Modulation of chronic vascular inflammation by iNKT cells

iNKT 细胞对慢性血管炎症的调节

• 批准号: 8197586
• 负责人: Luc Van Kaer
• 金额: $ 37.99万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197586
• 关键词: Agonist; Animals; Antigens; Atherosclerosis; Autoimmunity; Blood Vessels; CD28 gene; CD80 gene; Cardiovascular system; Cells; Cellular biology; Chronic; Development; Disease; Experimental Models; Foundations; Galactosylceramides; Glycolipids; Goals; Heart Diseases; Human; Immune response; Immune system; Immunotherapy; Inflammation; Inflammation Mediators; Inflammatory; Insulin-Dependent Diabetes Mellitus; Investigation; Knowledge; Laboratories; Laboratory Study; Ligands; Lupus; Measures; Modality; Molecular; Multiple Sclerosis; Mus; Pathway interactions; Pattern; Phenotype; Play; Preventive; Principal Investigator; Pristane; Process; Production; Property; Publishing; Research Personnel; Role; Stimulus; Stroke; Surface; T cell anergy; T cell therapy; T-Cell Activation; Testing; Therapeutic; Toll-like receptors; Validation; Vascular Diseases; Vascular System; Work; anergy; base; cell type; cytokine; in vivo; insight; killer T cell; lupus-like; microbial; microorganism antigen; novel; prevent; receptor; response; vascular inflammation

PROJECT SUMMARY/ABSTRACT Invariant natural killer T (iNKT) cells play an important role in the progression of chronic inflammatory diseases of the vasculature, including atherosclerosis and lupus-associated vascular disease. The overall goal of this application is to obtain in depth understanding of the in vivo mechanisms underlying iNKT cell activation by various stimuli and to utilize this information for the development of better therapeutic approaches of chronic inflammatory diseases of the vascular system. The investigators of this application have shown that the iNKT cell antigen -galactosylceramide (-GalCer) can prevent the development of lupus-like disease in mice, but paradoxically exacerbates the development of atherosclerosis in susceptible animals. Despite the impact of - GalCer treatment on a variety of disease processes, our understanding of the response of iNKT cells themselves to various stimuli is limited. Recent studies from the PI's laboratory have demonstrated that in vivo activation of iNKT cells with -GalCer results in a dynamic response by these cells that is characterized by surface receptor downmodulation, expansion, cytokine production, cross-talk with other cells, homeostatic contraction, and acquisition of an anergic phenotype. Guided by these preliminary findings, studies in this application will test the overall hypothesis that iNKT cells, by responding to a variety of endogenous and exogenous molecular patterns, can modulate the progression of chronic inflammatory diseases of the vascular system. This hypothesis will be tested in the following integrated Specific Aims. Aim 1 will investigate the mechanisms by which iNKT cells respond to endogenous and exogenous molecular patterns that modulate the progression of inflammatory vascular disease. These studies will be focused on identifying iNKT cell stimuli that can induce iNKT cell anergy and to investigate the role of co-stimulatory receptors in the acquisition of this anergic phenotype. Aim 2 will investigate the impact of iNKT cell anergy on the capacity of these cells to modulate chronic inflammatory vascular disease. A major goal of this aim will be to identify iNKT cell-based treatment modalities that can protect susceptible mice against the development of both lupus-like autoimmunity and atherosclerosis. Aim 3 will investigate the response of human iNKT cells to glycolipid antigens and microbial products, which will permit validation of the mouse studies. Completion of the work described in this proposal will provide novel insight into fundamental iNKT cell biology and the immunomodulatory activities of iNKT cells during the progression of vascular diseases. These studies will build a foundation of knowledge upon which safe and effective iNKT cell-based therapies for lupus, atherosclerosis and other chronic inflammatory diseases of the cardiovascular system can be developed.

项目总结/摘要 不变的自然杀伤T（iNKT）细胞在慢性炎症性疾病的进展中起重要作用 包括动脉粥样硬化和狼疮相关的血管疾病。这个项目的总体目标是 应用是深入了解iNKT细胞激活的体内机制， 各种刺激，并利用这一信息的发展更好的治疗方法的慢性 血管系统的炎性疾病。该应用的研究人员已经表明， 细胞抗原-半乳糖神经酰胺（-GalCer）可以预防小鼠狼疮样疾病的发展，但 矛盾地加剧了易感动物中动脉粥样硬化的发展。尽管有- GalCer治疗多种疾病过程，我们了解iNKT细胞的反应 各种刺激是有限的。PI实验室最近的研究表明， 用β-GalCer激活iNKT细胞导致这些细胞的动态响应，其特征在于 表面受体下调、扩增、细胞因子产生、与其它细胞的串扰、稳态 收缩和获得无反应性表型。在这些初步研究结果的指导下， 应用程序将测试iNKT细胞通过响应各种内源性和 外源性分子模式，可以调节慢性炎症性血管疾病的进展， 系统将在以下综合具体目标中检验这一假设。目标1将调查 iNKT细胞对内源性和外源性分子模式的反应机制， 炎症性血管疾病的进展。这些研究将集中在识别iNKT细胞刺激 可以诱导iNKT细胞无反应性，并研究共刺激受体在获得这种无反应性中的作用 无反应性表型目的2将研究iNKT细胞无反应性对这些细胞的能力的影响， 调节慢性炎症性血管疾病。这一目标的一个主要目标是鉴定基于iNKT细胞的 可以保护易感小鼠免受狼疮样自身免疫性 和动脉粥样硬化。目的3将研究人iNKT细胞对糖脂抗原的应答， 微生物产品，这将允许验证小鼠研究。完成本报告所述的工作 该提案将为基本iNKT细胞生物学和免疫调节活性提供新的见解， iNKT细胞在血管疾病进展过程中的作用这些研究将建立一个知识的基础 在此基础上，安全有效的基于iNKT细胞的狼疮、动脉粥样硬化和其他慢性 心血管系统的炎性疾病可能发展。