Harnessing NKT Cell Activation by Glycolipids

自然杀伤T（NKT）细胞是参与免疫应答调节的强有力的先天性T细胞 范围从对病原体和肿瘤的反应到自身免疫的发展或抑制。激活 的NKT细胞可能为病毒和细菌感染，癌症和一系列疾病提供新的治疗方法。 自身免疫性疾病，如I型糖尿病、多发性硬化症和狼疮。NKT细胞分为两个 主要类别，I型（iNKT）和II型NKT细胞。两者都被糖脂激活，糖脂作为配体， 抗原呈递蛋白CD 1d。iNKT细胞的糖脂活化已经被广泛研究了更长时间。 超过二十年对II型细胞的了解要少得多。对利用NKT细胞刺激至关重要 在治疗上是控制反应性质的能力。尽管一些糖脂会引起 Th 1（与癌症和感染治疗相关）或Th 2（与自身免疫性疾病相关）细胞因子 已经鉴定了来自iNKT细胞的化合物，但是该偏倚通常在体内消失，或者化合物不能激活 人iNKT细胞。NKT细胞竞技场中的另一个需要是鉴定硫苷脂反应性细胞因子的有效活化剂。 II型NKT细胞和基线结构活性关系的发展在这些研究中很少，但 在人类中更为丰富的NKT细胞。与免疫学家，结构生物学家和物理学家合作， 化学家们的这一建议有两个主要的推动力：1）设计，合成和评估碳水化合物修饰 在与发育相关的背景下从iNKT细胞引发Th 1偏向的细胞因子应答的糖脂 人类抗癌疗法的研究。为了实现这一目标，将测试三个假设： 可以鉴定相关的C4”-类似物; B）神经酰胺和糖的C6”-位置的双重修饰可以 c）光化学交联的糖脂/CD 1d缀合物可以 用作抗原递送的途径并进一步增强Th 1偏向性。每个假设都是基于 涉及人细胞系和/或人源化小鼠模型的初步研究。这些研究将阐明 碳水化合物部分增强Th 1偏好的潜力。第二个重点是：（2）继续 建立对硫酸脂酶反应性II型NKT细胞的了解。大多数证据表明， 这些II型细胞反调节iNKT细胞;然而，当前资助期的结果显示， 某些硫苷脂会引发类似于iNKT细胞的反应。新的、拟议的和 硫苷脂正在/将被用于开发和改进药效学模型，以设计有效的激动剂 II型NKT细胞。

Natural killer T (NKT) cells are potent, innate-like T cells involved in the regulation of immune responses ranging from reaction to pathogens and tumors to the development or suppression of 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 for an antigen presenting protein, CD1d. Glycolipid activation of iNKT cells has been extensively studied for more than two decades. Much less is known about the Type II cells. Crucial to utilizing NKT cell stimulation therapeutically is the ability to control the nature of the response. Although a number of glycolipids that elicit Th1 (relevant for treatment of cancer and infections) or Th2 (relevant for autoimmune conditions) cytokines from iNKT cells have been identified, the bias often disappears in vivo, or the compounds fail to activate human iNKT cells. Another need in the NKT cell arena is identification of potent activators of sulfatide-reactive Type II NKT cells and development of baseline structural activity relationships in these much less explored, but more abundant in humans, NKT cells. In collaboration with immunologists, structural biologists and physical chemists this proposal has two major thrusts: 1) Design, synthesize and evaluate carbohydrate modified glycolipids that elicit a Th1 biased cytokine response from iNKT cells in contexts relevant for the development of human anti-cancer therapies. To realize this goal three hypotheses will be tested: a) More potent, clinically relevant C4”-analogs can be identified; b) Dual modifications of the ceramide and C6”-position of the sugar can be used to enhance potency and Th1 bias; c) Photochemically cross-linked glycolipid/CD1d conjugates can be used as an avenue for antigen delivery and to further enhance Th1 bias. Each hypothesis is based on solid preliminary studies involving human cell lines and or a humanized mouse model. The studies will elucidate the potential of the carbohydrate moiety for enhancing Th1 bias. The second major thrust is: 2) To continue to build understanding of sulfatide-reactive Type II NKT cells. Most evidence has suggested that the activation of these Type II cells counter-regulates iNKT cells; however results from the current funding period have shown that certain sulfatides elicit responses similar to iNKT cells. Current results and outcomes from new, proposed sulfatides are being/will be used to develop and refine pharmacophoric models for designing potent agonists for Type II NKT cells.