Polymeric biomaterial-based microparticle vaccine for amelioration of Type 1 diab

用于改善 1 型糖尿病的基于聚合物生物材料的微粒疫苗

基本信息

批准号：
8592629
负责人：
Jamal S Lewis
金额：
$ 22.62万
依托单位：
ONEVAX, LLC
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8592629
关键词：
Address Animal Model Antigen Presentation Antigen Targeting Antigen-Presenting Cells Antigens Autoantigens Autoimmune Diseases Autoimmune Responses B-Lymphocytes Biocompatible Materials Biodistribution Biological Biological Availability Biological Factors Biomedical Engineering Blood Cells Cholecalciferol Clinic Collaborations Data Dendritic Cells Development Diabetes Mellitus Digestive System Disorders Drug Formulations Encapsulated Failure Figs - dietary Florida Funding Goals Health Heart Diseases Homing Human Immune Immune system Immunity In Vitro Inbred NOD Mice Incidence Injectable Injection of therapeutic agent Institutes Insulin Insulin-Dependent Diabetes Mellitus Kidney Diseases Kidney Failure Left Life Lymph Maintenance Mediating Medicine Methods Mission Modification Nature Pancreas Particle Size Particulate Patients Phagocytes Pharmaceutical Preparations Phase Phenotype Physiological Pre-Clinical Model Prevention Public Health Qualifying Regulation Regulatory T-Lymphocyte Resolution Self Tolerance Shipping Ships Site Structure of beta Cell of islet Surface System T-Lymphocyte Technology Therapeutic Time Toxic effect Translating Treatment Cost United States National Institutes of Health Universities Vaccination Vaccines Work base cell type college conditioning controlled release design glucose metabolism in vivo mouse model novel novel therapeutics particle pre-clinical preclinical safety preclinical study prevent public health relevance research clinical testing response socioeconomics targeted delivery

项目摘要

DESCRIPTION (provided by applicant): Type 1 Diabetes (T1D) is thought to result from a breakdown of self-tolerance that is characterized by T cell-mediated destruction of the insulin-producing ¿-cells in the pancreas. Ultimately, glucose metabolism is interrupted, resulting in the development of life-threatening complications such as heart disease and renal failure. A number of factors are known to promote advantageous immune cell responses in experimental systems for T1D. However, systemic delivery of these agents often results in significant harmful off-target effects. We have pioneered a novel, biomaterial-based, particle vaccine system for in vivo delivery of pro- tolerance factors and insulin antigen, targeted to a key immune cell type, dendritic cells (DCs). Dendritic cells are professional antigen presenting cells (APCs), directly involved in T cell and B cell immunity, including the maintenance of tolerance to self-antigens. Moreover, exogenous conditioning of DCs with certain immuno-modulatory agents has been shown to induce a pro- tolerance DC phenotype as well as ameliorate T1D. Vaccination with DC-targeting microparticles (MPs) holds promise to correct T1D autoimmune responses, critically, without the costly ex vivo manipulations required of DC-based cellular therapy. Our long term goal is to develop an easily injectable, particle vaccine capable of prevention and reversal of T1D in humans. This approach greatly enhances the potential for widespread use. The objective of this Phase I proposal is to complete preclinical studies that demonstrate the feasibility of our most promising particle vaccine formulation for use in humans. More specifically, we want to assess biodistribution, bioavailability, toxicity and potentially harmful ff-target effects of the particle vaccine in preclinical models of T1D. Our preliminary data strongly suggests that this biomaterial-based, particle vaccine system holds promise for correcting autoimmune responses in T1D. Additionally, our strategic collaborations with the Biomedical Engineering Department, College of Medicine and Diabetes Center of Excellence at the University of Florida boost our capability to complete the desired goals.

描述（由应用程序提供）：1型糖尿病（T1D）被认为是由于自耐受的崩溃而导致的，这种糖尿病的特征是胰腺中产生胰岛素的细胞的T细胞介导的破坏。最终，葡萄糖代谢被中断，导致威胁生命的并发症（如心脏病和肾衰竭）的发展。已知许多因素可促进T1D实验系统中有利的免疫细胞反应。但是，这些代理的全身交付通常会导致明显的有害脱靶效果。我们开创了一种新型的，基于生物材料的颗粒疫苗系统，用于体内耐耐受因子和胰岛素抗原，该系统针对关键免疫物类型树突状细胞（DCS）。树突状细胞是专业的抗原呈递细胞（APC），直接参与T细胞和B细胞免疫性，包括维持对自我抗原的耐受性。此外，已证明具有某些免疫调节剂的DC的外源调节可诱导耐受性DC表型以及改善T1D。使用DC靶向微粒（MP）疫苗接种有望纠正T1D自身免疫反应，而无需基于直流的细胞疗法所需的昂贵的离体操纵。我们的长期目标是开发一种易于注射的颗粒疫苗，能够预防和人类T1D的逆转。这种方法大大提高了宽度使用的潜力。该阶段I建议的目的是完成临床前研究，以证明我们最有前途的颗粒疫苗公式用于人类的可行性。更具体地说，我们希望评估T1D临床前模型中粒子疫苗的生物分布，生物利用度，毒性和潜在有害的FF靶标作用。我们的初步数据强烈表明，这种基于生物材料的颗粒疫苗系统有望纠正T1D中的自身免疫反应。此外，我们与佛罗里达大学医学和糖尿病学院卓越中心生物医学工程系的战略合作提高了我们完成所需目标的能力。