This application seeks to determine the mechanism for the reduced response to pneumococcal capsular polysaccharides (PS) with aging, a particular concern since pneumonia is a major cause of death in the elderly. The investigator has developed a mouse model for this reduced response and will utilize this in the proposed work. Previous work by the investigator's laboratory suggests that poor responses can be augmented by addition of splenic adherent cells or by use of monophosphoryl lipid A. Additionally, use of DHEA, an agent recently shown to influence cytokine production by T-cells, increased response in aged mice. From these and other data, the investigator proposes that both an intrinsic B-cell and other cytokine deficits result in the poor response to PS with aging. The work is divided into five specific aims. In the first, the role of CD40 and apoptosis in the B-cell unresponsiveness. In the second, the nature of the splenic accessory cell defect will be explored. In the third, the target cell for DHEA will be defined. In the fourth, the information obtained in the mouse model system will be extended to the human, using a peripheral blood in vitro response system. In the fifth, the unresponsiveness of neonates will be investigated using an in vitro system and using btk-transgenic mice.
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