Chemokines in a novel murine model of DTH in the brain

本研究将主要在波兰进行，作为NIH资助# 1 R01 NS 32151“中枢神经系统炎症中的趋化因子”的延伸。白细胞浸润中枢神经系统（CNS）是许多神经免疫性疾病的关键事件。淋巴细胞和巨噬细胞进入大脑的募集可能是中枢神经系统中趋化因子（趋化因子细胞因子）表达的结果。在本研究中，我们分析了在多发性硬化症(MS) -实验性自身免疫性脑脊髓炎（EAE）动物模型中，特定的趋化因子对及其受体如何调控炎症细胞向中枢神经系统的募集。在本研究中，我们希望扩展这些研究，并分析趋化因子和趋化因子受体在脑内注射卡介苗（BCG）诱导的ms样CNS病变的新描述的局灶模型中的作用。该模型是脑延迟型超敏反应（DTH）的一个例子，其特征是在脑纹状体中存在单个核炎症灶。与EAE脑不同，DTH模型是由非中枢神经系统抗原（BCG）诱导的，可以观察炎症反应引发的旁观者脑损伤。类似类型的中枢神经系统损伤被认为是多发性硬化症的发病机制。本研究将集中在以下三个具体目标：1)建立和表征小鼠脑DTH反应模型。首先，将描述小鼠脑DTH反应模型。最初这个模型是几年前在老鼠身上描述的。小鼠DTH模型将使我们能够使用大鼠无法使用的几种小鼠试剂，并在未来使用转基因动物。2)脑DTH模型趋化因子及趋化因子受体表达分析。一旦描述了新模型的组织病理学，我们将解决趋化因子在其发展中的潜在作用。分析DTH病变发展过程中脑内趋化因子和趋化因子受体的表达。本项目将以目的3趋化因子抑制剂预防和治疗脑DTH模型结束。脑内一些趋化因子及其受体很可能在bcg诱导的神经炎症模型中上调。这一观察结果可能导致用抗趋化因子策略调节这种病理。上调的趋化因子也将成为Aim 3的靶标。这里提出的研究将补充正在进行的研究，没有重叠。这些研究结果可能为神经炎性疾病提供新的治疗策略。

DESCRIPTION (provided by applicant) This research will be done primarily in Poland as an extension of NIH grant # 1 R01 NS 32151 "Chemokines in CNS inflammation." Leukocyte infiltration into the central nervous system (CNS) is a key event in many neuroimmunologic diseases. The recruitment of lymphocytes and macrophages into the brain is likely the result of chemokine (chemoattractant cytokine) expression in the CNS. In the parent grant we analyze how specific pairs of chemokines and their receptors govern recruitment of inflammatory cells to the CNS during animal model of multiple sclerosis (MS) - experimental autoimmune encephalomyelitis (EAE). In this proposal, we would like to extend those studies and analyze the role of chemokines and chemokine receptors in a newly described focal model of MS-like CNS lesions induced by intracerebral injection of bacillus Calmette-Guerin (BCG). This model is an example of brain delayed type hypersensitivity (DTH) reaction and is characterized by the presence of a single mononuclear inflammatory focus in brain striatum. Unlike EAE brain, the DTH model is induced by non-CNS antigen (BCG) and allows observation of bystander damage to the brain triggered by inflammatory reaction. Similar types of CNS damage is postulated for MS pathogenesis. This research will concentrate on the following three Specific Aims: 1) Development and characterization of the murine model of brain DTH reaction. Initially, murine model of brain DTH reaction will be described. Originally this model was described in rats a few years ago. Mouse DTH model will enable us to use several murine reagents not available for rats and use genetically modified animals in the future. 2) Analysis of chemokines and chemokine receptor expression in brain DTH model. Once the histopathology of a new model is described, we will address the potential role of chemokines in its development. Expression of chemokines and chemokine receptors in the brain during development of DTH lesion will be analyzed. This project will be concluded with Aim 3) Prevention and treatment of brain DTH model with chemokine inhibitors. Some chemokines and their receptors are most likely upregulated in the brain during BCG-induced model of neuroinflammation. This observation may lead to modulation of this pathology with anti-chemokine strategy. Upregulated chemokines will also be targeted in Aim 3. Research proposed here will complement ongoing studies by the parent grant without overlap. Results of those studies may suggest new therapeutic strategies for neuroinflammatory disorders.