The aim of this thesis was to examine the adjuvant and anti-inflammatory properties of L. fermentum PC1 using in vivo animal models and tissue culture cell lines. L. fermentum PC2 and L. acidophilus L10 were used as comparative strains for interpretation of the L fermentum PC1 properties.
L. fermentum PC1 functioned efficiently as an oral adjuvant in a murine model. The magnitude and nature of the response was influenced by the dosing regime and dose of adjuvant, type of co-administered antigen and host genetics. In addition, L. fermentum PC1 was shown to redirect a Th2 response polarized by cholera toxin (CT), and to a certain degree maintained a Th1 biased response after priming with L. fermentum PC1 and subsequent boosting with CT.
The possible cellular mechanism(s) whereby L. fermentum PC1 functioned as an adjuvant include: by production of cytokine from dendritic cells, macrophages and epithelial cells; upregulated expression of co-stimulatory molecules on dendritic cells; enhanced uptake of by-stander soluble antigen; and enhanced intracellular bacterial killing by macrophages; and enhanced capacity of dendritic cells to activate naïve T cells.
The anti-inflammatory capacity of L. fermentum PC1 primed macrophages was examined in vitro using two different inflammatory stimulators: LPS and ultra high molecular weight polyethylene wear particles (WP). L. fermentum PC1 was able to down-regulate LPS, but not the WP induced inflammation. L. fermentum PC1 also significantly down regulated S. Typhimurium induced inflammation in epithelial cells. This effect was mediated by factors present in both the cell wall extracts and spent culture medium of L. fermentum PC1. Characterization of the anti-inflammatory molecules(s) revealed it to be of a molecular weight of Mr 1,000 – 6,000, heat stable, with optimum functionality at pH 4-5, and contains carbohydrate and protein moieties.
It was concluded L. fermentum PC1 functioned as an adjuvant and factors were identified that influenced an optimum response. Significant insight into the cellular mechanisms behind its adjuvanticity has been obtained. In addition, the anti-inflammatory function of L. fermentum PC1 appears to be dependent on the nature of the inflammatory stimuli and is mediated by a soluble factor.
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