Sensitization to brain antigens following stroke.

中风后对脑抗原敏感。

• 批准号: 7175355
• 负责人: KYRA J BECKER
• 金额: $ 26.24万
• 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/7175355
• 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; Nervous System Trauma; 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; abstracting; acute stroke; base; disability; experience; improved; in vivo; neurobehavioral; novel; post stroke; prevent; programs; research study

DESCRIPTION (provided by applicant): 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 neurological 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 of costimulatory molecules and alter the context in which antigens are presented to lymphocytes, thus promoting their sensitization to brain antigens. Preliminary data suggest that 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; this tolerance 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. (End of Abstract)

描述（由申请人提供）： 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期间会感染，而那些感染的人比那些没有感染的人经历更多的残疾。全身性感染如何导致卒中期间的神经损伤尚不清楚。本提案中概述的实验的基本原理是基于以下事实：中风后血脑屏障（BBB）的完整性存在破坏，这使得免疫系统在脑和外周淋巴器官中遇到新的中枢神经系统（CNS）抗原。抗原接触后产生的免疫应答类型由接触部位微环境的组成决定。伴随感染的全身炎症反应可诱导共刺激分子的表达，并改变抗原呈递给淋巴细胞的环境，从而促进其对脑抗原的敏感性。初步数据表明，动物在中风后确实对大脑产生了自身免疫反应，对CNS抗原敏感的淋巴细胞有助于脑损伤，这可能解释了为什么中风后感染与更差的结果相关。因此，操纵缺血后免疫反应可能是治疗中风的有效治疗干预。使用中风的动物模型和一些体内和体外免疫学测定，我们计划证实和扩展我们先前的发现，这些发现表明对CNS的致敏与中风后更差的结果相关。拟议的研究还将纳入神经和行为表现的敏感措施。更重要的是，我们希望表明诱导对CNS抗原的免疫耐受，即使是在卒中发作后，也将阻止CNS自身免疫的发展;这种耐受应转化为卒中预后的改善。鉴于美国每年发生超过700，000例中风，并且至少175，000例中风患者将发展为伴随感染，免疫调节疗法可能对公共健康具有显著影响。(End摘要）