Dendritic Cells in Innate Immunity

先天免疫中的树突状细胞

• 批准号: 7652140
• 负责人: BALI PULENDRAN
• 金额: $ 29.3万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652140
• 关键词: Address; Allogenic; Antigen-Presenting Cells; Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Characteristics; Class; Complement; Complex; Cytokine Network Pathway; DNA; Databases; Decision Making; Dendritic Cells; Evaluation; Flagellin; Goals; Helminths; Helper-Inducer T-Lymphocyte; Human; IgE; Immune; Immune response; Immune system; Immunity; In Vitro; Interleukin-4; Interleukin-5; Learning; Ligands; MAP Kinase Signaling Pathways; Macaca; Macaca mulatta; Mediating; Microbe; Modeling; Mus; Natural Immunity; Nature; Pattern recognition receptor; Peptidoglycan; Phase; Phenotype; Poly I-C; Porphyromonas gingivalis; Production; Proteins; Reagent; STF; Schistosoma; Signal Pathway; Signal Transduction; Staphylococcus aureus; Stimulus; T-Lymphocyte; TLR2 gene; TLR3 gene; TLR5 gene; TLR7 gene; Th2 Cells; Vaccines; Zymosan; chemokine; cytokine; egg; eosinophil; immune function; in vivo; knowledge base; microbial; monocyte; novel strategies; pathogen; pre-clinical; programs; receptor; response; toll-like receptor 4

The immune system has evolved different types of immunities, each one specialized for the elimination of particular classes of pathogens. In response to intracellular microbes, CD4+ T-helper (Th) cells differentiate into Thl cells, which produce IFN-y; in contrast, helminths induce the differentiation of Th2 cells, whose cytokines (principally IL-4, IL-5 & ILl0) induce IgE and eosinophil-mediated destruction of the pathogens. While cytokines produced early in the response are crucial in determining the Th polarization of the immune response, the mechanism by which a given pathogen stimulates a particular type of immunity is unknown. Several observations hint at a possible mechanism. First, distinct types of dendritic cell (DC) subsets differentially can induce Thl and Th2 responses. Second, different microbial stimuli signal through distinct pattern recognition receptors on antigen presenting cells (APC). For example, LPS from E.coli signals through the Toll-like receptor 4 (TLR4), while peptidoglycan from Staphylococcus aureus, and zymosan, signal through TLR2. Third, different microbial stimuli differentially activate DCs to elicit distinct classes of immune responses. For example, while E.cofi LPS stimulates IL-12(p70) production by DCs and primes a Thl response, P.gingivafis LPS or schistosome egg antigens (SEA) do not elicit IL-12(p70), and favor Th2 responses. In this context, it is unclear whether signaling through distinct TLRs can elicit different immune responses. Here, we hypothesize that: (i) signaling via different TLRs can evoke qualitatively different types of responses in DCs, which ultimately mediate distinct classes of immune responses; (ii)learning how microbial stimufi manipulate DCs to modulate the immune response will offer valuable lessons to vaccinologists wishing to achieve the same goal These issues will be addressed using highly purified TLR-dependent and TLR-independent microbial stimuli, including E.cofi LPS, different TLR2 stimuli [such as peptidoglycan (PGN), zymosan, the lipopetide STF from M.tubercolosis, and the small synthetic molecules Pam3 Cys, and MALP], the TLR5 stimulus flagellin, the TLR7 stimuli imidazoquinolines, the TLR9 stimulus CpG DNA, and the TLR3 stimulus poly-I-C, as well as classic Th2 inducers such as SEA and filarial proteins. These reagents will be used to probe the immune stimulatory potential of DC subsets from humans and rhesus macaques. Aim 1. To determine the phenotype, function, and major intracellular signaling pathways induced in human DC subsets by specific TLR.dependent and TLR.independent stimufi Aim 2. To determine the types of CD4+ and CD8+ T cell responses stimulated in vitro by human DC$ activated with various TLR.dependent and TLR-independent stimuli _im 3. To determine the phenotype, function and immune stimulatory capacity of DC subsets from rhesus macaques stimulated in vitro with various TLR.dependent and TLR.independent stimufi Thus, this project will generate a knowledge-base about the responsiveness of DCs in humans and macaques to various TLR stimuli. This, together with the in vivo mice studies proposed in Project 2, Program 3, are expected to yield valuable pre-clinical information, as a prelude to the evaluation of such strategies in Phase 1/11clinical trials.

免疫系统已经进化出不同类型的免疫力，每一种都专门用于消除特定的免疫系统。 病原体的种类。响应于细胞内微生物，CD4 + T辅助（Th）细胞分化成Thl细胞， 产生IFN-γ;相反，蠕虫诱导Th2细胞的分化，其细胞因子（主要是IL-4、IL-5和IL 10） 诱导IgE和嗜酸性粒细胞介导的病原体破坏。虽然细胞因子在反应早期产生， 在决定免疫反应的Th极化中是至关重要的， 刺激特定类型的免疫力是未知的。一些观察结果暗示了一种可能的机制。第一，区别 不同类型的树突状细胞（DC）亚群可以不同地诱导Th1和Th2应答。第二，不同的微生物刺激 通过抗原呈递细胞（APC）上不同模式识别受体进行信号传导。例如，来自大肠杆菌的LPS 通过Toll样受体4（TLR4）发出信号，而来自金黄色葡萄球菌的肽聚糖和酵母聚糖发出信号， 通过TLR2。第三，不同的微生物刺激差异激活DC，以引起不同类别的免疫应答。 例如，虽然大肠杆菌LPS刺激DC产生IL-12（p70）并引发Thl应答，但牙龈卟啉单胞菌LPS或 虫卵抗原（SEA）不诱导IL-12（p70），而有利于Th2应答。在这种情况下，不清楚是否 通过不同TLR的信号传导可引发不同的免疫应答。在这里，我们假设：（i）通过 不同的TLR可以在DC中引起不同类型的反应，其最终介导不同的免疫应答。 免疫反应的类别;（ii）了解微生物刺激如何操纵DC来调节免疫反应。 反应将为希望实现同样目标的疫苗学家提供宝贵的经验教训。 使用高度纯化的TLR依赖性和TLR非依赖性微生物刺激物，包括大肠杆菌LPS， TLR2刺激物[如肽聚糖（PGN）、酵母聚糖、来自结核分枝杆菌的脂肽STF和小的合成的TLR2刺激物]。 分子Pam3 Cys和MALP]、TLR5刺激鞭毛蛋白、TLR7刺激咪唑并喹啉、TLR9刺激 CpG DNA和TLR3刺激多聚-I-C，以及经典的Th2诱导物如SEA和丝虫蛋白。这些 试剂将用于探测来自人和恒河猴的DC亚群的免疫刺激潜力。 目标1.确定人DC诱导的表型、功能和主要的细胞内信号通路 特异性TLR依赖性和TLR非依赖性刺激的亚群 目标2.目的探讨人DC活化后体外刺激的CD4+和CD8 + T细胞应答的类型。 各种TLR依赖性和TLR非依赖性刺激 _im 3.研究恒河猴DC的表型、功能和免疫刺激活性 用各种TLR依赖性和TLR非依赖性刺激体外刺激猕猴， 因此，该项目将产生关于人类和猕猴中DC对以下物质的反应性的知识库： 各种TLR刺激。这与项目2，项目3中提出的体内小鼠研究一起，预计将产生 有价值的临床前信息，作为在I/II期临床试验中评价此类策略的前奏。