Engineered tolerogenic exosomes for treating type 1 diabetes autoimmunity

用于治疗 1 型糖尿病自身免疫的工程化耐受性外泌体

基本信息

批准号：
10248351
负责人：
Matthew Becker
金额：
$ 3.97万
依托单位：
UNIVERSITY OF FLORIDA
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：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10248351
关键词：
Address Adoptive Cell Transfers Adoptive Transfer Adult Affect American Anti-Inflammatory Agents Antigen-Presenting Cells Antigens Autoimmune Autoimmune Diabetes Autoimmunity Benchmarking Beta Cell Biocompatible Materials Biological Biomedical Engineering CD8-Positive T-Lymphocytes Cancer Biology Cell Adhesion Molecules Cell Communication Cell Therapy Cell-Free System Cells Cellular immunotherapy Ceramides Child Cholesterol Clinical Trials Coculture Techniques Complex Country Development Diabetes Mellitus Disease Disease Progression Effectiveness Elements Endocrinology Engineering Environment Face Flow Cytometry Foundations Goals HLA Antigens Half-Life Harvest Health Care Costs Immune Immune Tolerance Immunity Immunologics Immunosuppression Immunotherapy In Vitro Incidence Institutes Insulin-Dependent Diabetes Mellitus Intercellular adhesion molecule 1 Journals Knockout Mice Knowledge Lentivirus Vector Life Lipid Bilayers Major Histocompatibility Complex Malignant Neoplasms Medicine Membrane Membrane Microdomains Microscopy Modeling Monitor Mus Outcome Pancreas Parents Particulate Pathogenesis Patient risk Patients Peptides Performance Population Prevalence Proteins Rag1 Mouse Regulatory T-Lymphocyte Research Research Personnel Role Safety Signal Transduction Source Specificity Sphingomyelins Spleen Structure of beta Cell of islet System T-Cell Activation T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Time Training Tumor-Derived Vesicle autoreactive T cell autoreactivity base cell killing cell type college cost curative treatments cytotoxicity diabetogenic disease natural history efficacy evaluation engineered exosomes exosome graft vs host disease humane endpoint immunocytochemistry immunoregulation in vivo lymph nodes mouse model nanoparticulate overexpression personalized medicine prevent programmed cell death ligand 1 programmed cell death protein 1 tool tumorigenesis virtual

项目摘要

Project Summary / Abstract The objective of this project is to engineer an exosome-based therapeutic platform to counteract pancreatic beta-cell autoimmunity as a strategy to treat or prevent type 1 diabetes (T1D). We hypothesize that exosomes can provide a virtually unlimited source of nanoparticulate, cell-free MHC-complexed antigen that, alongside appropriate negative regulators of immunity, can induce antigen-specific tolerance to beta cell autoreactive T cells without compromising system-wide immunity. Exosomes are small (30-150nm) biologically active membrane vesicles secreted by most cell types. Exosomal membranes are composed of a lipid bilayer with many lipid rafts that are enriched in cholesterol, sphingomyelin, and ceramide, giving them a long circulatory half-life in vivo and an extended shelf life. Exosomes can display immunostimulatory or immunoregulatory functions. Antigen presenting cells secrete large numbers of exosomes enriched in MHC peptide complexes and the adhesion molecule ICAM-1, enabling them to interface directly with T cells to control immune outcomes. In general, particulate antigen, such as that associated with exosomes, is far more immunologically potent than soluble, monomeric antigen. Our hypothesis and objective will be tested through performance of the following aims: • Aim 1 will establish that exosomes can be engineered to overexpress the immunoregulatory molecule programmed death-ligand 1 (PD-L1) and can act through this molecule and native MHC loaded with peptide antigen to suppress activated T cells in an antigen specific manner in vitro. • Aim 2 will evaluate the in vivo performance and mechanisms of tolerogenic exosomes in a mouse model of autoimmune diabetes. The prevalence of T1D in the U.S. continues to increase, despite growing knowledge of the pathogenesis and natural history of the disease, as well as better treatment options. Therefore, there is a significant need for a curative therapy that addresses the underlying autoimmune aspects of the disease by interfacing with autoreactive T cells. The key element of this proposal is directing multimeric, exosome-bound PD-L1 in an antigen specific manner to suppress diabetogenic T cells, thus addressing autoreactivity without compromising systemic immunity. The training environment shared between the UF Biomedical Engineering department and the UF Diabetes Institute allows for unique opportunities to collaborate and receive expert advice from leaders in both biomaterials and T1D autoimmunity. Training goals will be met by attending weekly seminars with leading researchers in biomaterials and T1D from around the country, professional development seminars offered through the College of Medicine, College of Medicine Endocrinology Grand Rounds, and weekly journal clubs.

项目概要/摘要该项目的目标是设计一个基于外泌体的治疗平台来对抗胰腺癌 β 细胞自身免疫作为治疗或预防 1 型糖尿病 (T1D) 的策略。可以提供几乎无限的纳米颗粒、无细胞 MHC 复合抗原来源，适当的免疫负调节剂，可以诱导对 β 细胞自身反应性 T 的抗原特异性耐受细胞而不损害系统范围的免疫力。外泌体是大多数细胞类型分泌的小型（30-150nm）生物活性膜囊泡。外泌体膜由脂双层组成，脂双层具有许多富含胆固醇的脂筏，鞘磷脂和神经酰胺，赋予它们较长的体内循环半衰期和延长的外泌体保质期。可以表现出免疫刺激或免疫调节功能抗原呈递细胞分泌大量。富含 MHC 肽复合物和粘附分子 ICAM-1 的外泌体，使它们能够相互作用一般来说，颗粒抗原，例如与 T 细胞相关的抗原，可直接控制免疫结果。外泌体的免疫学效力比可溶性单体抗原强得多。我们的假设和目标将通过实现以下目标进行检验： • 目标 1 将确定外泌体可以被改造以过度表达免疫调节分子程序性死亡配体 1 (PD-L1)，可以通过该分子和负载有的天然 MHC 发挥作用肽抗原在体外以抗原特异性方式抑制活化的T细胞。 • 目标 2 将评估小鼠模型中耐受性外泌体的体内性能和机制自身免疫性糖尿病。尽管人们对发病机制的认识不断加深，但美国 1 型糖尿病的患病率仍在持续增加因此，非常需要了解该疾病的自然史以及更好的治疗选择。一种治疗方法，通过与该提案的关键要素是指导多聚体、外泌体结合的 PD-L1。抗原特异性方式抑制致糖尿病 T 细胞，从而在不影响自身反应的情况下解决自身反应问题全身免疫。佛罗里达大学生物医学工程系和佛罗里达大学糖尿病系共享的培训环境研究所提供了独特的合作机会并接受生物材料领域领导者的专家建议和 T1D 自身免疫的培训目标将通过参加由领先研究人员参加的每周研讨会来实现。来自全国各地的生物材料和 T1D，通过学院提供的专业发展研讨会医学院、医学院内分泌学大查房和每周期刊俱乐部。