The Role of chemokines in Autoimmune Encephalomyelitis

描述(申请人提供)：实验性自身免疫性脑脊髓炎(EAE)是一种复发-缓解性中枢神经系统(CNS)脱髓鞘疾病，可作为多发性硬化症(MS)的动物模型。疾病的诱发伴随着中枢神经系统的组织病理学，其特征是单个核细胞的浸润，由T细胞、巨噬细胞和B细胞组成。巨噬细胞、T细胞和B细胞的中枢神经系统浸润导致慢性复发性缓解性瘫痪，类似于在部分MS患者中看到的情况。本应用的主要目的之一是研究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的运输中起重要作用的趋化因子以及在EAE发病机制中的生物学作用。我们假设，在EAE的发生和发展过程中，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的运输。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。以下具体目标将被用来检验我们的假说：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调节中的作用。这将通过以下方式完成：1)检测各种受体在中枢神经系统巨噬细胞迁移和小胶质细胞定位中的作用，方法是使用特异的趋化因子受体基因敲除和小分子质量拮抗剂；2)确定CCR6及其配体CCL20(MIP-3α)在调节持续疾病期间树突状细胞向中枢神经系统的运输以及树突状细胞向外周淋巴组织的迁移中的作用，以刺激自身反应性T细胞。利用CCR6基因敲除小鼠和体内抗CCL20治疗将被用来确定这种配体-受体组合在疾病调控中的机制。3)明确CCL22及其受体CCR4在调节EAE缓解和复发中的作用。这将通过利用CCR4基因敲除小鼠和体内适当时间点的抗CCL22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，并为开发治疗持续疾病的新型趋化因子和趋化因子受体疗法提供基础。

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.