NALT-BASED ADJUVANTS FOR MUCOSAL IMMUNITY IN AGING

基于 NALT 的佐剂可增强衰老过程中的粘膜免疫能力

• 批准号: 7904801
• 负责人: Kohtaro Fujihashi
• 金额: $ 28万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904801
• 关键词: Adjuvant; Affect; Age; Aging; Antibodies; Antigens; Applications Grants; B-Lymphocytes; Bacterial Infections; Breathing; Cell physiology; Communicable Diseases; Dendritic Cells; Elements; Event; Goals; Grant; Immune; Immune response; Immune system; Immunity; Immunization; Immunologic Deficiency Syndromes; Individual; Infection; Ligands; Maintenance; Mediating; Molecular; Molecular Target; Mucosal Immune Responses; Mucosal Immunity; Mus; Nose; Plasmids; Play; Population; Predisposition; Regulation; Risk; Role; Secretory Immunoglobulin A; Th2 Cells; Tissues; Vaccines; Viral; Virus Diseases; acquired immunity; aged; base; efficacy evaluation; gastrointestinal; high risk; older patient; pathogen; respiratory; response; senescence

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.

描述（由申请人提供）：已经表明，衰老个体是部分免疫缺陷的，并具有因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中对不同传染病的敏感性增加的关键因素。但是，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。鼻咽相关的淋巴组织（NALT）在诱导和调节保护性粘膜和全身免疫反应对粘膜感染的诱导和调节中起着核心作用。与年龄相关的抗原（Ag）特异性粘膜和全身免疫力的诱导和调节中发生了与年龄相关的下降。然而，尽管NALT诱导的全身免疫力，鼻腔免疫未能诱导两只老鼠的粘膜免疫反应。这些结果表明，基于NALT的免疫力受衰老的影响较小。该赠款的假设是，具有适当粘膜佐剂的鼻腔免疫实际上可以恢复通过NALT引发和介导的Ag特异性粘膜免疫反应。因此，该赠款将阐明给定鼻疫苗的老年小鼠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的影响以及树突细胞（DCS）在维持NALT组织中的作用以及Ag特异性分泌IgA（S-LGA）抗体（AB）抗体的诱导和调节。我们在最后三个具体目标中的努力将重点放在评估先天和免疫性介导的分子佐剂在老年小鼠中诱导病毒和细菌感染的保护性免疫的功效。具体而言，我们将：1）确定NALT中T和B细胞功能与年龄相关的免疫学变化； 2）评估DC在NALT组织中的作用和Ag特异性免疫的启动； 3）恢复年龄小鼠的Ag特异性S-LGA ABS和Th1/Th2细胞反应，将FLT3配体（PFL）的质粒作为粘膜佐剂； 4）评估PFL的功效以及CPG ODN补偿免疫衰老； 5）确定DC靶向剂量（PFL和CPG）在衰老小鼠中对病毒和细菌病原体的组合的疗效。

项目成果

Dendritic cell-targeting DNA-based nasal adjuvants for protective mucosal immunity to Streptococcus pneumoniae.

• DOI: 10.1111/1348-0421.12487
• 发表时间: 2017-06
• 期刊: Microbiology and immunology
• 影响因子: 2.6
• 作者: Kataoka K;Fukuyama Y;Briles DE;Miyake T;Fujihashi K
• 通讯作者: Fujihashi K

A molecular mucosal adjuvant to enhance immunity against pneumococcal infection in the elderly.

• DOI: 10.4110/in.2015.15.1.9
• 发表时间: 2015-02
• 期刊: Immune network
• 影响因子: 6
• 作者: Fukuyama Y;Ikeda Y;Ohori J;Sugita G;Aso K;Fujihashi K;Briles DE;McGhee JR;Fujihashi K
• 通讯作者: Fujihashi K

Mucosal adjuvants for vaccines to control upper respiratory infections in the elderly.

• DOI: 10.1016/j.exger.2014.01.006
• 发表时间: 2014-06
• 期刊: EXPERIMENTAL GERONTOLOGY
• 影响因子: 3.9
• 作者: Fujihashi, Kohtaro;Sato, Shintaro;Kiyono, Hiroshi
• 通讯作者: Kiyono, Hiroshi

Mucosal Immunosenescence in the Gastrointestinal Tract: A Mini-Review.

• DOI: 10.1159/000368897
• 发表时间: 2015
• 期刊: Gerontology
• 影响因子: 3.5
• 作者: Sato S;Kiyono H;Fujihashi K
• 通讯作者: Fujihashi K