Immune responses to pneumococcal polysaccharide antigens are important for protection against pneumococcal infections but are absent in neonates and are reduced in the aged. Using Pnu-Imune vaccine that is made up of 23 serotypes of pneumococcal polysaccharides and TNP-Ficoll, two type 2 thymus independent (TI)-2 antigens, we have shown that neonates and the aged have an accessory cell deficiency in addition to their B-cell defects. This deficiency is overcome by supplementation with accessory cell derived cytokines, IL-1 and IL-6. The neonatal macrophages make less IL-l and IL-12 in response to TI stimuli such as TNP-Ficoll and lipopolysaccharide. This application is directed at testing the molecular basis of accessory cell defects leading to B-cell unresponsiveness to polysaccharide antigens in the neonates and the aged. It is hypothesized that toll-like receptor (TLR) expression and/or TLR signaling pathways may be defective in neonatal macrophages. Also, B-cell macrophage interactions required for TI responses may involve the macrophage derived cytokine BLyS and its B-cell receptors, TACI and BCMA, which may be dysfunctional in the neonate. Towards this goal five specific aims are proposed. 1. To determine if the defect in neonatal and the aged macrophages is limited to IL-1 and IL-12 or is a general property of macrophages in the neonate and the aged. 2. To test the hypothesis that the molecular nature of the defect in neonatal accessory cells that contributes to TI-2 unresponsiveness is in TLR expression or in the TLR signaling pathway. 3. To determine the role of dendritic cells in neonatal and aged unresponsiveness to polysaccharide antigens. 4. To determine if the restoration of neonatal B-cell responses to polysaccharides is due to their ability to signal neonatal B-cells/accessory cells via TLR signaling pathway. 5. To determine the role of monocyte-derived TNF like molecule, BLyS and its receptor (TACI), in B-cell-macrophage interactions and to determine if neonates or aged have defects in this ligand receptor system. Results from these studies should in future allow us to design and test agents that can augment accessory cell function and in turn to develop more effective polysaccharide vaccines for the neonate and the aged.
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