CNS antigen sensitization in stroke.

描述（由申请人提供）：本研究的主要目的是确定有多少患者在卒中后对脑抗原致敏（产生Th 1免疫应答），以及卒中后即刻感染是否会增加对这些抗原致敏的风险。这项研究的基本原理是基于这样一个事实，即血脑屏障的完整性在中风中被破坏;免疫系统的细胞因此在大脑和体循环中都遇到了新的中枢神经系统（CMS）抗原。这种遭遇可能导致对这些抗原的免疫应答，并且遭遇部位的微环境决定了所产生的免疫应答的性质。例如，全身性炎症反应，如感染时发生的炎症反应，可诱导共刺激分子的表达，并促进淋巴细胞对脑抗原的敏感性（Th 1免疫反应）。在中风的动物模型中，对CMS抗原致敏的淋巴细胞有助于脑损伤，并且免疫应答的操纵改善中风的结果。免疫反应的类似操作可以为临床干预提供治疗靶点。然而，迄今为止，试图操纵中风患者的免疫反应没有产生任何临床益处，甚至有害。因此，在临床中风中进行进一步的免疫调节试验之前，需要了解缺血后免疫应答的性质和后果。出于本研究的目的，将在急性缺血性卒中患者中连续评价1年内对脑抗原的抗原特异性免疫应答;将在卒中后即刻发生感染的患者与未发生感染的患者之间比较免疫应答类型（Th 1与Th 2/Th 3）。还将评估卒中亚型和内源性免疫调节反应对脑抗原致敏可能性的影响。通过磁共振成像检测的白色疾病和脑萎缩的进展将用作Th 1应答的病理后果的替代量度。本研究的数据将用于计划未来的卒中患者免疫调节试验。

DESCRIPTION (provided by applicant): The primary aims of this study are to determine how many patients become sensitized (develop a Th1 immune response) to brain antigens after stroke and whether infection in the immediate post-stroke period increases the risk of becoming sensitized to those antigens. The rationale for this study is based on the fact that the integrity of the blood-brain barrier is breached in stroke; cells of the immune system thus encounter novel central nervous system (CMS) antigens in both the brain and in the systemic circulation. This encounter may result in an immune response to those antigens and the microenvironment at the site of encounter determines the nature of the immune response generated. For instance, a systemic inflammatory response, such as occurs with infection, could induce the expression of costimulatory molecules and promote sensitization of lymphocytes (Th1 immune response) to brain antigens. In animal models of stroke, lymphocytes sensitized to CMS antigens contribute to cerebral injury and manipulation of the immune response improves outcome from stroke. Similar manipulation of the immune response could provide a therapeutic target for clinical intervention. To date, however, attempts at manipulating the immune response in patients with stroke have produced either no clinical benefit or even harm. Thus, prior to conducting further trials of immune modulation in clinical stroke, the nature and the consequences of the post-ischemic immune response need to be understood. For the purposes of this study, antigen-specific immune responses to brain antigens will be evaluated serially over the course of 1 year in patients who present with acute ischemic stroke; the type of immune response, Th1 versus Th2/Th3, will be compared between patients who develop infection in the immediate post-stroke period and those who do not. The effect of stroke subtype and endogenous immunomodulatory responses on the likelihood of becoming sensitized to brain antigens will also be assessed. Progression of white matter disease and brain atrophy, as detected by magnetic resonance imaging, will be used as a surrogate measure of the pathologic consequences of a Th1 response. Data derived from this study will be used to plan future trials of immunomodulation in patients with stroke.