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

基本信息

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
项目类别：
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

项目摘要

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（例如花生或鸡蛋）的患病率在全球范围内不断增加，美国受影响人数接近 3200 万人，约占总人口的 10%。疾病，目前的治疗标准包括服用抗组胺药、皮质类固醇和仅针对过敏症状的白三烯抑制剂，例如特异性免疫疗法。 Th2 偏倚是过敏的基础，但这需要长时间使用可溶性抗原和药物来增加剂量目前尚无可用于产生耐受性的治疗方法。这项研究的长期目标是开发一个基于纳米颗粒（NP）的平台。用于诱导对特定食物过敏原的耐受性以抑制不良免疫的现成治疗反应，同时不影响免疫反应的其余部分。 Lonnie Shea（co-PI）开创了一种方法，最初应用于自身免疫性疾病（1 型糖尿病、多发性硬化症），其中纳米颗粒负载有抗原，静脉注射后， NP技术已获得许可并于近期成功完成。针对乳糜泻（一种 Th1 自身免疫性疾病）的 2a 期研究，旨在推动这项技术的发展。 NP面向过敏性疾病的治疗，我们建议研究针对过敏性疾病的NP设计。将抗原递送至 APC，同时也影响其表型和 T 细胞的激活。例如抗原载量和成分，可以影响 T 细胞的激活，我们将识别这些特性可以耐受 Th2 反应，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细胞等反应，与自身免疫中的 Th1/17 反应不同值得注意的是，设计理化特性的能力可能有助于纳米粒子的翻译，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可能是无需结合 API 即可更轻松地实现。具体目标 1 将研究 NP 设计和调节 APC 的细胞和分子反应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 NP 的关键属性。区分 i) NP 特性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，以及 iv) 预致敏食物过敏中耐受诱导的功效具体目标 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，还影响频率、受体。这项创新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。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，以及效应细胞反应，随后改善过敏性疾病。