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Immunoregulation by hepatocyte growth factor in malignant mesothelioma

Cook, Nathan Luke 2008. Immunoregulation by hepatocyte growth factor in malignant mesothelioma. PhD Thesis, Cardiff University.

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This thesis is an investigation into effect of elevated levels of hepatocyte growth factor (HGF) on immune responses. High levels of HGF are found in cancer such as in MPM patient serum and pleural fluid. However, little is known about the consequence of high HGF levels on the development and function of dendritic cells and contribution of these effects to tumour immune evasion. A pre-treatment in vitro model system was applied to study the effects of high HGF concentrations on the development of dendritic cells (DC) from monocytes. The effects of HGF on the phenotype of dendritic cell, functional characteristics, including migration, phagocytosis and T cell stimulation were analysed. Using this model system I discovered a previously un-reported immature DC-like phenotype, caused by the pre-treatment of monocytes for 24 h prior to induction of iDC development by GM-CSF/IL-4: Delayed differentiation of DC alone generates a Th2 bias, which is further enhanced by the presence of HGF. HGF pre-treated DCs express both monocyte marker CD 14 and DC marker CD209 (DC-SIGN). They are able to take up antigen by phagocytosis. However, they produce increased levels of IL-10 and express elevated levels Programmed Death 1 (PD-1) ligand, PD-L1. HGF-pre-treated DC also display impaired ability to stimulate allo-T cell proliferation and antigen-specific IFN-y production. HGF pre-treated DC induces increased IL-10 production by T cells. Blocking IL-10 with a neutralizing antibody restores normal DC differentiation, partially reduced PD-L1 levels and restored T cell stimulatory capacity of DC. The physiological relevance of these findings was demonstrated by similar effects on DC developed in the presence of mesothelioma pleural fluid, in a HGF dependent manner. This thesis demonstrates that HGF is an immunosuppressive factor that can contribute to tumour-induced regulation of DC function and T cell responses.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
ISBN: 9781303196799
Date of First Compliant Deposit: 30 March 2016
Last Modified: 16 May 2018 11:00

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