Sensitization to brain antigens following stroke.

描述(由申请人提供)： 在发达国家，中风是导致残疾的主要原因。至少有25%的中风患者会在急性中风期间被感染，那些被感染的人比那些没有感染的人经历更多的残疾。系统性感染是如何导致中风期间的神经损伤的，目前还不清楚。这项建议中概述的实验的基本原理是基于这样一个事实，即中风后血脑屏障(BBB)的完整性受到破坏，使免疫系统能够在大脑和外周淋巴器官中遇到新的中枢神经系统(CNS)抗原。在抗原相遇时产生的免疫反应的类型由相遇地点微环境的组成决定。伴随感染而来的全身性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，中风后动物确实会对大脑产生自身免疫反应，而对中枢神经系统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较差的预后有关。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措施。利用卒中动物模型和大量体内和体外免疫学分析，我们计划证实和推广我们先前的发现，即对中枢神经系统的敏感性与卒中后更差的预后相关。拟议的研究还将纳入神经和行为表现的敏感指标。更重要的是，我们希望证明，诱导对中枢神经系统抗原的免疫耐受，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；这种耐受应该转化为改善卒中的预后。鉴于美国每年发生的中风超过70万例，而且至少有17.5万名中风患者会同时感染，免疫调节疗法可能会对公共健康产生重大影响。(摘要结束)

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)