T-cell suicide gene therapy in the management of graft versus host disease following allogeneic bone marrow transplatation

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T-cell suicide gene therapy in the management of graft versus host disease following allogeneic bone marrow transplatation

Qasim, Waseem; (2003) T-cell suicide gene therapy in the management of graft versus host disease following allogeneic bone marrow transplatation. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Haematopoietic stem cell transplantation (HSCT) is established therapy for primary immunodeficiencies, congenital disorders of the haematopoietic system and certain forms of leukaemia. Donor T cells present in the graft are known to mediate a number of beneficial effects including protection against graft rejection, antiviral immunity and anti-leukaemic activity. However, T cells also mediate graft versus host disease (GVHD), which can be a major cause of morbidity and mortality following allogeneic HSCT. The routine depletion of T cells from the graft has greatly reduced the incidence and severity of GVHD, but can result in a loss of graft potency and prolonged periods of immunodeficiency. One strategy that aims to harness T cells for their beneficial properties and eliminate them in the event of GVHD involves the ex-vivo modification of donor T cells to carry the Herpes Simplex Virus thymidine kinase suicide gene. Such genetically modified T cells (GM-T) are rendered sensitive to elimination when exposed to the anti-viral prodrug, Ganciclovir. This study has adopted recently described hybrid murine retroviral vectors to deliver the HSVTK gene, or an improved analogue HSVTKSR39, into leukaemic T cells and primary T cells. Selection of modified T cells based on the co-expression of cell surface marker proteins resulted in highly enriched populations of T cells. In vitro, the HSVTKSR39 mutant gene was superior to the wild type HSVTK as a T cell suicide gene when used in combination with both Ganciclovir and Aciclovir. A model of human T cell xeno-engraftment in immunodeficient mice was employed to test the efficacy of the mutant suicide gene system in vivo. The impact of T cell activation on phenotype and function was investigated. Changes in subset distribution and activation markers were demonstrated, although the T cell receptor repertoire remained unchanged. T cells were highly activated after the transduction procedure and were prone to exhaustion during functional assays involving exposure to antigen pulsed dentritic cells.

Type:	Thesis (Doctoral)
Qualification:	Ph.D
Title:	T-cell suicide gene therapy in the management of graft versus host disease following allogeneic bone marrow transplatation
Open access status:	An open access version is available from UCL Discovery
Language:	English
Additional information:	Thesis digitised by ProQuest.
Keywords:	Health and environmental sciences; Stem cell transplantation
URI:	https://discovery.ucl.ac.uk/id/eprint/10101359