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

• 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
• 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

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.

项目摘要 /摘要 该项目的目的是设计一个基于外部的治疗平台来抵消胰腺 β细胞自身免疫性作为治疗或预防1型糖尿病（T1D）的策略。我们假设外泌体 可以提供几乎无限的纳米含量，无细胞的MHC复合抗原的来源 适当的免疫调节剂可以诱导抗原特异性耐受性对β细胞自动反应t 细胞没有损害全系统免疫力。 外泌体是大多数细胞类型的小（30-150nm）生物活性膜蔬菜。 外泌体膜由脂质双层组成，许多脂质筏富含胆固醇， 鞘磷脂和神经酰胺为它们提供了长期的在体内半衰期和延长的保质期。外部 可以显示免疫刺激或免疫调节功能。抗原呈现细胞分泌大量 富含MHC剥皮复合物和粘合分子ICAM-1的外泌体的摄入剂，使它们能够接口 直接与T细胞控制免疫结局。通常，特定的抗原，例如 外泌体在免疫学上比固体单体抗原具有更大的潜在潜力。 我们的假设和目标将通过以下目标进行检验： •AIM 1将确定可以设计外泌体以过表达免疫调节分子 编程的死亡配体1（PD-L1），可以通过该分子和加载的本地MHC作用 肽抗原在体外以抗原特异性方式抑制活化的T细胞。 •AIM 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。 美国T1D的患病率不断增加，目的地对发病机理的知识不断增加 和疾病的自然史以及更好的治疗选择。因此，非常需要 一种治疗疗法，通过与 自动反应性T细胞。该提案的关键要素是指导多属性，外泌体结合的pd-l1 抗原特定方式抑制糖尿病性T细胞，从而解决自动反应性而不会造成损害 系统性免疫。 UF生物医学工程部与UF糖尿病之间共享的培训环境 Institute允许提供独特的机会，并从两种生物材料中的领导者那里获得并获得专家建议 和T1D自身免疫。通过与领先的研究人员一起参加每周的半手，将实现培训目标 来自全国各地的生物材料和T1D，全国各地的专业发展中心 医学，医学院内分泌学院大巡回赛和每周期刊俱乐部。