Sensitization to brain antigens following stroke.

在发达国家，中风是导致残疾的主要原因。至少25%的中风患者会 在他们的急性中风过程中被感染，而那些被感染的人经历更多 残疾的人比那些保持无感染的人更多。全身性感染如何导致神经损伤 中风期间的情况还不是很清楚。本提案中概述的实验的基本原理是基于 事实上，中风后血脑屏障(BBB)的完整性被破坏，这使得 免疫系统将在大脑和大脑中遇到新的中枢神经系统(CNS)抗原 外周淋巴器官。在遇到抗原时产生的免疫反应的类型是 由相遇地点的微环境组成决定。系统性的 伴随感染的炎症反应可诱导共刺激分子的表达 分子并改变抗原呈递给淋巴细胞的环境，从而促进其 对脑部抗原敏感。初步数据表明，动物确实会产生自身免疫反应。 中风后对大脑的影响以及对中枢神经系统抗原致敏的淋巴细胞有助于脑损伤， 这可能解释了为什么中风后的感染与更差的结局有关。操纵 因此，缺血后免疫反应可能是一种有效的治疗干预措施。 中风的治疗。 利用中风的动物模型和一些体内和体外的免疫学分析，我们计划 证实和扩展我们之前的发现，即对中枢神经系统的敏化与更糟糕的 卒中后的转归。拟议的研究还将纳入神经和神经功能的敏感指标 行为表现。更重要的是，我们希望证明免疫耐受的诱导 中枢神经系统抗原，即使在中风发病后，也将阻止中枢神经系统自身免疫的发展； 应该转化为中风预后的改善。鉴于美国每年有超过70万人中风 在美国，至少有175,000名中风患者会同时感染， 免疫调节疗法可能会对公众健康产生重大影响。

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.