (GVHD), the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). However, its efficacy is only partial and many patients develop lethal GVHD despite CsA. A strategy of genetic immunosuppression based on conditional elimination of donor T cells expressing the Herpes simplex type 1 thymidine kinase (TK) suicide gene was recently developed. In this system, ganciclovir (GCV) selectively kills dividing but not quiescent TK T cells. Since CsA is known to have a cytostatic effect on T cells, it could negatively interfere with the division-dependent TK gene therapy. We thus tested whether administration of CsA would antagonize elimination of alloreactive donor TK T cells mediated by GCV in a murine model of GVHD. In vivo experiments revealed that, contrary to GCV, CsA only transiently controlled alloactivation-induced T cell proliferation, and likewise could not prevent lethal GVHD. When T cells resumed proliferation under CsA, they were however still sensitive to GCV. Survival, as well as immune reconstitution, was excellent in mice treated with GCV alone or in combination with CsA. These observations should help to design improved suicide gene therapy trials in the field of allogeneic HSCT. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|