Thesis

T cell gene therapy in vascular pathology

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Awarding institution
  • University of Strathclyde
Date of award
  • 2012
Thesis identifier
  • T13387
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Abstract
  • The immune system is a key contributor to atherosclerosis-related cardiovascular diseases (CVD) however, at present there are no targeted therapies specific for the inflamed vessel wall. Multiple leukocyte subsets have been shown to play a significant role in CVD and among them, CD4 T cells are receiving growing interest. Here we investigated whether T cells could be utilised as delivery vehicles in experimental atherosclerosis, for therapeutic molecules inserted via viral vector. Using multiphoton microscopy, we developed a protocol for the imaging of immune cells within the atherosclerotic aorta, confirming homing of a relevant number of leukocytes to the inflamed vessel following adoptive transfer. Transferred cells in the aorta were found to behave in a similar manner to cells found in the peripheral lymph nodes. We then constructed GFP and IL-10 expressing adenoviral vectors and used them in the optimisation of CD4+ T cell transduction. The biological activity of the produced IL-10 was assessed and GFP transduced cells were transferred into recipient mice and their migration tracked using flow cytometry. Transduction of CD4+ T cells reached 80%. IL-10 produced by the transduced cells was shown to be biologically active and importantly, the transferred modified cells were shown to migrate and survive comparably to non-transduced cells in a non-inflamed context without causing liver toxicity. Unfortunately, transduction of B6 T cells through various means was found to be unsuccessful therefore we could not evaluate the effect of IL-10 secreting T cells in atherosclerotic mice. In conclusion, the results of this thesis indicate that the use of genetically modified T cells could be a viable approach in the treatment of inflammatory disorders.
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Note
  • This thesis was previously held under moratorium from 16th May 2013 until 16th May 2017.
DOI
Date Created
  • 2012
Former identifier
  • 999892313402996

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