Novel Humanized Mice to Study CD1b/c-Mediated Immunity

描述（由申请人提供）：尽管小鼠模型已被广泛用于研究哺乳动物的免疫系统，但由于小鼠和人的免疫系统之间存在相当大的差距，因此其不是理解人免疫系统的理想实验模型。这种差异包括CD 1b和CD 1c分子的表达;这些I组CD 1分子的基因和蛋白表达存在于人类中，但在小鼠中不存在。这些CD 1分子是能够提呈含有脂质部分的抗原并在体外刺激人T细胞的重要分子。因此，我们创造了表达CD 1b和CD 1c分子的“人源化”小鼠。这是通过使用细菌人工染色体（BAC）技术产生人CD 1b/c转基因小鼠，然后将CD 1b/c-BAC转基因小鼠与人β 2微球蛋白转基因小鼠杂交来完成的。这种BAC技术允许产生携带大片段外源基因组DNA的小鼠，因此以忠实的方式表达转基因。事实上，我们发现，这些CD 1分子的表达模式，由不同的细胞类型在我们的人源化小鼠是非常相似的，在人类中所报道的，通过流式细胞术测定和免疫组织化学。有趣的是，已知与CD 1b/c分子结合并在体外激活人类T细胞的大多数抗原是来自结核分枝杆菌的脂质。M.大部分由脂质组成的结核病是世界范围内最重要的新兴传染病之一的原因，也是潜在的生物恐怖主义因子。因此，人CD 1b/c转基因小鼠的成功产生将使我们能够研究以下目的： 具体目的1：确定人CD 1b/c转基因小鼠中新产生的CD 1介导的免疫的性质。 具体目标二：确定CD 1介导的免疫对分枝杆菌的保护作用，已知分枝杆菌的脂质成分与CD 1b/c结合并激活人类T细胞。

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.