Modulation of chronic vascular inflammation by iNKT cells

项目摘要/摘要 不变自然杀伤T细胞在慢性炎症性疾病进展中的重要作用 血管系统，包括动脉粥样硬化和狼疮相关性血管疾病。这个项目的总体目标是 应用是通过以下方式深入了解iNKT细胞激活的体内机制 各种刺激，并利用这些信息开发更好的治疗方法 血管系统的炎性疾病。这项申请的调查人员已经证明，iNKT 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 自相矛盾地加剧了易感动物的动脉粥样硬化的发展。尽管受到了- Galer对多种疾病过程的治疗，我们对iNKT细胞反应的理解 他们自己对各种刺激的反应是有限的。最近来自PI实验室的研究表明，在体内 用-GalCer激活iNKT细胞会导致这些细胞的动态反应，其特征是 表面受体下调、扩张、细胞因子产生、与其他细胞的串扰、内环境平衡 收缩，并获得一种无能表型。在这些初步发现的指导下，对这一领域的研究 应用程序将测试iNKT细胞的总体假设，通过对各种内源性和 外源性分子模式，可以调节血管慢性炎症性疾病的进展 系统。这一假设将在以下综合的具体目标中得到检验。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细胞无能，并研究共刺激受体在获得这种无能中的作用 无能表型。目的2将研究iNKT细胞无能对这些细胞能力的影响 调节慢性炎症性血管疾病。这一目标的一个主要目标将是鉴定基于iNKT细胞的 可以保护易感小鼠免受狼疮样自身免疫的发展的治疗方式 和动脉粥样硬化。目的3将研究人iNKT细胞对糖脂抗原和 微生物产品，这将使小鼠研究得到验证。完成本文件中描述的工作 该提案将为基础iNKT细胞生物学和免疫调节活性提供新的见解 血管疾病进展过程中的iNKT细胞。这些研究将建立一个知识的基础 在此基础上安全有效的iNKT细胞治疗狼疮、动脉粥样硬化和其他慢性疾病 心血管系统的炎症性疾病可能会发生。

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.