Immunoregulatory NK cells in Multiple Sclerosis

多发性硬化症中的免疫调节 NK 细胞

• 批准号: 7370067
• 负责人: Bibiana Bielekova
• 金额: $ 7.36万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2008-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7370067
• 关键词: Age; Animals; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Autologous; Biological Assay; Brain; Cell physiology; Cells; Chromium; Clinical; Clinical Trials; Complex; Condition; Daclizumab; Data; Defect; Development; Disease; Effector Cell; Employee Strikes; Evolution; Exposure to; Figs - dietary; Flow Cytometry; Functional disorder; Goals; Human; IL2RA gene; Immune; Immune Tolerance; Immune response; Immune system; Inflammation; Inflammatory; Interferon-beta; Interferons; Interleukin-17; Knowledge; Laboratories; Lead; Letters; Life; Maintenance; Malignant Neoplasms; Measures; Mediating; Molecular; Multiple Sclerosis; Natural Killer Cells; Nature; Neuraxis; Numbers; Pathogenesis; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phase II Clinical Trials; Phenotype; Physiological; Play; Population; Predisposition; Production; Regulation; Regulatory Pathway; Reporting; Research; Rest; Role; Roquinimex; Sampling; Signal Transduction; Standards of Weights and Measures; Stimulus; T cell regulation; T-Cell Activation; T-Cell Development; T-Lymphocyte; TNFSF10 gene; Testing; Therapeutic; Therapeutic Agents; Translating; Treatment outcome; United States National Institutes of Health; Work; autoreactive T cell; base; burden of illness; cell killing; concept; cytotoxicity; experience; granzyme A; humanized monoclonal antibodies; immunoregulation; in vivo; innovation; insight; killings; long term memory; neuroimmunology; novel; perforin; prevent; response; sex; virus development

DESCRIPTION (provided by applicant): The objective of this proposal is to investigate the immunoregulatory role of natural killer (NK) cells in Multiple Sclerosis (MS). NK cells are important effector cells participating in the protection against viruses and the development of malignancies. However, NK cells appear to be critically involved in the crosstalk between innate and adaptive immune responses and may help to maintain immune tolerance. Important defects in NK numbers and/or function have been reported in patients with autoimmune disorders, including MS, and in animals susceptible to induction of autoimmunity. Additionally, several therapeutic agents that were shown to effectively suppress inflammation in MS (IFN-beta, linomide and Daclizumab) stimulate NK cell function. However, the mechanism(s) by which NK cells may participate in the maintaining of the immune tolerance remain undefined. We hypothesize that the defective immunoregulation of T cell responses by NK cells is an important factor in MS pathogenesis. Our long-term goal is to apply mechanistic insight into NK-mediated immunoregulation to develop new/more effective therapies for MS. The goal of this application is to elucidate the key cellular and molecular mechanisms and rules of interaction between human NK cells and T cells in order to determine if NK-mediated regulation of T cell responses is important for the maintenance of immune tolerance under physiological conditions. Additionally, we want to determine if NK-mediated immunoregulatory mechanisms are deficient in untreated MS patients and whether Daclizumab therapy restores these deficiencies. This goal will be achieved in 3 Specific Aims: (1) Determine the effect of NK cells on T cell priming toward Th17 phenotype; (2) Define the extent and mechanism of NK-mediated killing of autoreactive T cells and (3) Determine the in vivo relevance of the NK-mediated mechanisms of immunoregulation defined in Aims 1&2 by analyzing paired baseline and treatment samples from the Phase II clinical trial of Daclizumab monotherapy in untreated MS patients, and by correlating the effect of Daclizumab on these immunoregulatory mechanisms with clinical and paraclinical (i.e. MRI) measures of their MS disease activity. These studies will provide new insight into how NK cells participate in the maintenance of immune tolerance and how deficiencies in NK cell function can lead to the development of autoimmunity. We expect that this knowledge will translate into the development of new therapies for MS and other autoimmune diseases.

描述（由申请方提供）：本提案的目的是研究自然杀伤（NK）细胞在多发性硬化（MS）中的免疫调节作用。NK细胞是参与抵抗病毒和恶性肿瘤发展的重要效应细胞。然而，NK细胞似乎在先天性和适应性免疫应答之间的串扰中起关键作用，并且可能有助于维持免疫耐受。在自身免疫性疾病（包括MS）患者和易诱导自身免疫的动物中，已报告了NK数量和/或功能的重要缺陷。此外，几种治疗药物，显示有效地抑制炎症的MS（IFN-β，利诺胺和达利珠单抗）刺激NK细胞功能。然而，NK细胞参与维持免疫耐受的机制仍不明确。我们推测NK细胞对T细胞应答的免疫调节缺陷是MS发病机制中的一个重要因素。我们的长期目标是将对NK介导的免疫调节的机制的洞察应用于开发新的/更有效的MS疗法。本申请的目标是阐明人NK细胞和T细胞之间相互作用的关键细胞和分子机制和规则，以确定NK介导的T细胞应答调节对于在生理条件下维持免疫耐受是否重要。此外，我们想确定NK介导的免疫调节机制是否在未经治疗的MS患者中存在缺陷，以及Daclizumab治疗是否可以恢复这些缺陷。这一目标将通过三个具体目标来实现：（1）确定NK细胞对T细胞向Th 17表型致敏的影响;（2）确定NK介导的自身反应性T细胞杀伤的程度和机制，和（3）确定目的1和2中定义的NK介导的免疫调节机制的体内相关性。2通过分析来自未经治疗的MS患者中Daclizumab单药治疗II期临床试验的配对基线和治疗样本，并通过将达克珠单抗对这些免疫调节机制的作用与其MS疾病活性的临床和临床旁（即MRI）测量相关联。这些研究将为NK细胞如何参与维持免疫耐受以及NK细胞功能缺陷如何导致自身免疫的发展提供新的见解。我们希望这些知识将转化为MS和其他自身免疫性疾病的新疗法的开发。