CNS MICROVASCULAR PERICYTE AND EAE

CNS 微血管周细胞和 EAE

基本信息

批准号：
6632134
负责人：
PAULA DORE-DUFFY
金额：
$ 19.78万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-06-18 至 2006-05-31
项目状态：
已结题

项目摘要

The hallmark of tissue pathology in multiple sclerosis (MS) is the migration of one or more leukocyte subsets across the blood brain barrier (BBB) into the parenchymal tissue with resultant demyelination and plaque formation. It is now known that migration involves a permissive BBB. From the standpoint of the BBB permission to migrate is the result of a complicated series of cross-talk mechanisms between the cellular constituents of the BBB, the endothelial cell (EC), the pericyte (PC), and the astrocyte. While a plethora of literature is available on EC and astrocyte biophysiology very little is known of the role played by the PC. We have developed techniques to isolate primary PC and have endeavored to study its involvement in leukocyte-BBB interactions. Previous studies have shown that PC have immune potential. They express adhesion molecules and synthesize and release a variety of cytokines. Leukocytes appear to cluster around the PC in vivo in MS tissue and in vitro. We question whether PC are involved in T-cell priming in EAE. Ag primed CD4 splenic T-cells from both rats and mice adhere to cultured PC. CD4 T-cells with a cytokine secreting phenotype consistent with T1 cells adhere readily to nonactivated PC while T2 cells do not. Activated PC adhere to both cytokine secreting phenotypes. PC present antigen to primed leukocytes, express co-stimulatory molecules and can restimulate memory effector cells to either T1 or T2 phenotype. We propose that PC may be involved in selection and polarization of leukocytes that migrate across the BBB in inflammatory CNS disorders such as MS. We will study their role in induction of primary effector cells in Ag-specific TCR transgenic mice, as well as the restimulation of memory TO to memory effector cells in primed animals. The potential role of PC cytokines will be examined.

多发性硬化症（MS）组织病理学的标志是，一个或多个白细胞亚群在血液脑屏障（BBB）中迁移到实质组织中，导致脱髓鞘和斑块形成。现在众所周知，迁移涉及允许的BBB。从BBB许可的迁移许可的角度来看，是BBB，内皮细胞（EC），周细胞（PC）和星形胶质细胞的细胞成分之间的一系列复杂的串扰机制的结果。虽然在EC和星形胶质细胞生物生理学上获得了大量文献，但对于PC扮演的角色却鲜为人知。我们已经开发了隔离主要PC的技术，并努力研究其参与白细胞-BBB相互作用。先前的研究表明，PC具有免疫潜力。它们表达粘附分子并合成并释放各种细胞因子。白细胞在MS组织和体外的体内似乎聚集在PC周围。我们质疑PC是否参与EAE中的T细胞启动。来自大鼠和小鼠的Ag启动的CD4脾脏T细胞粘附在培养的PC上。具有与T1细胞一致的细胞因子分泌表型的CD4 T细胞很容易粘附在未激活的PC上，而T2细胞则没有。激活的PC粘附在两种细胞因子分泌表型上。 PC呈现对启动白细胞的抗原，表达共刺激分子，并可以将记忆效应细胞与T1或T2表型重新刺激。我们建议PC可能参与炎症性中枢神经系统疾病（如MS）中跨BBB迁移的白细胞的选择和极化。我们将研究它们在Ag特异性TCR转基因小鼠中诱导主要效应细胞的作用，以及将记忆重新启用至引发动物的记忆效应细胞。将检查PC细胞因子的潜在作用。