Allergen Loaded Nanoparticles for Food Allergy Tolerance

负载过敏原的纳米颗粒可提高食物过敏耐受性

• 批准号: 10264878
• 负责人: STEPHEN D MILLER
• 金额: $ 76.43万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-16 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10264878
• 关键词: Acute Disease; Address; Adrenal Cortex Hormones; Adverse reactions; Affect; Allergens; Allergic; Allergic Disease; Allergy to eggs; Allergy to peanuts; Anaphylaxis; Antigen Presentation; Antigen-Presenting Cells; Antigens; Antihistamines; Apoptotic; Autoimmune Diseases; B-Cell Activation; Basophils; Biodistribution; Celiac Disease; Cell Communication; Cell Transplantation; Cell physiology; Cells; Cessation of life; Clinical; Clinical Research; Clonal Deletion; Complex; Coupled; Developed Countries; Development; Disease; Disease model; Disease remission; Dose; Down-Regulation; Effector Cell; Elements; Encapsulated; Epitope spreading; Evaluation; Experimental Autoimmune Encephalomyelitis; Food Hypersensitivity; Formulation; Foundations; Frequencies; Generations; Glycolic-Lactic Acid Polyester; Goals; Graft Rejection; Health; Hepatic; Hypersensitivity; Immune; Immune System Diseases; Immune Targeting; Immune Tolerance; Immune response; Immune system; Immunity; Immunosuppression; Immunotherapy; Individual; Inflammation; Inflammatory; Infusion procedures; Insulin-Dependent Diabetes Mellitus; Interleukin-13; Interleukin-4; Interleukin-5; Intravenous; Leukotrienes; Liver; Measures; Mediating; Memory; Modeling; Molecular; Molecular Weight; Multiple Sclerosis; Mus; Pathogenicity; Pathology; Patients; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phenotype; Polymers; Population; Prevalence; Prevention; Property; Proteins; Protocols documentation; Recurrence; Regenerative Medicine; Regulatory T-Lymphocyte; Relapse; Research; Risk; Safety; Spleen; Splenocyte; Symptoms; System; T cell anergy; T cell response; T-Cell Activation; T-Lymphocyte; Technology; Th2 Cells; Time; Translations; Up-Regulation; Ursidae Family; Vaccines; Work; allergic response; anergy; anti-IgE; arm; base; biomaterial compatibility; clinical translation; cost; design; disorder prevention; egg; food allergen; food antigen; in vivo; inhibitor/antagonist; innovation; intravenous administration; mast cell; nanoparticle; nanoparticle delivery; omalizumab; particle; polarized cell; preservation; prevent; receptor expression; response; side effect; surfactant; trafficking

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.

项目摘要：食物过敏的患病率（例如花生或鸡蛋）在全球范围内都在增加 美国受影响的个人数量接近3200万，约有10％的人口。用于过敏 疾病，目前的治疗标准涉及抗组胺药，皮质类固醇和 仅针对过敏性症状的白细胞抑制剂。诸如特定免疫疗法之类的疗法针对 构成过敏的Th2偏差，但是，这需要长时间用固体抗原和 有不良反应的重大风险。目前尚无治疗方法来增强对 抗原。这项研究的长期目标是开发基于纳米颗粒（NP）的平台 现成的治疗，以诱导对特定食物过敏原的耐受性抑制未养育的免疫 反应，同时不影响免疫反应的其余元素。博士。斯蒂芬·米勒（Stephen Miller）和 Lonnie Shea（Co-Pis）开创了一种最初应用于自身免疫性疾病的方法（1型 糖尿病，多发性硬化症），其中NP装有抗原，静脉内给药后， 诱导对抗原的耐受性。 NP技术已获得许可并最近成功完成 乳糜泻的2A期研究（Th1自身免疫性疾病）。以移动这项技术的目标 为了治疗过敏性疾病，我们建议研究过敏性疾病的NP设计。 NP 将抗原提供给APC，但也影响其表型和T细胞的激活。 NP属性， 例如抗原加载和组成，可以影响T细胞的激活，我们将确定这些特性 可以耐受Th2响应，例如IL-4，IL-5和IL-13分泌，B细胞激活和效应细胞 肥大细胞和嗜碱性粒子等反应，它们与自身免疫性的Th1/17反应不同 疾病。值得注意的是，设计物理特性的能力可能有助于NP的翻译 在避免意外副作用的同时，获得良好的制造实践和临床认可可能是 没有合并的API，更容易获得。特定目标1将研究NP设计和 APC的细胞和分子反应调节花生和卵过敏模型的治疗 与O'Konek（Co-I）博士一起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性质对免疫细胞极化的影响，ii）抗原表现的效率， iii）NPS的体内运输和iv）耐受性食品过敏的耐受效率 疾病模型。特定的目标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，接收器 将测量肥大细胞和嗜碱性对过敏原暴露的表达和反应。这种创新 基于NP的方法将识别安全的NP，并将NP属性连接到APC，T细胞和 效应细胞反应，随后对过敏性疾病的改善。