Harnessing NKT Cell Activation by Glycolipids

利用糖脂激活 NKT 细胞

• 批准号: 10250477
• 负责人: Amy Howell
• 金额: $ 51.86万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250477
• 关键词: Address; Agonist; Amides; Anti-Infective Agents; Antigens; Antitumor Response; Autoimmune Diseases; Autoimmunity; Bacterial Infections; Benzophenones; Carbohydrates; Cell Therapy; Cells; Ceramides; Collaborations; Communicable Diseases; Cytotoxic T-Lymphocytes; Development; Disease; Esters; Evaluation; Funding; Glycolipids; Goals; Human; Human Cell Line; Immune response; Immunologist; In Vitro; Infection; Insulin-Dependent Diabetes Mellitus; Knock-in; Knock-in Mouse; Knowledge; Ligands; Link; Lipids; Lupus; Malignant Neoplasms; Mediating; Methods; Modification; Multiple Sclerosis; Mus; Nature; Outcome; Positioning Attribute; Proteins; Reaction; Receptor Cell; Solid; Structural Biologist; Structure; Structure-Activity Relationship; Study models; Sulfoglycosphingolipids; T cell response; T-Cell Activation; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Type II Epithelial Receptor Cell; Virus Diseases; alpha-galactosylceramide; analog; base; cancer therapy; carbene; clinical candidate; clinically relevant; crosslink; cytokine; data modeling; design; functional outcomes; humanized mouse; immunoregulation; improved; in vivo; interest; melanoma; model design; molecular modeling; mouse model; novel; novel therapeutics; pathogen; prevent; response; sugar; tumor

Natural killer T (NKT) cells are potent, innate-like T cells involved in the regulation of immune responses ranging from reaction to pathogens and tumors to the development or suppression of autoimmunity. Activation of NKT cells may provide new therapies for viral and bacterial infections, for cancer and for a range of autoimmune conditions, such as Type I diabetes, multiple sclerosis and lupus. NKT cells are divided into two major classes, Type I (iNKT) and Type II NKT cells. Both are activated by glycolipids which serve as ligands for an antigen presenting protein, CD1d. Glycolipid activation of iNKT cells has been extensively studied for more than two decades. Much less is known about the Type II cells. Crucial to utilizing NKT cell stimulation therapeutically is the ability to control the nature of the response. Although a number of glycolipids that elicit Th1 (relevant for treatment of cancer and infections) or Th2 (relevant for autoimmune conditions) cytokines from iNKT cells have been identified, the bias often disappears in vivo, or the compounds fail to activate human iNKT cells. Another need in the NKT cell arena is identification of potent activators of sulfatide-reactive Type II NKT cells and development of baseline structural activity relationships in these much less explored, but more abundant in humans, NKT cells. In collaboration with immunologists, structural biologists and physical chemists this proposal has two major thrusts: 1) Design, synthesize and evaluate carbohydrate modified glycolipids that elicit a Th1 biased cytokine response from iNKT cells in contexts relevant for the development of human anti-cancer therapies. To realize this goal three hypotheses will be tested: a) More potent, clinically relevant C4”-analogs can be identified; b) Dual modifications of the ceramide and C6”-position of the sugar can be used to enhance potency and Th1 bias; c) Photochemically cross-linked glycolipid/CD1d conjugates can be used as an avenue for antigen delivery and to further enhance Th1 bias. Each hypothesis is based on solid preliminary studies involving human cell lines and or a humanized mouse model. The studies will elucidate the potential of the carbohydrate moiety for enhancing Th1 bias. The second major thrust is: 2) To continue to build understanding of sulfatide-reactive Type II NKT cells. Most evidence has suggested that the activation of these Type II cells counter-regulates iNKT cells; however results from the current funding period have shown that certain sulfatides elicit responses similar to iNKT cells. Current results and outcomes from new, proposed sulfatides are being/will be used to develop and refine pharmacophoric models for designing potent agonists for Type II NKT cells.

自然杀伤T细胞(NKT)是一种强大的、先天的T细胞，参与免疫反应的调节 从对病原体和肿瘤的反应到自身免疫的发展或抑制。激活 NKT细胞的研究可能为病毒和细菌感染、癌症和一系列 自身免疫性疾病，如I型糖尿病、多发性硬化症和狼疮。NKT细胞分为两部分 主要分类为I型(INKT)和II型NKT细胞。两者都是由糖脂激活的，糖脂是 一种抗原提呈蛋白，CD1d。糖脂激活iNKT细胞已被广泛研究了更多 而不是二十年。对II型细胞的了解要少得多。利用NKT细胞刺激至关重要 在治疗学上是控制反应性质的能力。尽管一些糖脂可以引起 Th1(与癌症和感染的治疗相关)或Th2(与自身免疫疾病相关)细胞因子 从iNKT细胞中鉴定出来，这种偏倚往往在体内消失，或者化合物不能激活 人iNKT细胞。NKT细胞领域的另一项需要是鉴定硫脂反应的有效激活剂 II型NKT细胞与基线结构活性关系的发展在这些方面的研究要少得多，但 在人类中更为丰富的是NKT细胞。与免疫学家、结构生物学家和物理学家合作 化学家这项提议有两个主要推动力：1)设计、合成和评价修饰的碳水化合物 糖脂在与发育相关的环境中从iNKT细胞中诱导Th1偏向的细胞因子反应 人类抗癌疗法的一部分。为了实现这一目标，将检验三个假设：a)在临床上更有说服力 可以确定相关的C4“类似物；b)糖罐的神经酰胺和C6”位置的双重修饰 用于增强效力和Th1偏向；c)光化学交联的糖脂/CD1d结合物可以 用作抗原传递的途径，并进一步增强Th1偏向。每一种假设都是基于固体 涉及人类细胞系和/或人源化小鼠模型的初步研究。这些研究将阐明 碳水化合物部分增强Th1偏向的潜力。第二个主要推动力是：2)继续 了解硫脂反应II型NKT细胞。大多数证据表明， 这些II型细胞对iNKT细胞有反调节作用；然而，当前资助期的结果显示 某些硫脂可以引起类似于iNKT细胞的反应。当前结果和来自新的、建议的 硫脂正在/将被用于开发和改进用于设计有效激动剂的药理模型 用于II型NKT细胞。