The Role of Notch Signaling in Experimental Autoimmune Encephalomyelitis (EAE)

描述（由申请人提供）：实验性自身免疫性脑脊髓炎（EAE）是由自身抗原特异性T细胞介导的，依赖于关键的共刺激信号来完全激活和成熟。EAE被用作研究多发性硬化症（MS）的模型。在该模型中，抗原特异性CD4+ Th1细胞介导中枢神经系统（CNS）的炎症损伤。越来越多的证据表明Notch信号在CD4+ T细胞的外周成熟中起着不可或缺的作用。对Notch在小鼠抗原特异性自身免疫性脑脊髓炎中的作用的研究使我们观察到Notch信号以配体依赖的方式参与疾病的开始，并且Jaggedl和Jagged2在外周发挥免疫调节作用。本文概述了研究Notch信号在脑脊髓炎中的作用的分子和细胞方法。该项目的主要目标是识别和表征Notch配体在耐受性中的作用。该项目将使用融合蛋白和单克隆抗体治疗方法来研究体内的耐受性策略。在自身免疫、癌症免疫治疗和移植等免疫疾病中，操纵Notch信号可能会带来治疗机会，这可能被证明是抑制异常免疫激活的一种新方法。

DESCRIPTION (provided by applicant): Experimental autoimmune encephalomyelitis (EAE) is mediated by autoantigen-specific T cells dependent on critical costimulatory signals for their full activation and maturation. EAE is used as a model for the study of multiple sclerosis (MS). In this model, antigen-specific CD4+ Th1 cells mediate inflammatory damage in the central nervous system (CNS). A growing body of evidence suggests that Notch signaling plays an integral role in the peripheral maturation of CD4+ T cells. Examination of the role of Notch in murine antigen specific autoimmune encephalomyelitis has led us to the observation that Notch signaling is involved in the initiation of the disease in a ligand-dependent manner and that Jaggedl and Jagged2 play an immuno-regulatory role in the periphery. This proposal outlines molecular and cellular methods for studying the role of Notch signaling in encephalomyelitis. The major goal of this project is to identify and characterize Notch ligand(s) involvement in tolerance. This project will lead to the use of fusion proteins and monoclonal antibody therapy approaches to investigate tolerance strategies in vivo. Therapeutic opportunities that could arise from the manipulation of Notch signaling in immune disorders such as autoimmunity, cancer immunotherapy and transplantation, may prove to be a novel approach to suppress aberrant immune activation.