CD1-targeted Vaccination against Tuberculosis

CD1靶向结核病疫苗

• 批准号: 6689284
• 负责人: ROBERT L MODLIN
• 金额: $ 20.96万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6689284
• 关键词: Adenoviridae; CD1 molecule; MHC class II antigen; Mycobacterium tuberculosis; active immunization; antigen presenting cell; bacterial antigens; biotechnology; chimeric proteins; clinical research; cooperative study; helper T lymphocyte; human subject; immunity; immunoregulation; interferon gamma; intracellular transport; laboratory mouse; microorganism immunology; multidrug resistance; transfection; tuberculosis; tuberculosis vaccines; vaccine development; vector vaccine

DESCRIPTION (provided by applicant): The long-range goal of this project is to develop and validate the CD1-based vaccine technology platform to immunize humans against microbial pathogens. This approach is based on the knowledge that several of the CD1 proteins have specific targeting sequences that direct their traffic into endosomal compartments, structures also critical for antigen presentation by MHC class II molecules to CD4+ T cells. We will determine whether this novel vaccine strategy can induce protective immunity against Mycobacterium tuberculosis, a worldwide killer, and now because of multi-drug resistant tuberculosis, a potential agent of a bioterrorist attack. We propose to determine the trafficking pattern of CD1 chimers in antigen presenting cells including monocytes and dendritic cells. The ability of CD1 targeting to be used in immunization in humans will be assessed by studying the immune response to an M. tuberculosis antigen ESAT-6. In addition, the ability of ESAT-6/CD1 fusion constructs to immunize human T cell responses in vitro will be investigated. To determine whether ESAT-6/CD1 chimers can induce protective immunity, ESAT-6/CD1 fusion constructs will be used to immunize mice, which will be subsequently challenged with virulent M. tuberculosis. The studies proposed will help develop and test the efficacy of CD1-based DNA vaccines for the prevention of infectious disease, including those from natural pathogens and bioterrorist attacks. Specifically, it should be possible to develop a new approach to the prevention of tuberculosis, including multidrug resistant tuberculosis, in humans. Finally, the CD1-based vaccine technology should prove useful in the vaccination against microbial pathogens in which MHC class II-restricted presentation of antigen to CD4+ T cells is required for host defense.

描述（由申请人提供）：该项目的远程目标是开发和验证基于CD1的疫苗技术平台，以使人类免受微生物病原体的侵害。这种方法是基于以下知识：几种CD1蛋白具有特定的靶向序列，可将其交通引导到内体室中，结构对于MHC II类分子对CD4+ T细胞的抗原表现也至关重要。我们将确定这种新颖的疫苗策略是否可以诱导防止结核分枝杆菌的保护性免疫，这是全球杀手，现在由于多药耐药性结核病，这是生物恐怖袭击的潜在药物。我们建议确定在包括单核细胞和树突状细胞在内的抗原呈递细胞中CD1嵌合体的运输模式。 CD1靶向用于人类免疫的能力将通过研究对结核分枝杆菌抗原ESAT-6的免疫反应来评估。此外，将研究ESAT-6/CD1融合构建体在体外免疫T细胞反应的能力。为了确定ESAT-6/CD1 CHIMER是否可以诱导保护性免疫，ESAT-6/CD1融合构建体将用于免疫小鼠，随后将对结核分枝杆菌施加挑战。提出的研究将有助于开发和测试基于CD1的DNA疫苗预防传染病的功效，包括自然病原体和生物恐怖症的疾病。具体而言，应该有可能在人类中开发一种预防结核病的新方法，包括抗多药的结核病。最后，基于CD1的疫苗技术应证明在针对微生物病原体的疫苗接种中有用，其中MHC II类限制性抗原的表现为 CD4+ T细胞是宿主防御所必需的。