Harnessing NKT Cell Activation by Glycolipids

描述（由申请人提供）：自然杀伤T细胞（NKT）是一种有效的调节性T细胞，已被证明与人体对感染和肿瘤进展的反应密切相关。也有强有力的证据表明，NKT细胞以这种方式调节免疫系统，以防止自身免疫。激活NKT细胞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）提供新的治疗方法。NKT细胞分为两大类，I型（iNKT）和II型NKT细胞。两者都被糖脂激活，糖脂作为抗原呈递蛋白CD1d的配体。iNKT细胞的糖脂活化已经被广泛研究了超过十五年。对II型细胞的了解要少得多。现在清楚的是，利用NKT细胞刺激治疗的关键是控制免疫反应性质的能力。虽然已经鉴定出许多糖脂类可引起iNKT细胞选择性的Th1或Th2反应，但这种偏差通常在体内消失，或者这些化合物不能激活人iNKT细胞。NKT细胞领域的另一个需求是鉴定硫脂反应型II型NKT细胞的有效激活剂，并在这些很少被探索的NKT细胞中建立基线结构活性关系。在与免疫学家、结构生物学家和物理化学家的合作下，本提案有两个主要目标：1)合成和评估具有结构特征的糖脂，这些结构特征旨在引发与感染性疾病和癌症治疗相关的Th1偏倚反应。为了实现这一目标，将测试三个假设：a)一些Th1倾斜糖脂在体内作为抗原- cd1d复合物持续存在的能力允许I型NKT细胞的长时间激活，这是Th1偏向增强的重要决定因素；b)糖的4”位修饰可用于刺激I型NKT细胞产生与人类相关的Th1偏倚反应；c)将内体加工作为设计特征的要求可用于诱导更明显的Th1偏倚。每一种假设都是基于涉及人类细胞系和人源化小鼠模型的坚实的初步研究。额外的评估，包括这些和相关类似物的晶体学研究，为进一步探索Th1偏倚的基础提供了机会。第二个重点是：2)了解硫脂-糖脂结构对硫脂反应型II型NKT细胞功能结局的影响。与iNKT细胞相比，这些细胞受到的关注要少得多，但有证据表明，这些II型细胞的激活可以反调节I型NKT细胞。然而，目前还没有针对II型细胞的强效激动剂。我们建议利用已知的关于配体如何与CD1d相互作用的性质以及关于II型配体的新发现来开发药效模型，为II型NKT细胞设计有效的激动剂。

DESCRIPTION (provided by applicant): Natural Killer T (NKT) cells are potent, regulatory T cells that have been shown to be intimately involved in the body's response to infection and tumor progression. There is also strong evidence that NKT cells regulate the immune system in such a way as to prevent 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 to an antigen presenting protein, CD1d. Glycolipid activation of iNKT cells has been extensively studied for more than a decade and a half. Much less is known about the Type II cells. What is now clear is that crucial to utilizing NKT cell stimulation therapeutically is the ability to contrl the nature of the immune response. Although a number of glycolipids that elicit a selective Th1 or Th2 response from iNKT cells have been identified, the bias often disappears in vivo, or the compounds fail to active human iNKT cells. Another need in the NKT cell arena is for the identification of potent activators of sulfatide-reactive Type II NKT cells and the development of baseline structural activity relationships in these much less explored NKT cells. In collaboration with immunologists, structural biologists and physical chemists this proposal has two major thrusts: 1) To synthesize and evaluate glycolipids with structural features designed to elicit a Th1 biased response relevant for the treatment of infectious diseases and cancer. To realize this goal three hypotheses will be tested: a) The ability of some Th1 skewing glycolipids to persist as antigen-CD1d complexes in vivo allows for the prolonged activation of Type I NKT cells, which is a significant determinant for enhanced Th1 bias; b) Modifications on the 4"-position of the sugar can be used to stimulate Type I NKT cells toward a Th1 biased response relevant to humans; c) A requirement for endosomal processing as a design feature can be used to induce a more pronounced Th1 bias. Each of the hypotheses is based on solid preliminary studies involving human cell lines and or a humanized mouse model. Additional evaluations, including crystallographic studies of these and related analogs, provide an opportunity to further explore the basis of Th1 bias. The second major thrust is: 2) To understand sulfatide-glycolipid structural influences on functional outcomes with sulfatide-reactive Type II NKT cells. These have received far less attention than the iNKT cells, but evidence is emerging that the activation of these Type II cells can counter- regulate the Type I NKT cells. However, there are no potent agonists for Type II cells. We propose to utilize what is known about the nature of how ligands interact with CD1d and what is emerging about Type II ligands to develop pharmacophoric models to design potent agonists for Type II NKT cells.