ANTIGEN SPECIFIC T CELL ACCUMULATION IN THE CNS

T淋巴细胞进入中枢神经系统(CNS)是多种自身免疫性和感染性疾病病理的重要组成部分，这些疾病与脑内炎症有关，包括病毒性脑炎、慢性脑膜炎和多发性硬化症(MS)。通常，炎症反应包括以下几个阶段：1.激活的T细胞的初始进入阶段；少数活化的、抗原特异的T细胞的优先聚集和部位特异性存活；募集阶段，由这些抗原特异性T细胞产生的炎症介质有助于非抗原特异性白细胞的涌入，导致炎症反应的放大。这项应用的主要目标是在了解抗原特异性T细胞在中枢神经系统炎症反应早期启动阶段进入和积累的机制方面取得进展。我们工作的第一部分(具体目标1和2)将侧重于了解抗原特异性T细胞反应是如何通过全身或中枢神经系统的抗原引入而启动的。我们将比较不同的抗原刺激途径，并确定哪种途径导致脑实质和脑脊液(CSF)中T细胞反应最严重。由于在正常动物中发现的极少数抗原特异性T细胞很难监测，我们将使用我们实验室已有的一项新技术，涉及T细胞受体转基因动物及其各自的抗原。通过这种方式，我们将能够跟踪单一特异性T细胞群体在中枢神经系统中的积累。具体目标3的目标将是干扰抗原特异性和非特异性T细胞进入中枢神经系统的初始进入(阶段1)。控制T细胞最初进入阶段的分子将被定义。对这一过程的描述将对理解疾病的发病机制和开发有效的免疫疗法至关重要。我们相信，该研究项目的成功完成将有助于加深对T细胞在中枢神经系统炎症性疾病中的作用的了解，并将为控制中枢神经系统炎症性疾病的新的治疗方法(如MS)提供基础。

The influx of T lymphocytes into the Central Nervous System (CNS) is an important part of the pathology of various autoimmune and infectious diseases, which are associated with inflammation in the brain, including viral encephalitis, chronic meningitis and Multiple Sclerosis (MS). Typically, inflammatory reactions involve the following phases: 1.) the initial entry phase of activated T cells; 2.) the preferential accumulation and site-specific survival of a small number of activated, antigen specific T cells; 3.) recruitment phase, in which, inflammatory mediators produced by these antigen specific T cells contribute to the influx of non-antigen specific leukocytes resulting in an amplification of the inflammatory response. The primary goal of this application is to achieve progress toward understanding the mechanism of entry and accumulation of antigen specific T cells in the early initiation phase of CNS inflammatory reactions. The first part of our work (Specific Aims 1 and 2) will focus on understanding how antigen specific T cell responses are initiated by systemic or CNS introduction of antigens. We will compare different routes of antigenic stimulation and determine which one results in the most exacerbated T cell response in the brain parenchyma and Cerebral Spinal Fluid (CSF). Because of the difficulties in monitoring the very small numbers of antigen specific T cells found in a normal animal, we will use a novel technology already available in our laboratory, involving T cell receptor transgenic animals and their respective antigens. In this way we will be able to follow the accumulation of a monospecific T cell population in the CNS. The goal of Specific Aim 3 will be to interfere with the initial entry (phase 1) of antigen specific and non-specific T cells into the CNS. Molecules governing this initial entry phase of T cells will be defined. Characterization of this process will be crucial to understanding the pathogenesis of disease, and developing effective immunotherapies. We believe that the successful completion of this research project will lead to an improved understanding of the role of T cells in CNS inflammatory diseases and will provide the foundation for new therapeutic methodologies for controlling CNS inflammatory diseases, such as MS.