ANTIGEN SPECIFIC T CELL ACCUMULATION IN THE CNS

T淋巴细胞涌入中枢神经系统（CNS）是各种自身免疫性和传染性疾病病理的重要组成部分，这些疾病与脑部炎症有关，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T细胞的初始进入期；2)少量活化的抗原特异性T细胞的优先积累和位点特异性存活；募集期，由这些抗原特异性T细胞产生的炎症介质促进非抗原特异性白细胞的涌入，导致炎症反应的放大。本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起始阶段的进入和积累机制方面取得进展。我们工作的第一部分（Specific Aims 1和2）将重点了解抗原特异性T细胞反应是如何通过系统或中枢神经系统引入抗原而启动的。我们将比较不同的抗原刺激途径，并确定哪一种导致脑实质和脑脊液（CSF）中T细胞反应最加剧。由于很难监测在正常动物中发现的非常少量的抗原特异性T细胞，我们将使用我们实验室已经可用的新技术，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，我们将能够跟踪中枢神经系统中单特异性T细胞群的积累。特异性靶向3的目标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（1期）。控制T细胞初始进入阶段的分子将被定义。这一过程的表征对于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，本研究项目的成功完成将有助于进一步了解T细胞在中枢神经系统炎症性疾病中的作用，并为控制中枢神经系统炎症性疾病（如多发性硬化症）的新治疗方法提供基础。

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.