THE ROLE OF CHEMOKINES IN AUTOIMMUNE ENCEPHALOMYELITIS

实验性自身免疫性脑脊髓炎（EAE）是一种复发缓解型中枢神经系统（CNS）脱髓鞘疾病，可作为多发性硬化症（MS）的动物模型。疾病诱导伴有以T细胞、巨噬细胞和B细胞组成的单核细胞浸润为特征的中枢神经系统组织病理学。巨噬细胞、T细胞和B细胞浸润中枢神经系统导致慢性复发缓解性瘫痪，类似于在MS患者亚群中所见的情况。本应用程序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，包括确定在活动性和继发性EAE发展中以及在急性EAE，缓解期和复发期EAE中重要的趋化因子。特异性趋化因子在CNS募集抗原特异性T细胞、非特异性T细胞和巨噬细胞中的相对作用将被研究。此外，趋化因子已被证明具有免疫改变作用，如T细胞共刺激、T细胞细胞因子表达和T细胞分化。因此，趋化因子在EAE中调节持续免疫反应中的作用也将被确定。我们假设选择性趋化因子和趋化因子受体的时间中枢表达模式调节急性和复发性EAE的免疫发病机制。这种调节包括对单核细胞化学吸引的影响以及细胞因子反应的免疫调节。以下具体目标将被解决，以验证我们的假设：1)确定趋化因子对急性和复发性EAE诱导和进展的调节；2) CC趋化因子在急性和复发性EAE中促炎和抗炎细胞因子反应的免疫调节中的作用。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提供基础，这些疗法旨在针对炎症性脱髓鞘疾病诱导和进展过程中参与致病性淋巴细胞向中枢神经系统迁移的分子。

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. One o 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 development of active and adoptive EAE, as well as during acute EAE, remission, and relapses of EAE. The relative role of specific chemokines in the CNS recruitment of antigen specific T cells as well as non-specific T cells and macrophages will be investigated. Furthermore, chemokines have been shown to have immune altering effects such as T cell co-stimulation, T cell cytokine expression, and T cell differentiation. Therefore, the role of chemokines in regulating the ongoing immune response in EAE will also be determined. We hypothesize that a temporal CNS expression pattern of selective chemokines and chemokine receptor regulates the immunopathogenesis of acute and relapsing EAE. This regulation includes effects on mononuclear cell chemoattraction as well as immunomodulation of cytokine responses. The following specific aims will be addressed to test our hypothesis: 1) Determination of chemokine regulation of acute and relapsing EAE induction and progression; 2) The role of CC chemokines in the immunomodulation of pro-inflammatory and anti-inflammatory cytokine responses during acute and relapsing EAE. These studies will help to understand the immunopathogenesis of MS and provide a basis for the development of novel chemokine and chemokine receptor therapies designed at targeting molecules involved in the migration of pathogenic lymphocytes into the CNS during the induction and progression of inflammatory demyelinating diseases.