CNS antigen sensitization in stroke.

描述（由申请人提供）：本研究的主要目的是确定中风后有多少患者对脑抗原敏感（产生Th1免疫反应），以及中风后立即感染是否会增加对这些抗原敏感的风险。这项研究的基本原理是基于这样一个事实：血脑屏障的完整性在中风中被破坏；因此，免疫系统细胞在大脑和体循环中都会遇到新的中枢神经系统（CMS）抗原。这种接触可能导致对这些抗原的免疫反应，而接触部位的微环境决定了产生的免疫反应的性质。例如，全身炎症反应，如感染，可以诱导共刺激分子的表达，促进淋巴细胞对脑抗原的敏化（Th1免疫反应）。在脑卒中动物模型中，对CMS抗原敏感的淋巴细胞有助于脑损伤，而控制免疫反应可改善脑卒中的预后。类似的免疫反应操作可以为临床干预提供治疗靶点。然而，到目前为止，试图控制中风患者的免疫反应的尝试要么没有产生临床效益，要么甚至是有害的。因此，在进行进一步的临床脑卒中免疫调节试验之前，需要了解缺血后免疫反应的性质和后果。为了本研究的目的，将对急性缺血性卒中患者在1年内对脑抗原的抗原特异性免疫反应进行连续评估；将比较在中风后立即发生感染的患者和未发生感染的患者之间的免疫反应类型，Th1与Th2/Th3。脑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也将被评估。通过磁共振成像检测白质疾病和脑萎缩的进展，将被用作Th1反应病理后果的替代测量。从这项研究中获得的数据将用于计划未来中风患者免疫调节的试验。

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.