Binding and Presentation of Lipid Antigens by CD1

CD1 与脂质抗原的结合和呈递

• 批准号: 8495847
• 负责人: Steven A Porcelli
• 金额: $ 38.23万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495847
• 关键词: Adjuvant; Agonist; Antigen Receptors; Autoimmune Diseases; Autoimmunity; Binding; Biochemical; Biological Assay; Biological Models; CD1 Antigens; CD8B1 gene; Cell physiology; Cells; Chemicals; Chemosensitization; Cholesterol; Complex; Detergents; Exclusion; Fractionation; Galactosylceramides; Glycolipids; Goals; Health; Human; Image; Immune response; Immune system; Immunity; Immunotherapeutic agent; Immunotherapy; Infection; Insulin-Dependent Diabetes Mellitus; Lead; Libraries; Ligands; Lipids; Maintenance; Malignant Neoplasms; Membrane Microdomains; Methods; Monoclonal Antibodies; Multiple Sclerosis; Mus; Pattern; Pharmaceutical Preparations; Prevention; Production; Property; Proteins; Reagent; Regulation; Resistance; Role; Structure-Activity Relationship; System; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Vaccination; Vaccine Adjuvant; Vaccines; allograft rejection; analog; base; cytokine; human disease; improved; invariant chain; long term memory; mouse model; novel; novel vaccines; pathogen; prevent; response; therapeutic development; translational study

DESCRIPTION (provided by applicant): T lymphocytes known as type 1 or invariant NKT cells (iNKT cells) recognize specific lipid ligands presented by the CD1d protein, and this component of the CD1-dependent immune response is highly conserved between humans and mice. Many detailed studies in mouse models have shown that iNKT cells contribute to immune responses against pathogens, elimination of malignant tumors, maintenance of immunological tolerance and prevention of autoimmune diseases. Great progress in understanding and potentially harnessing the many immunological activities of iNKT cells has been made in recent years as a result of the identification of various forms of synthetic a-galactosylceramide (aGalCer) that specifically activate these cells. The current proposal is focused on the identification of modified forms of aGalCer that activate different cytokine patterns when used to stimulate mouse or human iNKT cells. Numerous Th2-cytokine biasing forms of aGalCer have been identified in our ongoing studies, and we propose new synthetic approaches to create additional aGalCer analogues that will include examples with tolerogenic or proinflammatory activities based on cytokine production or other effects. These compounds will be characterized in detail using assay systems to analyze both mouse and human iNKT cell responses to identify those that are most suitable to carry forward into translational studies. Using new monoclonal antibody reagents specific for CD1d/aGalCer complexes, and soluble iNKT cell antigen receptors, we will carry out a range of studies to determine the mechanisms that lead to the stimulation of markedly different patterns of cytokines by various aGalCer analogues. Studies to optimize the adjuvant properties of selected aGalCer analogues in model systems of vaccination are also proposed. These studies will increase our understanding of the mechanisms governing the regulation of the many potential activities of iNKT cells, and will contribute to development of therapeutic applications for glycolipid activators of this T cell subset.

描述（由申请人提供）：被称为 1 型或不变 NKT 细胞（iNKT 细胞）的 T 淋巴细胞识别 CD1d 蛋白呈现的特定脂质配体，并且 CD1 依赖性免疫反应的这一组成部分在人类和小鼠之间高度保守。小鼠模型中的许多详细研究表明，iNKT 细胞有助于针对病原体的免疫反应、消除恶性肿瘤、维持免疫耐受和预防自身免疫性疾病。近年来，由于鉴定了特异性激活这些细胞的各种形式的合成α-半乳糖神经酰胺（aGalCer），在理解和潜在利用 iNKT 细胞的许多免疫活性方面取得了巨大进展。目前的提案重点是鉴定 aGalCer 的修饰形式，当用于刺激小鼠或人类 iNKT 细胞时，这些修饰形式会激活不同的细胞因子模式。我们正在进行的研究中已经鉴定出多种 Th2 细胞因子偏向形式的 aGalCer，并且我们提出了新的合成方法来创建其他 aGalCer 类似物，其中包括基于细胞因子产生或其他效应的耐受性或促炎活性的例子。这些化合物将使用测定系统详细表征，以分析小鼠和人类 iNKT 细胞反应，以确定最适合进行转化研究的化合物。使用针对 CD1d/aGalCer 复合物和可溶性 iNKT 细胞抗原受体的新型单克隆抗体试剂，我们将进行一系列研究，以确定导致各种 aGalCer 类似物刺激明显不同模式的细胞因子的机制。还提出了在疫苗接种模型系统中优化所选 aGalCer 类似物佐剂特性的研究。这些研究将增进我们对 iNKT 细胞许多潜在活性的调节机制的理解，并将有助于开发该 T 细胞亚群的糖脂激活剂的治疗应用。