ANTIGEN SPECIFIC T CELL ACCUMULATION IN THE CNS

T淋巴细胞流入中枢神经系统（CNS）是各种自身免疫性和感染性疾病的病理学的重要部分，这些疾病与脑中的炎症相关，包括病毒性脑炎、慢性脑膜炎和多发性硬化症（MS）。 通常，炎症反应涉及以下阶段：1.）活化T细胞的初始进入阶段; 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; 3.）募集期，其中由这些抗原特异性T细胞产生的炎性介质促进非抗原特异性白细胞的流入，导致炎症反应的放大。本申请的主要目标是在理解CNS炎症反应早期起始阶段抗原特异性T细胞进入和积累的机制方面取得进展。我们工作的第一部分（特异性目的1和2）将集中于了解抗原特异性T细胞应答是如何通过全身或CNS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）中最严重的T细胞反应。 由于在正常动物中发现的抗原特异性T细胞数量非常少，因此很难监测，我们将使用我们实验室中已有的新技术，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CNS中单特异性T细胞群的积累。 特异性目标3的目标是干扰抗原特异性和非特异性T细胞最初进入CNS（第1阶段）。将定义控制T细胞的这种初始进入阶段的分子。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，该研究项目的成功完成将导致对T细胞在CNS炎性疾病中的作用的更好理解，并将为控制CNS炎性疾病（如MS）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.