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J Leukoc Biol. 2005 Apr;77(4):503-12. Epub 2005 Jan 3.

The unresponsiveness of aged mice to polysaccharide antigens is a result of a defect in macrophage function.

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Department of Microbiology, Immunology and Molecular Genetics, Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536-0230, USA.


A reduction in macrophage (MPhi) function with aging makes mice less responsive to bacterial capsular polysaccharides, such as those present in the pneumococcal polysaccharide vaccine, a model of thymus independent (TI) antigen (Ag). Using trinitrophenol (TNP)-lipopolysaccharide (LPS) and TNP-Ficoll, two other well-studied TI Ag, we studied the mechanistic basis of reduced MPhi function in the aged. We show that aged mice are profoundly hyporesponsive to these TI Ag. As a result of a requirement for MPhi, highly purified B cells from young-adult mice do not respond to TI Ag. When purified, young B cells were immunized with TNP-Ficoll, the antibody production from those cultures reconstituted with MPhi from aged mice was significantly lower than that seen with young MPhi. Consequently, this unresponsiveness can be overcome by a mixture of interleukin (IL)-1beta and IL-6. Upon stimulation with LPS, in comparison with young MPhi, aged MPhi secreted reduced amounts of IL-6, tumor necrosis factor alpha, IL-1beta, and IL-12, cytokines necessary for B cells to respond to TI Ag. LPS also induced aged MPhi to produce an excess of IL-10. Neutralization of IL-10 enhanced the production of proinflamatory cytokines by MPhi upon LPS stimulation and also induced Ab production by aged splenocytes. Thus, the inability of aged MPhi to help the B cell response appears to be caused by an excess of IL-10. As aged MPhi have a reduced number of cells expressing Toll-like receptor 4 and CD14, the imbalance in cytokine production might be partly a result of fewer cells expressing key components of the LPS receptor complex.

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