Binding and Presentation of Lipid Antigens by CD1

CD1 与脂质抗原的结合和呈递

基本信息

批准号：
9975679
负责人：
Steven A Porcelli
金额：
$ 46.72万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-07-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9975679
关键词：
Address Agonist Animal Model Antigen Presentation Antigens Antitumor Response Area Attention Autoimmunity Bacterial Vaccines Binding Biology Bypass CD 200 CD1 Antigens Cancer Model Cancer Vaccines Cell Surface Receptors Cell physiology Cells Cellular biology Cellular immunotherapy Chimeric Proteins Clinic Complex Cytotoxic T-Lymphocytes Data Development Disease Formulation Funding Galactosylceramides Gene Expression Profiling Glycolipids Goals Grant Human Immune system Immunity Immunotherapy Knock-in Mouse Laboratories Ligands Lipids Listeria monocytogenes Lymphocyte MHC Class I Genes Mediating Methods Modeling Mus Population Proteins Protocols documentation Publishing Regimen Research Role Stimulus Structure Structure-Activity Relationship Synthesis Chemistry System T cell anergy T cell therapy T-Cell Activation T-Lymphocyte Testing Therapeutic Therapeutic Effect Vaccine Adjuvant Vaccines Work allograft rejection analog anergy bacterial vector base cancer immunotherapy cancer therapy clinical development clinical translation clinically relevant design humanized mouse immunoregulation improved in vivo in vivo Model in vivo evaluation innovation insight method development model development mouse model neoplasm immunotherapy novel prevent protein expression response targeted treatment transcriptome transcriptomics tumor

项目摘要

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.

具有不变TCR链（Inkt细胞）的CD1D限制性NKT细胞是独特而保守的哺乳动物免疫系统的成分。在小鼠中的研究表明 Inkt细胞活化剂，例如CD1D呈现的糖脂抗原-半乳糖基酰胺（甘油）各种各样的动物模型，但是尽管在inkt细胞激活剂中具有显着的治疗作用癌症和其他疾病的鼠模型，该区域的进展缓慢到更先进的临床发展。该申请解决了可能是推进Inkt的主要局限性的问题基于细胞的疗法，并试图为这些障碍提供实用的解决方案。我们假设试图将Inkt细胞疗法转移到诊所中以进行癌症免疫疗法或作为疫苗调节器已被三个特定问题放慢了速度，所有这些都将是当前建议直接解决。首先是合成Inkt细胞的次优设计激活剂，我们将使用有关结构活动的最新发现来克服这些激活剂 alcer类似物的关系。第二个问题是Inkt细胞激动剂诱发的趋势响应细胞的删除和缺乏反应性（“ Anergy”），使其最多可以“单镜头” 治疗。我们将使用最近开发的新型糖脂递送方法来克服这一点局限性。我们还根据inkt细胞中最近的基因表达分析提出了研究，以鉴定控制激活后反感的细胞表面受体，该受体将提供机械洞察力克服它的厌食症和策略。该提案解决的第三个问题与对潜在Inkt细胞疗法开发的标准小鼠模型不足，我们为此将实施人类CD1D敲入小鼠作为体内评估的第一个实用的人源化模型基于INKT细胞的免疫疗法。总体而言，这种竞争性续订申请提案创新在持续努力的主要障碍方面解决了基于Inkt细胞的潜力的努力疗法。成功完成提案的目标应该提高我们的理解 Inkt细胞生物学，同时还有助于推动癌症免疫疗法领域的进展。