Role of T reg in live vaccination against leishmaniasis

T reg 在利什曼病活疫苗接种中的作用

• 批准号: 6814042
• 负责人: Susana Mendez
• 金额: $ 17.8万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-15 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6814042
• 关键词: CpG islands; Leishmania major; T lymphocyte; active immunization; antigen presentation; cell migration; cellular immunity; cytokine; dendritic cells; immune response; immunomodulators; interleukin 6; laboratory mouse; leishmaniasis; live vaccine; pharmacokinetics; phenotype; ulcer; zoonosis

DESCRIPTION (provided by applicant): Leishmania major (Lm) is the causative agent of zoonotic cutaneous leishmaniasis (ZCL), the most widely distributed form of ZCL in the Old World. The inoculation of live, non-attenuated Lm to produce a lesion that heals (leishmanization) is to date the only vaccine against leishmaniasis proven effective in humans. We have developed a live vaccine containing live Lm and immonostimulatory oligodeoxynucleotides (CpG ODNs) that ameliorates or abolish lesion due to vaccination and confers long term protection in the murine model. Our goal is to determine the role of regulatory T cells (Treg) in live vaccination against Lm. The specific hypothesis is that the absence of lesions due to live vaccination in the presence of CpG ODNs is caused by a downreagulation of Treg fuction caused by activation of dendritic cells (DCs) that leads to an enhanced immune response. We based this hypothesis on the observations that 1) CpG ODNs are known to activate DC function 2) Treg control the intensity of immune response by suppressing effector function and 3) DCs release IL-6 after CPG ODNs stimulation that partially suppress Treg function. Addition of CpG ODNs to live vaccination will stimulate DCs and therefore supersede Treg function, leading to an 1) enhanced effector immune response, 2) increased parasite killing and, thus, 3) absence of lesion due to vaccination. To prove that hypothesis, we present the following specific aims: 1. Define the relationship of CpG ODNs-activated APC and Treg in vitro. We will perform in vitro studies using DCs pulsed with live vaccine conditions and each of the components and determine their effect on DCs and Treg incubated with such DCs. 2. Characterize the in vivo role of CpG ODNs in modulating Treg function on the Lm/C57BI/6 model. We will vaccinate mice and extract DCs and Treg at different time points to study their function and phenotype. We will use those cells to reconstitute RAG -/- and determine their phenotype.

描述（由申请人提供）：Leishmania Major（LM）是人畜共患性皮肤利什曼病（ZCL）的病因，这是旧世界中ZCL分布最广泛的形式。接种活的，未衰减的LM以产生治愈的病变（利什曼化）是迄今为止唯一针对利什曼病的疫苗，证明对人类有效。我们已经开发了一种活疫苗，该疫苗含有活LM和ImmoNostimulationaly寡脱氧核苷酸（CpG ODN），该疫苗由于疫苗接种而改善或废除病变，并在鼠模型中赋予长期保护。我们的目标是确定调节性T细胞（TREG）在针对LM的实时疫苗接种中的作用。具体的假设是，在存在CpG ODN的情况下，由于在CPG ODN存在下导致病变的缺失是由树突状细胞激活（DC）引起的Treg摄影的降解引起的，这会导致免疫反应增强。我们基于以下观察结果：1）已知CpG ODN激活DC函数2）Treg通过抑制效应子函数来控制免疫反应的强度，而3）DCS在CpG ODN刺激后释放IL-6，该刺激部分抑制了TREG功能。在实时疫苗接种中添加CpG ODN将刺激DC，从而取代Treg功能，从而导致1）增强的效应子免疫反应，2）增加寄生虫杀戮，因此3）3）由于疫苗接种而没有病变。为了证明这一假设，我们提出以下特定目的：1。在体外定义了CpG ODNS激活的APC和Treg的关系。我们将使用与活疫苗条件和每个成分脉冲的DCS进行体外研究，并确定它们对DCS和Treg与此类DC孵育的影响。 2。表征CpG ODN在LM/C57BI/6模型上调节Treg函数中的体内作用。我们将在不同时间点接种小鼠，并提取DC和Treg，以研究其功能和表型。我们将使用这些细胞来重建抹布 - / - 并确定它们的表型。