Novel Humanized Mice to Study CD1b/c-Mediated Immunity

研究 CD1b/c 介导免疫的新型人源化小鼠

• 批准号: 6850518
• 负责人: MORIYA TSUJI
• 金额: $ 31.65万
• 依托单位: AARON DIAMOND AIDS RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-15 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6850518
• 关键词: CD1 molecule; Mycobacterium tuberculosis; T lymphocyte; active immunization; animal mortality; artificial chromosomes; bacterial antigens; bioterrorism /chemical warfare; disease /disorder model; emerging infectious disease; enzyme linked immunosorbent assay; flow cytometry; genetically modified animals; host organism interaction; immune response; immunocytochemistry; laboratory mouse; leukocyte activation /transformation; microorganism immunology; tuberculosis; virus infection mechanism

DESCRIPTION (provided by applicant): Although a mouse model has widely been used to study the immune system of mammals, it is not an ideal experimental model for understanding the human immune system as there is a considerable gap between the immune systems of mice and humans. This gap includes the expression of CD1b and CD1c molecules; the gene and the protein expression of these group I CD1 molecules are present in humans but absent in mice. These CD1 molecules are important molecules that can present antigens containing lipid moiety and stimulate human T cells in vitro. Therefore, we created "humanized" mice that express CD1b and CD1c molecules. This was done by generating human CD1b/c-transgenic mice using Bacterial Artificial Chromosome (BAC) technology, and then crossing the CD1b/c-BAC-transgenic mice to human beta2-microglobulin-transgenic mice. This BAC technology allows for the generation of mice carrying large fragments of foreign genomic DNA and, therefore, expressing transgenes in a faithful manner. In fact, we found that the expression patterns of these CD1 molecules by different cell types in our humanized mice are very much similar to those reported in humans as determined by a flow cytometric assay and by immunohistochemistry. Interestingly, most of the antigens, which are known to bind to CD1b/c molecules and activate human T cells in vitro, are lipids derived from Mycobacterium tuberculosis. M. tuberculosis, a majority of which is composed of lipids, is a cause of one of the most important emerging infectious diseases worldwide, and also a potential bioterrorism agent. Therefore, the successful generation of the human CD1b/c-transgenic mice will permit us to study the following Aims: Specific Aim 1: Determine the nature of newly generated CD1-mediated immunity in human CD1b/c transgenic mice. Specific Aim 2: Determine the protective role of the CD1-mediated immunity against mycobacteria, whose lipid components are known to bind to CD1b/c and activate human T cells.

描述（由申请人提供）：尽管鼠标模型已广泛用于研究哺乳动物的免疫系统，但它不是理解人类免疫系统的理想实验模型，因为小鼠和人类的免疫系统之间存在很大的差距。该差距包括CD1B和CD1C分子的表达。这些I组CD1分子的基因和蛋白质表达存在于人类中，但在小鼠中不存在。这些CD1分子是重要的分子，可以表现出含有脂质部分的抗原并在体外刺激人T细胞。因此，我们创建了表达CD1B和CD1C分子的“人性化”小鼠。这是通过使用细菌人工染色体（BAC）技术生成人类CD1B/C-转基因小鼠，然后将CD1B/C-BAC-转基因小鼠跨到人beta2-微球蛋白 - 经胞纤维蛋白转基因小鼠到的。该BAC技术允许产生携带大量外国基因组DNA碎片的小鼠，因此以忠实的方式表达转基因。实际上，我们发现，在人源性小鼠中，不同细胞类型的这些CD1分子的表达模式与通过流式细胞术测定和免疫组织化学确定的人类报道的人非常相似。有趣的是，已知与CD1b/c分子结合并在体外激活人T细胞的大多数抗原是源自结核分枝杆菌的脂质。结核分枝杆菌是大多数由脂质组成的，是全球最重要的新兴传染病之一的原因，也是潜在的生物恐怖剂。因此，人类CD1B/C-转基因小鼠的成功产生将使我们能够研究以下目标： 具体目标1：确定新生成的CD1介导的免疫的性质，在人CD1B/C转基因小鼠中。 具体目标2：确定CD1介导的免疫对分枝杆菌的保护作用，该脂质成分已知与CD1B/C结合并激活人T细胞。