Modulation of chronic vascular inflammation by iNKT cells

描述（由申请人提供）：不变的自然杀伤T（iNKT）细胞在血管系统慢性炎症性疾病（包括动脉粥样硬化和狼疮相关血管疾病）的进展中发挥重要作用。本申请的总体目标是深入了解各种刺激导致iNKT细胞活化的体内机制，并利用这些信息开发血管系统慢性炎性疾病的更好治疗方法。本申请的研究者已经表明，iNKT细胞抗原α-半乳糖神经酰胺（α-GalCer）可以预防小鼠中狼疮样疾病的发展，但矛盾的是加剧了易感动物中动脉粥样硬化的发展。尽管α-GalCer治疗对各种疾病过程有影响，但我们对iNKT细胞本身对各种刺激的反应的理解是有限的。来自PI实验室的最近研究已经证明，用α-GalCer体内活化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、与其他细胞的串扰、稳态收缩和无反应性表型的获得。在这些初步发现的指导下，本申请中的研究将测试iNKT细胞通过响应各种内源性和外源性分子模式可以调节血管系统慢性炎性疾病的进展的总体假设。将在以下综合具体目标中检验这一假设。目的1将研究iNKT细胞对调节炎性血管疾病进展的内源性和外源性分子模式的反应机制。这些研究将集中于鉴定可诱导iNKT细胞无反应性的iNKT细胞刺激物，并研究共刺激受体在获得这种无反应性表型中的作用。目的2将研究iNKT细胞无反应性对这些细胞调节慢性炎性血管疾病的能力的影响。这一目标的一个主要目标将是确定基于iNKT细胞的治疗方式，可以保护易感小鼠免受狼疮样自身免疫和动脉粥样硬化的发展。目的3将研究人iNKT细胞对糖脂抗原和微生物产物的反应，这将允许验证小鼠研究。本提案中所述工作的完成将为基础iNKT细胞生物学和iNKT细胞在血管疾病进展过程中的免疫调节活性提供新的见解。这些研究将建立一个知识基础，在此基础上可以开发安全有效的基于iNKT细胞的狼疮，动脉粥样硬化和心血管系统其他慢性炎症性疾病的治疗方法。 公共卫生相关性：拟议的研究将提供对免疫系统的特定细胞类型iNKT细胞影响血管疾病（如动脉粥样硬化和狼疮相关血管疾病）的机制的更好理解。这些拟议研究的结果将有助于开发血管疾病及其并发症（例如，心脏病和中风）。

DESCRIPTION (provided by applicant): 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 a-galactosylceramide (a-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 a-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 a-GalCer results in a dynamic response by these cells that is characterized by surface receptor down modulation, 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. PUBLIC HEALTH RELEVANCE: The proposed studies will provide a better understanding of the mechanism by which a particular cell type of the immune system, the iNKT cell, influences blood vessel diseases such as atherosclerosis and lupus- associated vascular disease. The results from these proposed studies will be instrumental for the development of novel preventive measures and therapies for blood vessel diseases and their complications (e.g., heart disease and stroke).