NALT-BASED ADJUVANTS FOR MUCOSAL IMMUNITY IN AGING

描述（由申请人提供）：研究表明，老年人部分免疫缺陷，病毒和细菌病原体感染的风险很高。粘膜免疫系统提供的第一道防线的改变被认为是解释老年人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与年龄相关的变化的理解仍然非常有限。鼻咽相关淋巴网状组织（NALT）在诱导和调节保护性粘膜和对粘膜感染的全身免疫反应中发挥核心作用。1岁小鼠的抗原（Ag）特异性粘膜和全身免疫的诱导和调节出现了早期年龄相关的下降，但在基于nalt的免疫中没有。然而，在两岁大的小鼠中，鼻腔免疫未能诱导粘膜免疫反应，尽管nalt诱导的全身免疫是完整的。这些结果表明，基于nalt的免疫受衰老的影响较小。本研究的假设是，使用适当的粘膜佐剂进行鼻腔免疫实际上可以恢复由NALT发起和介导的ag特异性粘膜免疫反应。因此，这项资助将阐明给予鼻腔疫苗的老年小鼠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，树突状细胞（dc）在维持NALT组织中的作用，以及ag特异性分泌IgA （S-lgA）抗体（Ab）反应的诱导和调节。在最后三个具体目标中，我们的努力将集中在评估先天免疫和获得性免疫介导的分子佐剂在诱导老年小鼠免受病毒和细菌感染的保护性免疫方面的功效。具体而言，我们将：1)确定NALT中T细胞和B细胞功能的年龄相关免疫变化；2)评估dc在NALT组织和抗原特异性免疫启动中的作用；3)给予Flt3配体质粒（pFL）作为黏膜佐剂，恢复老年小鼠ag特异性S-lgA抗体和Th1/Th2细胞应答；4)评价pFL联合CpG ODN对免疫衰老的补偿作用；5)确定佐剂（pFL和CpG）联合靶向DC对衰老小鼠病毒和细菌病原体的作用。

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.