Binding and Presentation of Lipid Antigens by CD1

描述（由申请人提供）：MHC I类蛋白的CD 1系统被牢固确立为一组抗原呈递分子，其激活对脂质和糖脂特异性的T细胞。被称为NK T细胞的T淋巴细胞群体识别由CD 1d蛋白呈递的特异性脂质配体，并且CD 1依赖性免疫应答的这一组分在人类和小鼠之间高度保守。在小鼠模型中的许多详细研究表明，CD 1d限制性NK T细胞有助于对病原体的免疫应答，消除恶性肿瘤和预防自身免疫性疾病。被称为KRN 7000的合成α-半乳糖基神经酰胺已被鉴定为糖脂配体，其结合CD 1d并强烈激活NK T细胞的多种效应子功能。通过与合成有机化学领域的知名专家的合作努力，申请人已经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保留了激活CD 1d限制性NK T细胞的能力，初步研究表明，它们具有与KRN 7000显著不同的免疫调节活性。目前的建议将调查一个大面板的新型α-半乳糖神经酰胺的免疫调节活性。待研究的这些化合物的性质包括诱导Th 1（炎性）相对于Th 2（抗炎）细胞因子产生，通过某些类型的抗原呈递细胞或在某些组织中特异性靶向NK T细胞活化，以及它们引起与NK T细胞凋亡相对的扩增的能力。拟议的实验将包括人和鼠NK T细胞的体外细胞培养研究，以及使用小鼠的体内研究。人们高度期望所提出的研究将直接有助于开发作用于NK T细胞的临床有用的免疫调节剂。

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.