201. Modulation of phosphatidylinositol 3-kinase (PI3K) as a tool to enhance anti-polysaccharide antibody response in the aged (45.23)
- Author
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Mosoka Fallah, R. Chelvarajan, and Subbarao Bondada
- Subjects
Immunology ,Immunology and Allergy - Abstract
The elderly are at risk to increased infection with Streptococcus pneumoniae, gram positive bacteria. This has been shown to be due to a reduced production of pro-inflammatory cytokines (IL-6, IL-12, TNF-α) by splenic macrophages (SM), as well as a decrease in the B-cell class-switching to IgG3 and IgA, isotypes that are critical for the opsonization and clearance of the pathogen. Here we showed that PI3K expression and activity are increased in aged compared to young SM. Phosphorylation of AKT and glycogen synthase kinase-3 (GSK-3), downstream targets of PI3K, was also more in the aged than young SM and B-cells. The PI3K inhibitor, LY294002, enhanced TLR-2 and TLR- 4 dependent pro-inflammatory cytokine secretion by SM from the aged. Moreover, low concentrations of the PI3K inhibitor enhanced TLR-4 induced class-switching to IgG3 and IgA. Interestingly, inhibition of GSK-3 also enhanced TLR-4 induced IgG3 and IgA secretion as well as B-cell proliferation. Hence, a pharmacological modulation of the PI3K-AKT-GSK pathway could be a potential vaccine enhancement strategy against infection with S. pneumoniae in the elderly. (Supported in part by NIH Grants)
- Published
- 2010