It has been shown that senescent individuals are partially immunodeficient and possess a high risk for infections by viral and bacterial pathogens. Alterations in the first line of defense provided by the mucosal immune system has been considered to be a key element to explain the increase in susceptibility to different infectious diseases seen in the senescent population. However, our understanding of the age-associated changes in the mucosal immune system remains very limited. Nasopharyngeal-associated lymphoreticular tissues (NALT) play a central role in the induction and regulation of protective mucosal and systemic immune responses to mucosal infections. An early age-associated decline occurs in the induction and regulation of antigen (Ag)-specific mucosal and systemic immunity in the Gl tract but not in the NALT-based immunity of one yr-old mice. However, nasal immunization failed to induce mucosal immune responses in two-yr old mice despite intact NALT-induced systemic immunity. These results suggest that NALT-based immunity was less affected by aging. The hypothesis of this grant is that nasal immunization with appropriate mucosal adjuvants can actually restore Ag-specific mucosal immune responses initiated and mediated via NALT. Thus, this grant will elucidate the cellular and molecular events in the NALT immune system in aged mice given nasal vaccines. To accomplish our major goal, the first two specific aims will focus on the effects of senescence on NALT and the role of dendritic cells (DCs) in the maintenance of NALT organization as well as the induction and regulation of Ag-specific secretory IgA (S-lgA) antibody (Ab) responses. Our efforts in the last three specific aims will focus on evaluation of the efficacy of innate- and acquired-immunity mediated molecular adjuvants for the induction of protective immunity from both viral and bacterial infections in aged mice. Specifically, we will: 1) Determine the age-associated immunological changes of T and B cell function in NALT; 2) Assess the role of DCs for NALT organization and initiation of Ag-specific immunity; 3) Restore Ag-specific S-lgA Abs and Th1/Th2 cell responses in aged mice given plasmid of Flt3 ligand (pFL) as mucosal adjuvant; 4) Evaluate the efficacy for pFL together with CpG ODN compensating for immune senescence; and 5) Determine the efficacy of DC targeting by a combination of adjuvants (pFL and CpG) against viral and bacterial pathogens in senescent mice. ? ?
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