Vaccine Development: Purinergic Agonists as Adjuvants

描述(申请人提供)：迫切需要开发更多和更好的疫苗来对抗自然病原体(例如艾滋病、SARS)和可能被生物恐怖分子利用的病原体(例如炭疽热)。这一应用将检验这样一种假设，即激活皮肤抗原提呈细胞表面表达的嘌呤能受体(即对嘌呤和相关激动剂做出反应的细胞表面受体)可以增强疫苗的有效性，从而定义一类新的佐剂。这一假说是基于皮肤中的抗原提呈细胞(即朗格汉斯细胞)上表达的嘌呤能受体，以及作用于嘌呤能受体的嘌呤和激动剂在体外增强了抗原提呈。如果这一假设是正确的，那么激活嘌呤能受体的药物可能会作为强有力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。 具体地说，我们建议：(1)确定作用于嘌呤受体的药物是否增强体内的细胞免疫；(2)确定作用于嘌呤受体的药物是否增强体内的体液免疫；以及(3)确定作用于嘌呤受体的药物是否增强疫苗接种的能力，以在明确定义的动物模型中提供针对肿瘤、感染源或毒素的攻击的保护性免疫。 虽然这一提议风险相对较大，但可能会有广泛适用和实质性的好处：(1)可以制定更有效、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，为开发新的疫苗开辟道路。(3)有可能开发针对感染性病原体和恶性肿瘤的新的治疗性疫苗。(4)这项工作可能提供体内数据支持一类新佐剂的存在，了解它们的作用机制将为免疫系统的调节提供洞察力。(5)这项工作可以提供对调节免疫反应的生理过程的洞察，并加深我们对已建立的佐剂机制的理解。

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.