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Glomerular gene transfer using genetically modified macrophages

In this thesis I show that macrophages (both cell lines and primary cultures) can be transfected by recombinant adenoviruses expressing -galactosidase (A-gal/Av1Bng), that the macrophages become activated by the transfection process and can be easily manipulated to localise to inflamed glomeruli after direct injection into the renal artery of rats with an experimentally induced glomerular inflammation caused by nephrotoxic nephritis. The injection of transfected macrophages reduces the severity of injury in this model of glomerulonephritis as shown by a reduction in the degree of albuminuria. This approach provides a favourable system for gene delivery in inflammatory disease and shows that both the functional properties of the transfected macrophage as well the transgene it is engineered to produce are relevant for in vivo gene transfer. This approach has also been used to determine the effect of macrophages expressing active TGF-1 on the development of glomerular inflammation. TGF-1 expressing macrophages localised efficiently to inflamed glomeruli and produced the cytokine in vivo. These cells produced a reduction in the level of albuminuria compared to unmodified disease but not in comparison to injection of macrophages transfected with adenovirus expressing -galactosidase. In addition there was no alteration in the infiltration by ED1 positive macrophages. Thus TGF-1 expressed in this manner appears unable to significantly modulate glomerular inflammatory disease and the potential reasons for this are discussed. The system I have developed of macrophage transfection and delivery provides a valuable approach to study and modulate inflammatory disease.
Date January 2001
CreatorsKluth, David Charles
PublisherUniversity of Aberdeen
Source SetsEthos UK
Detected LanguageEnglish
TypeElectronic Thesis or Dissertation

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