Sensitization to brain antigens following stroke.

中风后对脑抗原敏感。

• 批准号: 7345389
• 负责人: KYRA J BECKER
• 金额: $ 26.51万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7345389
• 关键词: Adoptive Transfer; Animal Model; Animals; Antigens; Autoimmune Responses; Behavioral; Blood - brain barrier anatomy; Blood Circulation; Brain; CNS autoimmunity; Cerebrum; Data; Developed Countries; Developing Countries; Development; Immune; Immune Tolerance; Immune response; Immune system; Immunization; Immunology procedure; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Lymphocyte; Lymphoid; Measures; Neuraxis; Neurologic; Neurologic Dysfunctions; Numbers; Organ; Outcome; Patients; Performance; Peripheral; Persons; Public Health; Research; Research Personnel; Site; Stroke; Systemic infection; Testing; Therapeutic Intervention; Time; Translating; United States; acute stroke; base; disability; experience; improved; in vivo; neurobehavioral; novel; post stroke; prevent; programs; research study

Stroke is a leading cause of disability in developed countries. At least 25% of persons who suffer stroke will become infected during the course of their acute stroke, and those who become infected experience more disability than those that remain infection free. How systemic infection contributes to neurologic injury during stroke is not well understood. The rationale for the experiments outlined in this proposal is based on the fact that there is a breach in the integrity of the blood-brain barrier (BBB) following stroke that allows the immune system to encounter novel central nervous system (CNS) antigens in both the brain and in peripheral lymphoid organs. The type of immune response generated upon antigen encounter is determined by the composition of the microenvironment at the site of the encounter. The systemic inflammatory response that accompanies an infection could induce the expression ofcostimulatory molecules and alter the context in which antigens are presented to lymphocytes, thus promoting their sensitization to brain antigens. Preliminary data suggestthat animals do develop an autoimmune response to brain following stroke and that lymphocytes sensitized to CNS antigens contribute to cerebral injury, which might explain why infection in the post-stroke period is associated with worse outcome. Manipulating the post-ischemic immune response could therefore be an effective therapeutic intervention for the treatment of stroke. Using an animal model of stroke and a number of in vivo and ex vivo immunologic assays,we plan to confirm and extend our prior findings which show that sensitization to CNS is associated with worse outcome after stroke. The proposed studies will also incorporate sensitive measures of neurological and behavioral performance. More importantly, we hope to show that induction of immunologic tolerance to CNS antigens, even after stroke onset, will prevent the development of CNS autoimmunity; thistolerance should translate to improved outcome from stroke. Given that over 700,000 strokes occur each year in the United States and that at least 175,000 of patients with stroke will develop a concomitant infection, an immune modulating therapy could have significant impact on public health.

中风是发达国家残疾的主要原因。至少有25%的中风患者 在急性中风过程中被感染，而那些被感染的人会经历更多的痛苦。 比那些保持无感染的人更有能力。全身性感染如何导致神经损伤 在中风期间，并没有很好地理解。本提案中概述的实验原理基于 事实上，中风后血脑屏障（BBB）的完整性存在缺口， 免疫系统遇到新的中枢神经系统（CNS）抗原在大脑和 外周淋巴器官在遇到抗原时产生的免疫应答的类型是 由相遇地点的微环境组成决定。全身 伴随感染的炎症反应可以诱导共刺激因子的表达， 分子并改变抗原呈递给淋巴细胞的环境，从而促进它们的免疫应答。 对脑抗原致敏。初步数据表明动物确实会产生自身免疫反应 对CNS抗原致敏的淋巴细胞导致脑损伤， 这可能解释了为什么中风后感染与更差的结果相关。操纵 因此，缺血后免疫应答可能是一种有效的治疗干预， 中风的治疗 使用中风的动物模型和一些体内和体外免疫学测定，我们计划 证实并扩展了我们先前的发现，即CNS致敏与更严重的 中风后的结果拟议的研究还将纳入神经系统和 行为表现更重要的是，我们希望表明诱导免疫耐受， CNS抗原，即使在中风发作后，也会阻止CNS自身免疫的发展; 应该可以改善中风的预后考虑到美国每年有超过70万人中风， 在美国，至少有175，000名中风患者会发生伴随感染， 免疫调节治疗对公众健康有重大影响。