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Title: Cytokines, cell adhesion molecules and bladder cancer immunotherapy
Author: Jackson, Andrew Mark
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1993
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The intravesical administration of Bacillus Calmette Guerin for the treatment of transitional cell carcinoma of the bladder is the most effective immunotherapy for any solid human malignancy. Despite this awesome accolade relatively little is understood of its mechanism of action. This study details the in vitro interaction between IL-2 activated lymphocytes and tumour cells, the effect of cytokines produced as a result of immunotherapy on tumour cells and the relationship of these findings to the situation in vivo. Bladder cancer cells were not found to be susceptible to NK cell activity but were found to be differentially susceptible to IL-2 activated lymphocytes. No correlation was evident between the histopathological grade of the tumour. The interaction between these cells was observed to involve intimate contact and the tumour cells were found to constitutively express either ICAM-1 or ICAM-2. The expression of these cell adhesion molecules correlated significantly with the sensitivity of the tumour cells to LAK mediated cytolysis. Following BCG therapy a variety of cytokines including IFNγ and TNFα are detected in the urine. When bladder cancer cells were cultured in the presence of recombinant IFNγ and TNFα an increase in the levels of ICAM-1 expression was observed. The optimal stimulation was found after 24 hours culture with 100Uml-1 IFNγ, whilst TNFα stimulated to a lesser extent. Culture in the presence of both cytokines was observed to synergistically induce or augment ICAM-1 expression. Following culture with IFNγ, the tumour cells displayed increased susceptibility to LAK activity, this was significantly correlated with increased ICAM-1 expression. The levels of tumour cell response to IFNγ could not be correlated with either the abundance or affinity of specific receptors as determined by Scatchard analysis. Thus investigations were initiated into the events down-stream of the ligand-receptor interaction. Monoclonal antibodies to ICAM-1, decreased the sensitivity of tumour cells to LAK activity. However, monoclonal antibodies to LFA-1 (the ligand for ICAM-1) further blocked the action of LAK cells.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available