Vaccine Development: Purinergic Agonists as Adjuvants

疫苗开发：嘌呤能激动剂作为佐剂

• 批准号: 6891607
• 负责人: RICHARD David GRANSTEIN
• 金额: $ 33.6万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-15 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6891607
• 关键词: antigen presentation; antigen presenting cell; biological signal transduction; cellular immunity; enzyme linked immunosorbent assay; humoral immunity; immune response; immunomodulators; laboratory mouse; microorganism disease chemotherapy; purinergic receptor; purines; radioimmunoassay; ricin; skin; vaccine development; vaccine evaluation; western blottings

DESCRIPTION (provided by applicant): There is a urgent need to develop more and better vaccines to combat both natural pathogens (e.g., AIDS, SARS) and pathogens that may be used by bioterrorists (e.g., anthrax). This application will test the hypothesis that activation of purinergic receptors (i.e. the cell surface receptors that respond to purines and related agonists), which are expressed on the surface of antigen presenting cells in the skin, can enhance the effectiveness of vaccines, thereby defining a new class of adjuvants. This hypothesis is based on evidence that purinergic receptors are expressed on antigen presenting cells in the skin (i.e., Langerhans cells) and that purines and agonists that act on purinergic receptors enhance antigen presentation in vitro. If this hypothesis is correct, then agents that activate purinergic receptors may serve as potent adjuvants to enhance the efficiency of vaccines. We will take two distinct approaches to test each of three aims. Specifically, we propose: (1) to determine if agents that act on purine receptors augment cell-mediated immunity in vivo; (2) to determine if agents that act on purine receptors enhance humoral immunity in vivo; and (3) to determine if agents that act on purine receptors enhance the ability of vaccination to provide protective immunity against challenge with tumors, infectious agents or toxins in well-defined animal models. Although this proposal is relatively risky, there may be broadly applicable and substantial benefits benefits: (1) More effective and, possibly safer, vaccination protocols may be developed. (2) Some molecules that are currently not suitable for vaccinations may gain effectiveness opening the way for the development of novel vaccines. (3) It may be possible to develop new therapeutic vaccines for infectious agents and malignancies. (4) This work may provide in vivo data to support the existence of a new class of adjuvants, and understanding their mechanism of action should provide insight into the regulation of the immune system. (5) This work may provide insights into the physiological processes that modulate the immune response and further our understanding of the mechanisms of established adjuvants.

描述（由申请人提供）：迫切需要开发更多更好的疫苗来对抗天然病原体（例如，艾滋病、SARS）和可能被生物恐怖分子利用的病原体（例如，炭疽）。本申请将测试嘌呤能受体（即，响应嘌呤和相关激动剂的细胞表面受体）的活化可以增强疫苗的有效性的假设，所述嘌呤能受体在皮肤中的抗原呈递细胞的表面上表达，从而定义了一类新的佐剂。该假设基于嘌呤能受体在皮肤中的抗原呈递细胞上表达的证据（即，Langerhans细胞），嘌呤和作用于嘌呤能受体的激动剂在体外增强抗原呈递。如果这一假设是正确的，那么激活嘌呤受体的药物可能作为有效的佐剂来提高疫苗的效率。我们将采取两种不同的方法来测试三个目标中的每一个。 具体而言，我们建议：（1）确定作用于嘌呤受体的试剂是否在体内增强细胞介导的免疫;（2）确定作用于嘌呤受体的试剂是否在体内增强体液免疫;和（3）确定作用于嘌呤受体的试剂是否在明确定义的动物模型中增强疫苗接种提供针对肿瘤、感染因子或毒素攻击的保护性免疫的能力。 虽然这一提议相对危险，但可能具有广泛适用性和实质性益处：（1）可以制定更有效和可能更安全的疫苗接种方案。(2)一些目前不适合接种疫苗的分子可能会获得有效性，为开发新型疫苗开辟道路。(3)有可能开发新的治疗性疫苗，用于感染性病原体和恶性肿瘤。(4)这项工作可能提供体内数据，以支持一类新的佐剂的存在，并了解其作用机制，应提供深入了解免疫系统的调节。(5)这项工作可能会提供深入了解的生理过程，调节免疫反应，并进一步了解既定的佐剂的机制。