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.

项目总结/摘要 该项目的目标是设计一种基于外泌体的治疗平台，以对抗胰腺癌。 β细胞自身免疫作为治疗或预防1型糖尿病（T1 D）的策略。我们假设外泌体 可以提供几乎无限的纳米颗粒、无细胞MHC复合抗原的来源， 适当的免疫负调节剂，可以诱导抗原特异性耐受β细胞自身反应性T细胞， 而不影响系统免疫力。 外泌体是由大多数细胞类型分泌的小（30- 150 nm）生物活性膜囊泡。 外泌体膜由具有许多富含胆固醇的脂筏的脂质双层组成， 鞘磷脂和神经酰胺，使它们在体内具有长的循环半衰期和延长的保质期。外来体 可以显示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， 直接与T细胞结合来控制免疫结果。一般来说，颗粒抗原，如与 外泌体比可溶性单体抗原的免疫效力强得多。 我们的假设和目标将通过以下目标的执行进行测试： ·目标1将确立外泌体可以被工程化以过表达免疫调节分子 程序性死亡配体1（PD-L1），并可以通过这种分子和负载有 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将在小鼠模型中评估致耐受性外来体的体内性能和机制 自身免疫性糖尿病。 尽管对发病机制的了解不断增加，但美国T1 D的患病率仍在继续增加 和疾病的自然史，以及更好的治疗方案。因此，非常需要 一种治疗性疗法，通过与以下药物相互作用来解决疾病的潜在自身免疫方面： 自身反应性T细胞该提议的关键要素是将多聚体、外泌体结合的PD-L1引导到一个靶向细胞中。 抗原特异性方式抑制致糖尿病性T细胞，从而解决自身反应性而不损害 全身免疫 UF生物医学工程系和UF糖尿病之间共享的培训环境 研究所提供了独特的合作机会，并从两种生物材料的领导者那里获得专家建议 T1 D自身免疫培训目标将通过参加每周一次的研讨会与领先的研究人员在 来自全国各地的生物材料和T1 D，通过学院提供的专业发展研讨会 医学院，医学内分泌学大圆桌会议，和每周杂志俱乐部。