The Role of chemokines in Autoimmune Encephalomyelitis

描述（由申请人提供）：实验性自身免疫性脑脊髓炎（EAE）是一种中枢神经系统（CNS）的复发-缓解型脱髓鞘疾病，可用作多发性硬化症（MS）的动物模型。疾病诱导伴随CNS组织病理学，其特征为单核细胞浸润，由T细胞、巨噬细胞和B细胞组成。巨噬细胞、T细胞和B细胞的CNS浸润导致慢性复发缓解性麻痹，类似于在MS患者亚群中所见。本申请的主要目标之一是解决趋化因子和趋化因子受体在PLP诱导的EAE中的作用，包括确定在调节巨噬细胞、小胶质细胞和树突状细胞运输和EAE发病机制中的生物学中重要的趋化因子。我们推测，特定的趋化因子和趋化因子受体调节巨噬细胞，小胶质细胞和树突状细胞运输的发展和EAE的进展。此外，这些细胞类型可以产生趋化因子，这些趋化因子也在EAE的进展中发挥调节作用。以下具体目标将被解决，以测试我们的假设1）确定巨噬细胞和小胶质细胞趋化因子受体表达在疾病进展的调节中的作用。这将通过使用特异性趋化因子受体基因敲除和小分子量拮抗剂测试各种受体在CNS巨噬细胞迁移和小胶质细胞定位中的作用来实现; 2）确定CCR 6及其配体CCL 20的作用（MIP-3 α）在进行性疾病期间调节树突状细胞向CNS的运输以及树突状细胞向外周淋巴组织的迁移，刺激自身反应性T细胞。将采用CCR 6敲除小鼠和体内抗CCL 20治疗来确定这种配体-受体组合在疾病调节中的机制。3)确定CCL 22及其受体CCR 4在EAE缓解和复发疾病的调节中的作用。这将通过利用CCR 4敲除小鼠和在适当的时间点进行体内抗CCL 22治疗来实现，以揭示这种趋化因子在疾病进展中的机制。这些研究将有助于了解MS的免疫发病机制，并为开发新的趋化因子和趋化因子受体疗法治疗正在进行的疾病提供基础。

DESCRIPTION (provided by applicant): Experimental autoimmune encephalomyelitis (EAE) is a relapsing-remitting demyelinating disease of the central nervous system (CNS) that serves as an animal model for multiple sclerosis (MS). Disease induction is accompanied by CNS histopathology characterized by mononuclear cell infiltrates, consisting of T cells, macrophages, and B cells. The CNS infiltration by macrophages, T cells, and B cells results in chronic relapsing remitting paralysis similar to what has been seen in a subset of MS patients. 1 of the major goals of this application is to address the role of chemokines and chemokine receptors in PLP-induced EAE, including determining the chemokines that are important in regulating macrophage, microglia, and dendritic cell trafficking and biology in EAE pathogenesis. We hypothesize that specific chemokines and chemokine receptors regulate macrophage, microglia, and dendritic cell trafficking in the development and progression of EAE. Furthermore, these cell types can produce chemokines that also play a regulatory role in the progression of EAE. The following specific aims will be addressed to test our hypothesis 1) Determine the role of macrophage and microglial chemokine receptor expression in the regulation of disease progression. This will be accomplished by testing the contribution of various receptors in CNS macrophage migration and microglia positioning through the use of specific chemokine receptor gene knockouts and small molecular weight antagonists; 2) Determine the role of CCR6 and its ligand CCL20 (MIP-3alpha) in the regulation of dendritic cell trafficking to the CNS during ongoing disease as well as dendritic cell migration to peripheral lymphoid tissue to stimulate autoreactive T cells. The use of CCR6 knockout mice and in vivo anti-CCL20 treatment will be employed to determine the mechanism of this ligand-receptor combination in disease regulation. 3) Determine the role of CCL22 and its receptor CCR4 in the regulation of EAE remission and relapsing disease. This will be accomplished by utilizing CCR4 knockout mice and in vivo anti-CCL22 treatment at appropriate time points to reveal the mechanism of this chemokine in disease progression. These studies will help to understand the immunopathogenesis of MS and provide a basis for the development of novel chemokine and chemokine receptor therapies for treatment of ongoing disease.