ADENOVIRUS FLT3 LIGAND INDUCES NALT DCs FOR SALIVARY GLAND S-lgA Ab RESPONSES

腺病毒 FLT3 配体诱导 NALT DC 产生唾液腺 S-IgA Ab 反应

基本信息

批准号：
7840769
负责人：
Kohtaro Fujihashi
金额：
$ 1.69万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7840769
关键词：
Adenoviruses Adjuvant Amylases Antibodies Antigens B-Lymphocytes CCL2 gene CD4 Positive T Lymphocytes Cell Migration Induction Cells Cholera Toxin Complementary DNA CpG dinucleotide Dendritic Cells Environment FLT3 ligand Frequencies Grant ITGAM gene ITGAX gene Immune Immune response Immunization Immunoglobulin A Immunoglobulins Interleukin-7 Intestines Lamina Propria Ligands Lymphoid Tissue Memory Monocyte Chemoattractant Proteins Mus Nose Plasmids Play Population Process Regulation Research Personnel Role Saliva Salivary Salivary Glands Salivary immunoglobulin A Secretory Immunoglobulin A Sterility Submandibular gland Surface System T-Lymphocyte TLR4 gene Testing Tissues Toll-like receptors Transgenic Mice base chemokine receptor commensal microbes cytokine migration programs promoter receptor expression response salivary cell trinitrophenyl-lipopolysaccharide

项目摘要

DESCRIPTION (provided by applicant): Over the past five years, we have studied the innate factors and immune cells which induce and regulate salivary secretory immunoglobulin (S-lgA) antibody (Ab) responses. We have shown that plasmids encoding the flt3 ligand (FL), lymphotactin (LTN), RANTES and MCP-1 cDNA as well as unmethylated cytosine-guanine dinucleotides oligodeoxynucleotide (CpG ODN), when used as nasal adjuvants, enhance both mucosal and systemic immune responses. Nasopharyngeal-associated lymphoreticular tissues (NALT) and the submandibular glands (SMGs) from mice given these nasal cDNA adjuvants showed increased numbers of dendritic cells (DCs) and were a key factor in the induction of salivary S-lgA Ab responses. Further, our recent study using an adenovirus (Ad) expressing FL cDNA (pFL) when used as nasal adjuvant significantly enhanced salivary S-lgA Ab responses. Based upon these findings, our overall hypothesis in this renewal application is that NALT DCs regulate salivary S-lgA Ab responses by processing Ag followed by their migration into the SMGs. More specifically, we hypothesize that targeting NALT with FL-based adjuvants will preferentially induce migration of NALT DCs into the SMGs and enhance the induction of mucosal S-lgA Ab responses. Our recent study showed that T cell-independent (Tl) Ag-specific salivary S- IgA Ab responses correlated with an increased number of B-1 B cells in the SMGs when mice were immunized nasally with Tl Ag plus native cholera toxin. Further, we found that increased levels of Toll-like receptor four (TLR4) expression by 78 T cells in the SMGs of mice given nasal Tl Ag. These results clearly showed that cross-talk between innate- and acquired-type immune cells was important in the induction of Ag-specific salivary S-lgA Ab responses even for immune responses to Tl Ags. We hypothesize that targeting NALT with FL-based adjuvants induce migration of NALT DCs to the SMGs that interact with B-1 B cells and y& T cells in the SMGs for the induction of mucosal S-lgA Ab responses. In order to test our hypothesis, we propose four Specific Aims. We will: 1) Characterization of chemokine receptor expression by Ad-FL-induced CD11b+ DCs in NALT for their maturation and their relocation into the SMGs. 2) Tracking Ad-FL-induced NALT DC migration for the induction of salivary S-lgA Ab responses. 3) Comparison of Ad- FL-induced NALT and SMG DCs for their immunological function in the induction of CD4'1' Th1- and Th2-type cytokine responses as well as long-lasting memory function. 4) Determination of the precise mechanism for cross-talk between Ad-FL-induced salivary DCs, B-1 B cells and yS T cells for salivary S-lgA Ab responses.

描述（由申请人提供）：在过去的五年中，我们研究了诱导和调节唾液分泌免疫球蛋白（S-LGA）抗体（AB）抗体（AB）反应的先天因素和免疫细胞。我们已经表明，编码FLT3配体（FL），淋巴结蛋白（LTN），RANTES和MCP-1 cDNA以及未甲基化的细胞质 - 瓜烷二核苷酸寡氧化核苷酸（CPG ODN），用作NASASAL辅助剂，增强MICCANTES和Systome consical connance n andance clance和系统，质粒。给定这些鼻cDNA辅助剂的小鼠的鼻咽相关淋巴细胞组织（NALT）和下颌下腺（SMG）显示出增加的树突状细胞（DCS），并且是唾液S-LGA AB反应诱导的关键因素。此外，我们最近使用腺病毒（AD）表达FL cDNA（PFL）的研究显着增强了唾液S-LGA AB反应。基于这些发现，我们在此更新应用中的总体假设是，NALT DC通过处理Ag，然后将其迁移到SMG中来调节唾液S-LGA AB反应。更具体地说，我们假设用基于FL的佐剂靶向NALT将优先诱导NALT DC迁移到SMG中，并增强粘膜S-LGA AB反应的诱导。我们最近的研究表明，当小鼠用TL AG和天然霍乱毒素鼻鼻子免疫时，SMGS中的B-1 B细胞数量增加与SMG中的B-1 B细胞数量增加有关。此外，我们发现给定鼻TL Ag的小鼠SMG中78个T细胞的Toll样受体四（TLR4）表达增加。这些结果清楚地表明，先天性和获得性型免疫细胞之间的串扰在诱导Ag特异性唾液S-LGA AB反应中也很重要，即使对于对TL AGS的免疫反应也是如此。我们假设用基于FL的佐剂靶向NALT会诱导NALT DC迁移到SMG中与B-1 B细胞和Y＆T细胞相互作用的SMG迁移，以诱导粘膜S-LGA AB反应。为了检验我们的假设，我们提出了四个具体目标。我们将：1）通过AD-FL诱导的NALT中的CD11b+ DC来表征趋化因子受体的表达，以使其成熟和迁移到SMG中。 2）跟踪AD-FL诱导的NALT DC迁移以诱导唾液S-LGA AB反应。 3）在诱导CD4'1'Th1-th1型细胞因子反应以及持久的记忆函数中，比较了Adfl诱导的NALT和SMG DC的免疫功能。 4）确定AD-FL诱导的唾液DC，B-1 B细胞和YS T细胞之间的精确机制，用于唾液S-LGA AB反应。