NALT-BASED ADJUVANTS FOR MUCOSAL IMMUNITY IN AGING

描述（由申请方提供）：已证明衰老个体部分免疫缺陷，并具有病毒和细菌病原体感染的高风险。粘膜免疫系统提供的第一道防线的改变被认为是解释衰老人群对不同传染病易感性增加的关键因素。然而，我们对粘膜免疫系统中年龄相关变化的理解仍然非常有限。鼻咽相关淋巴网状组织（NALT）在诱导和调节针对粘膜感染的保护性粘膜和全身免疫应答中起核心作用。早期年龄相关的下降发生在胃肠道中抗原（Ag）特异性粘膜和全身免疫的诱导和调节中，但不发生在1岁小鼠的基于NALT的免疫中。然而，鼻免疫未能诱导粘膜免疫应答，尽管在两岁小鼠的完整NALT诱导的全身免疫。这些结果表明，基于NALT的免疫力受衰老的影响较小。这项授权的假设是，鼻腔免疫与适当的粘膜佐剂，实际上可以恢复Ag特异性粘膜免疫反应启动和介导的NALT。因此，这项资助将阐明给予鼻疫苗的老年小鼠NALT免疫系统中的细胞和分子事件。为了实现我们的主要目标，前两个具体目标将集中在衰老对NALT的影响和树突状细胞（DC）在维持NALT组织以及Ag特异性分泌型伊加（S-IgA）抗体（Ab）反应的诱导和调节中的作用。我们在最后三个具体目标中的努力将集中于评估先天性和获得性免疫介导的分子佐剂在老年小鼠中诱导保护性免疫免受病毒和细菌感染的功效。具体而言，我们将：1）确定NALT中T和B细胞功能的年龄相关性免疫学变化; 2）评估DC在NALT组织化和启动Ag特异性免疫中的作用; 3）在给予Flt 3配体质粒（pFL）作为粘膜佐剂的老龄小鼠中恢复Ag特异性S-lgA Ab和Th 1/Th 2细胞应答; 4）评估pFL与CpG ODN一起补偿免疫衰老的功效;和5）确定通过佐剂（pFL和CpG）的组合靶向DC对抗衰老小鼠中的病毒和细菌病原体的功效。

DESCRIPTION (provided by applicant): 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.