Th1/Th2 Glycolipid Adjuvants

Th1/Th2 糖脂佐剂

• 批准号: 8247808
• 负责人: PAUL B SAVAGE
• 金额: $ 32.47万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8247808
• 关键词: Adjuvant; Affinity; Antibodies; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Bacteria; Bees; Behavior; Binding; Carbohydrates; Cells; Ceramides; Complex; Development; Disease; Ehrlichia; Event; Galactosylceramides; Generations; Glycolipids; Glycosphingolipids; Health; Human; Immune response; Infection; Label; Length; Ligands; Lipids; Measurement; Membrane; Microscopy; Modification; Nature; Oligosaccharides; Organism; Play; Positioning Attribute; Preparation; Process; Protein-Carbohydrate Interaction; Public Health; Relative (related person); Research; Role; Screening procedure; Sphingomonas; Structure; System; T cell response; 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）在调节免疫反应中发挥着重要作用。 NKT 细胞是 CD1d 呈递的糖脂抗原刺激，并且在过去几年中取得了重大进展 是为了理解这个过程而做出的。 NKT 细胞的天然抗原已被鉴定，并且晶体 CD1d 与糖脂结合的结构已得到解决。导致 NKT 细胞刺激的因素是 已阐明，糖脂运输和与 T 细胞受体 (TCR) 的特异性相互作用的重要性 正在出现。然而，糖脂运输以及与 TCR 的相互作用尚不清楚。建议的 研究包括开发用于研究特定贩运事件的标记糖脂； 具体而言，糖脂结构变化对贩运的影响以及糖脂结构变化如何影响 运输影响 NKT 细胞释放细胞因子的 Th1/Th2 偏向。糖脂和 CD1d 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 关联和刺激的要求。此外，糖脂的功能已被确定可以 进行修改而不会对 NKT 细胞刺激产生负面影响，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-CD1d 复合物的亲和力。 预计更高的亲和力将导致 NKT 细胞的长期刺激和细胞因子的增加 发布;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 提供该信息。产生 NKT 细胞天然抗原的已知生物体数量相当多 小，并且与已知直接刺激 NKT 细胞的细菌相关的细菌将被筛选以进行 NKT 刺激 行为。然后通过全合成确定并确认抗原的结构。 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 排斥反应和自身免疫性疾病。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。拟议的研究将增加 这种理解同时增强了刺激 NKT 细胞的糖脂库。