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Published online before print January 3, 2005

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(Journal of Leukocyte Biology. 2005;77:503-512.)
© 2005 by Society for Leukocyte Biology

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

R. Lakshman Chelvarajan^*,, Sarah M. Collins, Juliana M. Van Willigen and Subbarao Bondada^*,,1

^* Department of Microbiology, Immunology, and Molecular Genetics and
Sanders Brown Center on Aging, University of Kentucky, Lexington

¹ Correspondence: Department of Microbiology, Immunology, and Molecular Genetics and Sanders Brown Center on Aging, 329A Sanders-Brown Building, University of Kentucky, Lexington, KY 40536-0230. E-mail: bondada{at}uky.edu

A reduction in macrophage (M) 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 M function in the aged. We show that aged mice are profoundly hyporesponsive to these TI Ag. As a result of a requirement for M, 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 M from aged mice was significantly lower than that seen with young M. Consequently, this unresponsiveness can be overcome by a mixture of interleukin (IL)-1ß and IL-6. Upon stimulation with LPS, in comparison with young M, aged M secreted reduced amounts of IL-6, tumor necrosis factor , IL-1ß, and IL-12, cytokines necessary for B cells to respond to TI Ag. LPS also induced aged M to produce an excess of IL-10. Neutralization of IL-10 enhanced the production of proinflamatory cytokines by M upon LPS stimulation and also induced Ab production by aged splenocytes. Thus, the inability of aged M to help the B cell response appears to be caused by an excess of IL-10. As aged M 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.

Key Words: B lymphocytes • cytokines • LPS • TNP-Ficoll • TNP-LPS

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