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"Suicide" gene for the control of graft-versus-host disease
1Etablissement de Transfusion Sanguine de Franche-Comté, Université de Franche Comte, Besançon, France.
Abstract:
Specific and conditional in vivo ablation of alloreactive donor T cells after allogeneic hematopoietic stem cell transplantation could significantly contribute to preventing and treating graft-versus-host disease (GVHD). The use of donor T cells expressing a "suicide" gene such as the thymidine kinase gene of the herpes simplex virus 1 (HS-tk) has the potential of achieving such a goal. Ex vivo retroviral-mediated HS-tk gene transfer in human T cells as well as ganciclovir sensitivity of such gene-modified T cells is established. The prevention and treatment of GVHD induced by HS-tk-expressing donor T cells by ganciclovir has been demonstrated in murine models. Clinical trials involving the use of HS-tk-expressing T cells at time of transplantation in conjunction with a T-cell-depleted hematopoietic graft or subsequently for treatment of relapse or lymphoma associated with Epstein-Barr virus infection are currently underway. In vivo circulation of ganciclovir-sensitive gene-modified cells as well as the occurrence of ganciclovir-sensitive acute and chronic GVHD have been documented. If these initial exciting findings are confirmed, such an approach could significantly contribute to expanding the use of alloreactivity as a treatment modality.
Insights
Donor T cells engineered with a suicide gene (HS-tk) offer a promising strategy for preventing and treating graft-versus-host disease (GVHD) after stem cell transplants. Ganciclovir administration enables targeted elimination of these modified cells, controlling GVHD.
Area of Science:
- Immunology
- Gene Therapy
- Transplantation Immunology
Background:
- Graft-versus-host disease (GVHD) remains a significant challenge after allogeneic hematopoietic stem cell transplantation.
- Targeted elimination of alloreactive donor T cells is crucial for GVHD prevention and treatment.
Purpose of the Study:
- To evaluate the efficacy of donor T cells expressing the herpes simplex virus 1 thymidine kinase (HS-tk) suicide gene for GVHD control.
- To assess the safety and feasibility of using ganciclovir to ablate HS-tk-modified T cells in vivo.
Main Methods:
- Ex vivo retroviral gene transfer to introduce the HS-tk gene into human T cells.
- Administration of ganciclovir to induce selective ablation of HS-tk-expressing T cells.
- Evaluation in murine models and ongoing clinical trials.
Main Results:
- Established ganciclovir sensitivity of HS-tk-modified T cells.
- Demonstrated prevention and treatment of GVHD in murine models.
- Documented in vivo circulation of gene-modified cells and occurrence of ganciclovir-sensitive GVHD in clinical trials.
Conclusions:
- HS-tk gene-modified T cells combined with ganciclovir represent a viable strategy for managing GVHD.
- This approach holds potential for expanding the therapeutic applications of alloreactivity in transplantation.