Binding and Presentation of Lipid Antigens by CD1

具有恒定TCR γ链的CD 1d限制性NKT细胞（iNKT细胞）是一种独特且保守的 哺乳动物免疫系统的组成部分。小鼠研究显示， iNKT细胞活化剂，如CD 1d呈递糖脂抗原β-半乳糖神经酰胺（β-GalCer）， 各种各样的动物模型，但尽管iNKT细胞活化剂在 由于癌症和其他疾病的小鼠模型，这一领域进展缓慢，无法进行更先进的临床研究。 发展此应用程序解决了可能成为推进iNKT的主要限制的问题 基于细胞的疗法，并寻求为这些障碍提供实用的解决方案。我们假设 试图将iNKT细胞疗法应用于临床， 免疫疗法或作为疫苗佐剂的进展因三个具体问题而放缓，所有这些问题都将被 目前的提案直接涉及。第一个是合成iNKT细胞的次优设计 激活剂，我们将克服使用我们的工作的结构-活性最近发现 - GalCer类似物的关系。第二个问题是iNKT细胞激动剂诱导细胞凋亡的趋势。 反应细胞的缺失和低反应性（“无反应性”），使它们充其量是“单次激发” 治疗学我们将使用最近开发的新型糖脂递送方法来克服这一点 限制.我们还提出了基于iNKT细胞中最近的基因表达谱的研究，以确定 控制激活后无反应性的细胞表面受体，这将提供对 无能反应和克服它的策略。该提案涉及的第三个问题涉及 标准小鼠模型不足以开发潜在的iNKT细胞疗法，为此，我们 将人CD 1d基因敲入小鼠作为第一个实用的人源化模型用于体内评价 基于iNKT细胞的免疫疗法。总的来说，这种竞争性的续期申请提出了创新的 解决方案的主要障碍，在正在进行的努力，利用潜力的iNKT细胞为基础的 治疗学成功地实现该建议的目标应能增进我们对以下问题的理解： iNKT细胞生物学，同时也有助于推动癌症免疫治疗领域的进展。

CD1d-restricted NKT cells with invariant TCR chains (iNKT cells) are a unique and conserved component of the mammalian immune system. Studies in mice have shown dramatic in vivo effects of iNKT cell activators, such as the CD1d-presented glycolipid antigen -galactosylceramide (GalCer), in a wide variety of animal models, but despite remarkable therapeutic effects with iNKT cell activators in murine models of cancer and other diseases, this area has been slow to progress to more advanced clinical development. This application addresses issues that are likely to be major limitations in advancing iNKT cell-based therapeutics, and seeks to provide practical solutions to these impediments. We hypothesize that attempts to move iNKT cell therapeutics into the clinic for applications such as cancer immunotherapy or as vaccine adjuvants have been slowed by three specific issues, all of which will be directly addressed by the current proposal. The first is the suboptimal design of synthetic iNKT cell activators, which we will overcome using recent discoveries from our work on the structure-activity relationship of GalCer analogues. The second issue is the tendency of iNKT cell agonists to induce deletion and hypo-responsiveness of the responding cells (“anergy”), making them at best “single shot” therapeutics. We will use recently developed novel glycolipid delivery methods to overcome this limitation. We also propose studies based on recent gene expression profiling in iNKT cells to identify the cell surface receptors that control post-activation anergy, which will provide mechanistic insights into the anergic response and strategies to overcome it. A third issue addressed by the proposal relates to the inadequacy of standard mouse models for development of potential iNKT cell therapeutics, for which we will implement human CD1d knock-in mice as the first practical, humanized model for in vivo evaluation of iNKT cell-based immunotherapies. Overall, this competing renewal application proposes innovative solutions to major impediments in the ongoing effort to harness the potential of iNKT cell-based therapeutics. Successful completion of the aims of the proposal should advance our understanding of iNKT cell biology, while also helping to drive progress in the area of cancer immunotherapy.