ADJUVANT EFFECTS OF ALPHA GALACTOSYLCERAMIDES

α 半乳糖神经酰胺的辅助作用

• 批准号: 6633777
• 负责人: ALBERT S. BENDELAC
• 金额: $ 18.82万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6633777
• 关键词: Porifera; animal extract; antineoplastics; aquatic organism; ceramides; galactose; immunomodulators; laboratory mouse; leukocyte activation /transformation; natural killer cells

DESCRIPTION: (Adapted from applicant's abstract) Alpha-galactosylceramides (a-GalCer) isolated form marine sponges can prevent liver metastases of cancer cells. This remarkable anti tumor effect of a-GalCer is mediated by NKT cells, a specialized set of T cells restricted by CD1d, a member of the lipid antigen-presenting CD1 family. Upon in vivo injection, a-GalCer stimulates NKT cells which rapidly induce a complex cascade of cellular activation involving NK cells, dendritic cells, B cells and T cells. Thus, through the NKT cells, its primary target, a-GalCer exhibits the properties of a glycolipid adjuvant with the potential to enhance or modify a brad range of immune responses. The long term goal is to understand the protective value of the CD1 system of antigen presentation. This application focuses on determining the cellular and molecular consequences of activation of the CD1/NKT pathway with a-GalCer, the ligand of NKT cells, and their potential applications in host defense against infections and tumors, and in autoimmunity. The specific aims are 1- to characterize the cascade of activation events that follows NKT cell activation in vivo, by defining the respective contributions of the cell types, the surface receptors and the soluble mediators (cytokines and chemokines) that are sequentially induced; 2-to determine the consequences of of NKT cell activation on adaptive, antigen specific T and B cell responses, and dissect the adjuvant effects of a-GalCer on the individual components of these responses; 3- to determine the consequences of NKT cell activation during the course of autoimmune, infectious and tumoral conditions such as NOD mouse autoimmune diabetes, MCMV infection and liver metastases of melanoma. These studies offer an opportunity to dissect the molecular and cellular events involved in the adjuvant effect of a glycolipid molecule an may lead to clinical applications in the prevention and treatment of infectious, autoimmune and tumor conditions.

描述：（改编自申请人的摘要）α-半乳糖神经酰胺 从海绵中分离出来的 (a-GalCer) 可预防癌症肝转移 细胞。 a-GalCer 这种显着的抗肿瘤作用是由 NKT 细胞介导的， 一组受 CD1d（脂质成员）限制的特殊 T 细胞 抗原呈递 CD1 家族。体内注射后，a-GalCer 刺激 NKT 细胞快速诱导复杂的细胞激活级联，涉及 NK 细胞、树突状细胞、B 细胞和 T 细胞。因此，通过 NKT 细胞， 它的主要目标，a-GalCer 表现出糖脂佐剂的特性 具有增强或改变一系列免疫反应的潜力。这 长期目标是了解 CD1 系统的保护价值 抗原呈递。该应用程序侧重于确定细胞和 a-GalCer 激活 CD1/NKT 通路的分子后果 NKT 细胞的配体及其在宿主防御中的潜在应用 感染和肿瘤以及自身免疫。具体目标是 1- 表征 NKT 细胞激活后的级联激活事件 在体内，通过定义细胞类型各自的贡献， 表面受体和可溶性介质（细胞因子和趋化因子） 依次诱导； 2-确定NKT细胞激活的后果 适应性、抗原特异性 T 和 B 细胞反应，并剖析佐剂 a-GalCer 对这些反应的各个组成部分的影响； 3-至 确定 NKT 细胞激活过程中的后果 自身免疫、感染和肿瘤疾病，例如 NOD 小鼠自身免疫 糖尿病、MCMV 感染和黑色素瘤肝转移。这些研究提供 有机会剖析参与的分子和细胞事件 糖脂分子的辅助作用可能会导致临床应用 预防和治疗感染、自身免疫和肿瘤疾病。