Allergen Loaded Nanoparticles for Food Allergy Tolerance

项目概述：全球范围内对花生或鸡蛋等食物过敏的流行率正在上升， 美国受影响的人数接近3,200万人，≈占总人口的10%。治疗过敏 目前的治疗标准包括给予抗组胺药物、皮质类固醇和 白三烯抑制剂只针对过敏症状。特异性免疫疗法等疗法针对的是 导致过敏的Th2偏向，然而，这需要与可溶性抗原和 有很大的不良反应风险。目前还没有治疗方法来发展对这种疾病的耐受性 抗原。这项研究的长期目标是开发一种基于纳米颗粒(NP)的平台，可以 现成的治疗方法，用于诱导对特定食物过敏原的耐受性，以抑制不需要的免疫 免疫应答，同时不影响免疫应答的其余成分。斯蒂芬·米勒博士和 Lonnie Shea(共同PI)开创了一种最初应用于自身免疫性疾病(1型)的方法 糖尿病、多发性硬化症)，其中NPs装载有抗原，当静脉注射时， 诱导对抗原的耐受性。NP技术已经获得许可，最近成功完成 一项针对乳糜泻(Th1自身免疫性疾病)的2a期研究。目标是将这项技术 对于变态反应性疾病的治疗，我们建议研究用于变态反应性疾病的NP设计。《名利场》 将抗原传递给APC，但也影响它们的表型和T细胞的激活。NP属性， 例如抗原的负载和成分，可以影响T细胞的激活，我们将确定这些特性 可以耐受Th2反应，如IL-4，IL-5和IL-13的分泌，B细胞激活和效应细胞 自身免疫中不同于Th1/17反应的肥大细胞和嗜碱性粒细胞等反应 疾病。值得注意的是，设计物理化学性质的能力可以促进NP的翻译，如 在避免意想不到的副作用的同时实现良好的生产实践和临床批准可能是 无需结合API即可更轻松地实现。具体目标1将调查NP设计和 花生和鸡蛋过敏模型中APC细胞和分子反应的调节， O‘Konek博士(co-I)提供食物过敏方面的专业知识。我们建议研究NP的关键属性 为了区分i)NP属性对免疫细胞极化的影响，ii)抗原提呈的有效性， Iii)NPs在体内的转运，以及iv)耐受性诱导在预致敏食物过敏中的作用 疾病模型。特定目标2将确定NP递送的细胞和分子机制 影响T细胞表型，同时耐受Th2过敏性疾病。此外，频率，受体， 将测量肥大细胞和嗜碱性粒细胞对过敏原暴露的表达和反应。这是一项创新 基于NP的方法将识别安全的NP，并将NP属性与APC、T细胞和 效应细胞的反应，以及随后对过敏性疾病的改善。

Project Summary: The prevalence of food allergies, such as to peanut or egg, is increasing worldwide, with the number of individuals affected in the US approaching 32 million, ≈10% of the population. For allergic disease, the current standard of therapy involves administration of antihistamines, corticosteroids, and leukotriene inhibitors that only target allergic symptoms. Therapies such as specific immunotherapy target the Th2 bias that underlies allergy, however this requires long periods of dose escalation with soluble antigen and carries a significant risk of adverse reactions. No therapies are currently available to develop tolerance to the antigens. The long-term goal of this research is to develop a nanoparticle (NP) based platform that can be an off-the-shelf treatment for induction of tolerance to specific food allergens to inhibit undesired immune responses, while not affecting the remaining elements of the immune response. Drs. Stephen Miller and Lonnie Shea (co-PIs) have pioneered an approach that was initially applied to autoimmune disease (Type 1 Diabetes, multiple sclerosis) in which NPs are loaded with antigens, which upon intravenous administration, induce of tolerance to the antigen. The NP technology has been licensed and recently successfully completed a Phase 2a study for celiac disease (a Th1 autoimmune disease). With the goal of moving this technology toward the treatment of allergic diseases, we propose to investigate the NP design for allergic disease. The NP delivers the antigen to APCs, yet also influences their phenotype and activation of T cells. The NP properties, such as antigen loading and composition, can influence T cell activation, and we will identify those properties that can tolerize Th2 responses such as IL-4, IL-5, and IL-13 secretion, B cell activation, and effector cell responses such as mast cells and basophils, which are distinct from the Th1/17 responses in autoimmune disease. Notably, the ability to design the physicochemical properties may facilitate translation of the NPs, as achieving good manufacturing practices and clinical approval while avoiding unanticipated side effects may be more easily attainable without the incorporation of an API. Specific Aim 1 will investigate the NP design and modulation of cellular and molecular responses of APCs for the treatment of peanut and egg allergy models, with Dr. O’Konek (co-I) providing expertise in food allergy. We propose to investigate critical attributes of NPs to distinguish i) the impact of NP properties on immune cell polarization, ii) the efficacy of antigen presentation, iii) the in vivo trafficking of the NPs, and iv) the efficacy of tolerance induction in pre-sensitized food allergy disease models. Specific Aim 2 will determine the cellular and molecular mechanisms by which NP delivery affects T cell phenotypes while tolerizing Th2 allergic diseases. Furthermore, the frequency, receptor expression and response of mast cells and basophils to allergen exposure will be measured. This innovative NP-based approach would identify NPs that are safe, and will connect the NP properties to APC,T cell, and effector cell responses, and subsequently to the amelioration of allergic disease.