Th1/Th2 Glycolipid Adjuvants

Th1/Th2 糖脂佐剂

• 批准号: 7329678
• 负责人: PAUL B SAVAGE
• 金额: $ 31.73万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7329678
• 关键词: Adjuvant; Affinity; Antibodies; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Bacteria; Bees; Behavior; Binding; Carbohydrates; Cells; Ceramides; Classification; Complex; Development; Disease; Ehrlichia; Event; Galactosylceramides; Generations; Glycolipids; Glycosphingolipids; Health; Human; Immune response; Infection; Label; Length; Ligands; Lipids; Measurement; Membrane; Microscopy; Modification; Nature; Numbers; Oligosaccharides; Organism; Play; Positioning Attribute; Preparation; Process; Protein-Carbohydrate Interaction; Public Health; Relative (related person); Research; Role; Screening procedure; Sphingomonas; Structure; System; T-Cell Receptor; TCR Activation; Testing; Variant; cytokine; design; fluorophore; improved; killer T cell; response; small molecule; trafficking; tumor

Natural killer T cells (NKT cells) play an important role in regulating immune responses. NKT cells are stimulate by glycolipid antigens presented by CD1d, and in the last few years significant advances have been made in understanding this process. Natural antigens for NKT cells have been identified, and crystal structures of CD1d bound to glycolipids have been solved. As factors leading to NKT cell stimulation are elucidated, the importance of glycolipid trafficking and specific interactions with T cell receptors (TCRs) is emerging. However, glycolipid trafficking and interactions with TCRs are not well understood. Proposed research includes development of labeled glycolipids for use in studying specific trafficking events; specifically, the influences of structural variations of glycolipids on trafficking and how differences in trafficking influence the Th1/Th2 bias of cytokine release by NKT cells. Studies of glycolipid and CD1d interactions with TCRs will involve incremental structural modifications of known antigens to determine requirements for association and stimulation. In addition, glycolipid functionality has bee identified that can be modified without impacting negatively NKT cell stimulation, and this information provides a means of using small molecules appended to glycolipids to modify the affinity of TCRs for glycolipid-CD1d complexes. It is anticipated that higher affinity will result in prolonged stimulation of NKT cells and increased cytokine release; however, the impact of this affinity on cytokine release profiles is not known and these studies will provide that information. The number of known organisms producing natural antigens for NKT cells is rather small, and bacteria related to those know to stimulate NKT cell directly will be screened for NKT stimulatory behavior. Structures of antigens will then be determined and confirmed through total synthesis. Relevance to Public Health: Responses of NKT cells influence disease states including infection, tumor rejection, and autoimmune diseases. An understanding of how glycolipids stimulate different responses from NKT cells will facilitate use of these responses to improve human health. Proposed research will increase this understanding while augmenting the arsenal of glycolipids that stimulate NKT cells.

自然杀伤T细胞（NKT细胞）在调节免疫反应中起着重要作用。NKT细胞 由CD 1d呈递的糖脂抗原刺激，在过去几年中取得了重大进展， 在理解这个过程中。NKT细胞的天然抗原已经被鉴定，并且晶体 与糖脂结合的CD 1d的结构已经得到解决。由于导致NKT细胞刺激的因素是 阐明了糖脂运输和与T细胞受体（TCR）特异性相互作用的重要性， 正在浮现然而，糖脂运输和与TCR的相互作用还不清楚。提出 研究工作包括开发标记糖脂，用于研究特定贩运事件; 具体而言，糖脂的结构变化对运输的影响，以及糖脂的差异如何影响运输。 NKT细胞的Th 1/Th 2细胞因子释放的偏向性。糖脂与CD 1d的研究 与TCR的相互作用将涉及已知抗原的增量结构修饰，以确定 对联想和刺激的要求。此外，已经鉴定了糖脂功能性，其可以 在不负面影响NKT细胞刺激的情况下进行修饰，并且该信息提供了一种方法， 使用附加到糖脂上的小分子来改变TCR对糖脂-CD 1d复合物的亲和力。 预期更高的亲和力将导致NKT细胞的延长刺激和细胞因子的增加。 然而，这种亲和力对细胞因子释放曲线的影响尚不清楚，这些研究将 提供这些信息。产生NKT细胞天然抗原的已知生物体的数量相当多。 将筛选与已知直接刺激NKT细胞那些细菌相关的小细菌的NKT刺激性 行为然后通过全合成确定和确认抗原的结构。 与公共卫生的相关性：NKT细胞的反应影响疾病状态，包括感染，肿瘤 排斥和自身免疫性疾病。了解糖脂如何刺激不同的反应， NKT细胞将有助于利用这些反应来改善人类健康。建议研究将增加 这种理解，同时增加阿森纳的糖脂刺激NKT细胞。