NALT-BASED ADJUVANTS FOR MUCOSAL IMMUNITY IN AGING

描述(由申请人提供)：已有研究表明，年老的人有部分免疫缺陷，并具有被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老年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与年龄相关的变化的了解仍然非常有限。鼻咽相关淋巴网状组织(NALT)在诱导和调节对黏膜感染的保护性黏膜和全身免疫反应中起着核心作用。在1岁的小鼠中，抗原(Ag)特异性粘膜免疫和系统免疫的诱导和调节出现了早期的年龄相关性下降，但基于NALT的免疫却没有。然而，尽管完整的NALT诱导了系统免疫，鼻腔免疫仍未能在两岁大的小鼠中诱导粘膜免疫反应。这些结果表明，基于NALT的免疫受年龄影响较小。这项拨款的假设是，鼻腔免疫与适当的粘膜佐剂实际上可以恢复通过NALT启动和介导的Ag特异性粘膜免疫反应。因此，这笔拨款将阐明接受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组织中的作用以及对抗原特异性分泌型IgA(S-LGA)抗体(Ab)的诱导和调节。我们在后三个具体目标中的努力将集中在评估天然和获得性免疫介导的分子佐剂在诱导老年小鼠对病毒和细菌感染的保护性免疫方面的有效性。具体来说，我们将：1)确定NALT中T和B细胞功能的增龄性免疫学变化；2)评估DC在NALT组织和启动Ag特异性免疫中的作用；3)以Flt3配体(PFL)为黏膜佐剂，恢复老龄小鼠的Ag特异性S-LGA抗体和Th1/Th2细胞应答；4)评价PFL和CpG ODN联合使用对衰老小鼠免疫衰老的保护作用；以及5)确定联合佐剂(PFL和CpG)的DC靶向治疗衰老小鼠的有效性。

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.