Killed vaccines of the adjuvant Corynebacterium parvum have proved to be potent anti-tumour agents in a number of experimental systems and are currently being assessed clinically, either alone or as an adjunct to other cancer treatments. In animals, systemically administered C. parvum can exert a strong, non-specific anti-tumour action which is thought to be mediated principally by activated macrophages. The author carried out in vitro experiments analysing tho possible pathways loading to the production of such activated maorophages in C. parvum-treated CBA mice. The tumour studied was a methylcholanthrene-induced fibrosarcoma. It was found that spleen cells from mice treated intravenously, or intraperitoneally (but not subcutaneously) with C. parvum could induce, in vitro, anti-tumour cytotoxicity in normal, non-cytotoxic, murino peritoneal macrophages, provided that C. parvum was also present. This requirement for the presence of C. parvum was shown to be a specific one, other strains of C.parvum or other unrelated bacteria being ineffective. The macrophage-activating cell was found to be radio-sensitive, but resistant to treatment with sodium aurothiomalate or anti-macrophage serum. However, exposure of normal peritoneal macrophages to sodium aurothiomalate, either before or during activation with spleen cells, abrogated the cytotoxic effects. Nylon wool column separation of spleen cells into B cell-rich and B cell-depleted fractions indicated a possible requirement for B cells in the activation process. On the other hand a T cell requirement was shown by the failure of spleen cells from C. parvum-treated T cell-deprived mice to activate macrophages in vitro. Treatment of spleen cells with anti-9 serum prior to the activation process yielded inconclusive evidence with regard to the T cell dependence of macrophage activation. Spleen cells capable of activating macrophages in vitro did not appear in the C. parvum-treated mouse until after day 6 post C. parvum infection. This contrasted with the early appearance, by day 3, of cytotoxic spleen and peritoneal cells in intraperitoneal treated mice. This suggested the existence in vivo of two separate pathways leading to the stimulation of anti-tumour effector cells. In vitro induction of anti-tumour activity could also be achieved using locally-stimulated lymph node cells, or cell-free supernatants from mixed cultures of C. parvum-sensitised spleen cells and C. parvum. During the course of in vitro studies on C. parvum-activated macrophages it was observed that such macrophages lost their cytotoxic capacity on culture. This loss of activity could be delayed by the addition of C. parvum to the cultures. This maintenance effect by C. parvum was found to be radio-resistant, sensitive to sodium aurothiomalate, T cell dependent, and at least partially specific. The significance of these results and the possible mechanisms underlying them have been discussed in relation to the existing knowledge of C. parvum's biological and anti-tumour effects.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:648996 |
| Date | January 1978 |
| Creators | Cullen, R. T. |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/17135 |
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