Binding and Presentation of Lipid Antigens by CD1

CD1 与脂质抗原的结合和呈递

• 批准号: 7081389
• 负责人: Steven A Porcelli
• 金额: $ 33.73万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7081389
• 关键词: B lymphocyte; CD1 molecule; Schwann cells; T cell receptor; analog; antigen presentation; cell free system; cell line; cerebrosides; chemical binding; clinical research; combinatorial chemistry; dendritic cells; enzyme linked immunosorbent assay; gastrointestinal epithelium; genetically modified animals; human subject; hybridomas; immune response; immunoregulation; intracellular transport; keratinocyte; laboratory mouse; leukocyte activation /transformation; macrophage; microarray technology; natural killer cells; recombinant proteins

DESCRIPTION (provided by applicant): The CD1 system of MHC class I-like proteins is firmly established as a group of antigen presenting molecules that activates T cells specific for lipids and glycolipids. A population of T lymphocytes known as NK T cells recognizes 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 CD1d-restricted NK T cells contribute to immune responses against pathogens, the elimination of malignant tumors, and the prevention of autoimmune diseases. A synthetic alpha-galactosyl ceramide known as KRN7000 has been identified as a glycolipid ligand that binds to CD1d and strongly activates multiple effector functions of NK T cells. Through collaborative efforts with established experts in the area of synthetic organic chemistry, the applicant has developed novel approaches to the creation of alpha-galactosyl ceramides with a range of structural alterations. Many of these compounds preserve the ability to activate CD1d-restricted NK T cells, and preliminary studies indicate that the have immunomodulatory activities that are significantly different from those of KRN7000. The current proposal will investigate the immunomodulatory activities of a large panel of novel alpha-galactosyl ceramides. Properties of these compounds to be investigated include induction of Th1 (inflammatory) versus Th2 (anti-inflammatory) cytokine production, specific targeting of NK T cell activation by certain types of antigen presenting cells or in certain tissues, and their ability to cause expansion as opposed to apoptosis of NK T cells. The proposed experiments will include in vitro cell culture studies of both human and murine NK T cells, and in vivo studies using mice. There is a high expectation that the proposed studies will contribute directly to the development of clinically useful immunomodulatory agents that act on NK T cells.

描述（由申请人提供）：MHC I类蛋白的CD1系统被牢固地确定为一组抗原呈现的分子，该分子激活了特异性的脂质和糖脂特异性的T细胞。称为NK T细胞的T淋巴细胞群识别CD1D蛋白呈现的特定脂质配体，并且CD1依赖性免疫反应的这种成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，CD1D限制的NK T细胞有助于针对病原体，消除恶性肿瘤和预防自身免疫性疾病的免疫反应。称为KRN7000的合成α-半乳糖基神经酰胺已被鉴定为一种与CD1D结合并强烈激活NK T细胞的多重效应子功能的糖脂配体。通过与合成有机化学领域的既定专家的合作努力，申请人开发了新颖的方法来创建 具有一系列结构改变的α-半乳糖基神经酰胺。这些化合物中的许多都保留了激活CD1D限制的NK T细胞的能力，初步研究表明，具有与KRN7000的免疫调节活性明显不同。当前的建议将研究大量新型α-半乳糖基神经酰胺的免疫调节活性。这些要研究的化合物的特性包括诱导Th1（炎症）与Th2（抗炎）细胞因子的产生，特异性靶向NK T细胞激活某些类型的抗原呈递细胞或某些组织中的Th1（抗炎），以及它们与NK T细胞凋亡相反的膨胀能力。提出的实验将包括对人和鼠NK T细胞的体外细胞培养研究，以及使用小鼠的体内研究。人们高度期望拟议的研究将直接有助于对NK T细胞作用的临床有用的免疫调节剂的发展。