The Effect of Microtubule Stabilising Drugs on Immune-Mediated Excytosis

The microtubule network is involved in cellular processes including protein transport and cell division. Microtubule stabilising drugs (MSD) bind to microtubules and alter their dynamic balance in favour of the polymerised state. While primarily known for their anti-mitotic properties, MSD also exert immunomodulatory effects in vitro and in vivo. It is the aim of this project to investigate the effects of MSD on protein trafficking and secretion to determine how they affect immune-mediated exocytosis. Previous work in our lab demonstrated that macrophage responses to bacterial lipopolysaccharide, as measured by the production of TNF-a and nitric oxide, are inhibited by both paclitaxel and peloruside. In this thesis we continued this work and saw that inhibition was not affected by temporal IFN-y priming and found that altered production kinetics were not sufficient to explain the inhibition. To kill target cells cytotoxic T cells (CTL) reorganise their cytoskeleton so that lytic granules can traffic down microtubules to be delivered to the target. Using an in vitro model of CTL killing, we saw that MSD did not inhibit killing by CTL, lytic granule delivery to the cell surface, or antigen-stimulated Interferon-y (IFN-y) production by CTL. In contrast to this, in a murine model of antigen-induced killing we saw that a single dose of paclitaxel had a significant inhibitory effect on CTL-mediated cytolysis in vivo. Together these studies suggest that MSD have multiple immunomodulatory effects that are independent of their anti-proliferative effects. The data suggest that patients undergoing taxane therapy may be unable to fight infection long before the anti-mitotic effects of MSD are apparent.