Binding and Presentation of Lipid Antigens by CD1

CD1d限制性链不变的NKT细胞(iNKT细胞)是一种独特的、保守的 哺乳动物免疫系统的组成部分。在小鼠身上的研究表明，在体内有显著的作用 INKT细胞激活剂，如CD1d呈递的糖脂抗原-半乳糖基神经酰胺(GalCer)，在 各种各样的动物模型，但尽管iNKT细胞激活剂在 小鼠癌症和其他疾病的模型，这一领域一直进展缓慢，进入更高级的临床 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，如癌症 免疫治疗或作为疫苗佐剂的速度因三个具体问题而放缓，所有这些问题都将是 目前的提案直接涉及的问题。第一个是合成iNKT电池的次优设计 激活剂，我们将利用我们在结构-活性方面的最新发现来克服它 GalCer类似物的相互关系。第二个问题是iNKT细胞激动剂诱导 反应细胞的缺失和低反应性(“无能”)，使它们充其量是“一次射击”。 治疗学。我们将使用最近开发的新型糖脂给药方法来克服这一点 限制。我们还提出了基于iNKT细胞最新基因表达谱的研究，以确定 控制激活后无能的细胞表面受体，这将提供对 无能反应和克服它的策略。该建议涉及的第三个问题涉及 对于潜在的iNKT细胞疗法的开发，标准小鼠模型的不足，我们对此 将实施人类CD1d基因敲入小鼠作为第一个实用的、人性化的体内评估模型 以iNKT细胞为基础的免疫疗法。总体而言，这一相互竞争的续订应用程序提出了创新 解决正在进行的利用iNKT细胞潜力的主要障碍 治疗学。成功地完成提案的目标应该会促进我们对 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.