Role of T cells in ischemic brain damage

项目总结/摘要 脑卒中是世界范围内死亡和残疾的主要原因之一，是第三大死亡原因 残疾人在美国。临床和临床前研究表明，炎症在 缺血性卒中后急性和慢性神经组织损伤;然而， 参与神经炎症的机制还不完全清楚。目前没有可用的治疗靶向 急性免疫反应在脑缺血期间在大脑中发展，并且没有新的治疗方法 自1996年发现组织纤溶酶原激活剂疗法以来，我们 发现白细胞介素21（IL 21）是缺血性卒中后急性脑损伤的主要贡献者。IL21 在缺血脑血管周围和梗死脑实质中检测到表达细胞 组织中这增加了IL 21靶向治疗辅助目前治疗的可能性， 有益于中风管理。这项工作的长期目标是了解如何操纵 缺血性损伤后的急性炎症，以抑制中风引起的组织损伤。的目标 该建议旨在确定致病性滤泡辅助性T细胞（Tfh）和IL 21的作用机制， 参与急性中风引起的损伤。具体的假设是，最近发现的循环 致病性产生IL 21的Tfh细胞浸润到脑中的缺血组织中，其中IL 21有助于组织 通过诱导神经元死亡来损害。三个目标将研究Tfh细胞和IL 21如何促进缺血性损伤 在大脑里。在目标1中，我们将阐明驱动IL 21产生的Tfh细胞浸润、发育和分化的途径。 短暂性大脑中动脉缺血性损伤不同阶段中枢神经系统功能的变化 闭塞（tMCAO）。我们认为，选择性Tfh细胞募集阻断剂可以减少组织损伤， 中风在目的2中，我们将评估IL 21 R在缺血脑中的时空表达，并测试其在缺血脑中的可能性。 IL 21受体在神经元上表达的调节剂。我们认为，抑制神经元上IL 21 R的表达， 减少中风中的组织损伤。在目的3中，我们将描述IL 21 R在神经元中的作用。 缺血性中风的发病机制。我们将评估急性和慢性缺血性损伤和中枢神经系统 在神经元中选择性缺乏IL 21 R的小鼠中的炎症环境。 这项工作的成功完成将有助于更好地了解 致病性IL-21产生细胞促进缺血性损伤并鉴定新的治疗方法 中风的目标。

PROJECT SUMMARY/ABSTRACT Stroke is one of the leading causes of death and disability worldwide and is the third leading cause of death and disability in the United States. Clinical and preclinical studies suggest the importance of inflammation in acute and chronic neuronal tissue damage following ischemic stroke; however, the mechanisms and cells involved in neuroinflammation are not fully understood. There is currently no available treatment for targeting the acute immune response that develops in the brain during cerebral ischemia, and no new treatment has been introduced to stroke therapy since the discovery of tissue plasminogen activator therapy in 1996. We discovered that interleukin 21 (IL21) is a major contributor to acute brain injury after ischemic stroke. IL21 expressing cells were detected in perivascular regions and the infarcted parenchyma of ischemic human brain tissues. This raises the possibility that IL21–targeting therapies adjunct to current treatments might be beneficial in stroke management. The long-term goal of this work is to understand how to manipulate the acute inflammation following ischemic injury in order to inhibit stroke-induced tissue damage. The objective of this proposal is to define the mechanisms by which pathogenic follicular helper T cells (Tfh) and IL21 are involved in acute stroke-induced injury. The specific hypothesis is that the recently discovered circulating pathogenic IL21-producing Tfh cells infiltrate into ischemic tissues in the brain, where IL21 contributes to tissue damage by inducing neuronal death. Three aims will study how Tfh cells and IL21 contribute to ischemic injury in the brain. In Aim 1, we will elucidate the pathways that drive IL21-producing Tfh cell infiltration, development and function in the CNS during different stages of ischemic injury induced by transient Middle Cerebral Artery Occlusion (tMCAO). We propose that selective Tfh cell recruitment blockers could decrease tissue damage in stroke. In Aim 2, we will evaluate spatiotemporal expression of IL21R in the ischemic brain and test potential regulator(s) of IL21R expression on neurons. We propose that inhibiting IL21R expression on neurons could decrease tissue damage in stroke. In Aim 3, we will characterize the role of IL21R on neurons in the pathogenesis of ischemic stroke. We will evaluate acute and chronic ischemic damage and the CNS inflammatory milieu in mice that selectively lack IL21R in neurons. Successful completion of this work will lead to a better understanding of the mechanism by which pathogenic IL21-producing cells promote damage in ischemic injury and identify new therapeutic targets in stroke.