Harnessing NKT Cell Activation by Glycolipids

自然杀伤T细胞(NKT)是一种强大的调节性T细胞，已被证明是 密切参与对感染和肿瘤进展的反应。还有就是 强有力的证据表明，NKT细胞可能以这样一种方式调节免疫系统 防止自身免疫。利用NKT细胞的这种激活可能会提供新的 病毒和细菌感染、癌症和一系列自身免疫疾病的治疗 疾病，如I型糖尿病、多发性硬化症和狼疮。略高于一个 十年前，人们发现糖脂(尤其是)-半乳糖基神经酰胺()- GalCers)，可以通过作为一类新发现的 抗原提呈蛋白，CD1d。在过去的五年里，我们的实验室设计和 人工合成的糖基神经酰胺，其神经酰胺和糖表位不同，以便 探索这两个地区的作用。与免疫学家和物理化学家合作 和分析化学家，我们建议继续研究糖脂的作用 CD1d介导的免疫调节的结构，目标如下：1)-GalCers 将合成具有N-异构体的取代物以与结构上的 相关的，但生物学上不同的，O-，C-和S-)-GalCers；2)一组)-GalCers 设计并正在合成的目的是测试一种假设，即需要 抗原处理可以用来诱导高水平的Th1细胞因子，这些细胞因子是 被认为与糖脂的抗感染/抗癌活性有关；3)A 最近的X射线报告)-GalCer/CD1d/NKT T细胞受体Will的三元复合体 用来研究糖基是否可以用来影响细胞因子谱 和/或促进人类NKT细胞的扩增；4)MS法测定 糖脂的异常比率将被开发并用于评估是否存在 不受欢迎的异常者水平较低。

Natural Killer T (NKT) cells are potent regulatory T cells that have been shown to be intimately involved in the response to infection and tumor progression. There is also strong evidence that NKT cells may regulate the immune system in such a way as to prevent autoimmunity. Harnessing this 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. A little more than a decade ago it was revealed that glycolipids, particularly )-galactosylceramides ()- GalCers), could activate NKT cells by serving as ligands to a newly recognized class of antigen presenting proteins, CD1d. For the last five years our lab has designed and synthesized glycosyl ceramides that vary in the ceramide and sugar epitopes in order to probe the role of both regions. In collaboration with immunologists and physical chemists and analytical chemists we propose to continue to investigate the role of glycolipid structure in CD1d mediated immunomodulation with the following goals: 1) )-GalCers with N-anomeric replacements will be synthesized for comparison to the structurally related, but biologically distinct, O-, C- and S-)-GalCers; 2) A set of )-GalCers has been designed and is being synthesized to test the hypothesis that compounds that require antigen processing can be used to induce high levels of Th1 cytokines, which are believed to be responsible for the anti-infective/anti-cancer activities of glycolipids; 3) A recent x-ray report of a ternary complex of )-GalCer/CD1d/NKT T cell receptor will be used to investigate if the saccharide moiety can be used to influence cytokine profiles and/or enhance NKT cell expansion in humans; 4) An MS method for determining anomeric ratios of glycolipids will be developed and used to evaluate the presence of low levels of unwanted anomers.