Allergen Loaded Nanoparticles for Food Allergy Tolerance

项目摘要：食物过敏的流行，如花生或鸡蛋，在世界范围内正在增加， 美国受影响的人数接近3200万，占人口的10%。治疗过敏性 疾病，目前的治疗标准涉及抗组胺药，皮质类固醇， 仅针对过敏症状的白三烯抑制剂。特异性免疫疗法等疗法靶向 Th 2偏倚是过敏的基础，然而这需要可溶性抗原的长期剂量递增， 有很大的不良反应风险目前没有疗法可用于产生对本发明的药物的耐受性。 抗原这项研究的长期目标是开发一种基于纳米粒子（NP）的平台， 用于诱导对特定食物过敏原的耐受性以抑制不希望的免疫的现成治疗 免疫反应，而不影响免疫反应的其余元素。斯蒂芬米勒博士和 Lonnie Shea（合作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NP装载有抗原，当静脉内施用时， 诱导对抗原的耐受。NP技术已获得许可，最近已成功完成 一项针对乳糜泻（一种Th 1自身免疫性疾病）的2a期研究。我们的目标是将这项技术 对于过敏性疾病的治疗，我们建议研究用于过敏性疾病的NP设计。的NP 将抗原递送至APC，还影响它们的表型和T细胞的活化。NP属性， 如抗原负载和组成，可以影响T细胞活化，我们将确定这些特性， 其可以耐受Th 2应答，如IL-4、IL-5和IL-13分泌、B细胞活化和效应细胞 肥大细胞和嗜碱性粒细胞等应答，这与自身免疫性疾病中的Th 1/17应答不同。 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 实现良好的生产规范和临床批准，同时避免意外的副作用， 更容易获得，而无需加入API。具体目标1将研究NP设计， 调节APC的细胞和分子应答以治疗花生和鸡蛋过敏模型， O 'Konek博士（co-I）提供食物过敏方面的专业知识。我们建议研究关键属性的NP 为了区分i）NP性质对免疫细胞极化的影响，ii）抗原呈递的功效， iii）NP的体内运输，和iv）在预致敏食物过敏中耐受诱导的功效 疾病模型特异性目标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Th 2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变应原暴露的表达和反应。这一创新 基于NP的方法将识别安全的NP，并将NP性质与APC、T细胞和免疫球蛋白相关联。 效应细胞应答，并随后改善过敏性疾病。

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.