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.
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