ADJUVANT EFFECTS OF ALPHA GALACTOSYLCERAMIDES

α 半乳糖神经酰胺的辅助作用

• 批准号: 6685886
• 负责人: ALBERT S. BENDELAC
• 金额: $ 26.77万
• 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/6685886
• 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）alpha-galactosylceramides （a-galcer）孤立形式的海洋海绵可以预防癌症的肝转移 细胞。 A-Galcer的这种显着的抗肿瘤作用是由NKT细胞介导的， 一组专门的T细胞，受脂质的成员限制为CD1D 抗原呈递CD1家族。体内注射后，a-galcer刺激NKT 迅速诱导复杂的细胞激活级联的细胞涉及 NK细胞，树突细胞，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 有可能增强或修改Brad范围的免疫反应范围。这 长期目标是了解CD1系统的保护价值 抗原表现。该应用的重点是确定细胞和 CD1/NKT途径激活A-Galcer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，以及自身免疫性。具体目标是1至 表征遵循NKT细胞激活的激活事件的级联激活事件 在体内，通过定义细胞类型的各自贡献， 表面受体和可溶性介质（细胞因子和趋化因子） 依次诱导； 2以确定NKT细胞激活的后果 关于自适应，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细胞激活的后果 自身免疫，传染性和肿瘤状况，例如点头小鼠自身免疫性 黑色素瘤的糖尿病，MCMV感染和肝转移。这些研究提供 剖析涉及的分子和细胞事件的机会 糖脂分子的辅助作用可能导致临床应用 在预防和治疗传染性，自身免疫和肿瘤状况中。