Immunoengineered nanotechnology for targeted expansion of regulatory T cells

用于定向扩增调节性 T 细胞的免疫工程纳米技术

基本信息

批准号：
10320464
负责人：
Jamie Berta Spangler
金额：
$ 42.04万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2020-04-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320464
关键词：
Address Adoption Adoptive Transfer Affinity Animal Model Animals Antibodies Antibody Affinity Antigen-Presenting Cells Antigens Area Autoimmune Autoimmune Diseases B-Lymphocytes Binding Biological Models Biomedical Engineering Biotechnology Cell Communication Cell model Cells Chimeric Proteins Chronic Disease Clinical Complex Development Diabetes Mellitus Disease Dissociation Dose Drug Design Effector Cell Encapsulated Engineering Goals Graft Rejection Health Human Immobilization Immune Immune Tolerance Immune response Immune system Immunology Immunosuppression Immunosuppressive Agents Immunotherapy In Vitro Incidence Inflammatory Bowel Diseases Insulin Insulin-Dependent Diabetes Mellitus Interleukin 2 Receptor Interleukin-2 Interleukin-6 Islets of Langerhans Kinetics Logistics Lymphocyte Subset Major Histocompatibility Complex Medical Medicine Metabolic hormone Modeling Molecular Conformation Monitor Multiple Sclerosis Mus Nanotechnology Outcome Pathogenicity Patients Peptides Protein Engineering Protocols documentation Regulatory T-Lymphocyte Rheumatoid Arthritis Route Safety Scheme Signal Transduction Sirolimus Specificity Structure Surface System T-Cell Activation T-Lymphocyte Technology Testing Therapeutic Therapeutic Effect Time Toxic effect Transgenic Organisms Transplantation Transplantation Tolerance Treatment Efficacy autoreactive T cell autoreactivity base cell growth chronic autoimmune disease clinically relevant combat controlled release cytokine design diabetogenic effector T cell global health immune activation immunoengineering immunoregulation in vivo innovation interest islet mouse model nanoparticle new technology novel particle prevent receptor response therapeutic development tool transplantation medicine virtual

项目摘要

PROJECT SUMMARY/ABSTRACT Development of an immunoengineered technology to selectively stimulate and expand regulatory T (TReg) cells in vivo would be transformative for autoimmune disease treatment and transplantation medicine. Extensive evidence has established that adoptively transferred TReg cells, and in particular antigen-specific TReg cells, effectively suppress pathogenic autoimmune activity to combat disease. However, logistical and manufacturing complications as well as safety concerns associated with ex vivo expanded T cells impede clinical adoption of this approach. Thus, there is an unmet medical need for an off-the-shelf, non-cellular platform that activates antigen-specific TReg cells to manifest immunosuppression directly in patients. The interleukin-2 (IL-2) cytokine potently activates TReg cells, and has proven to be a promising alternative to adoptive TReg cell transfer. However, IL-2 concurrently stimulates activation of effector cells, resulting in harmful off-target effects and toxicities. Co- administration of IL-2 in complex with certain anti-cytokine antibodies preferentially activates and expands TReg over effector cells, but concerns about cytokine/antibody complex dissociation hinder the therapeutic development of this approach. Furthermore, IL-2 treatment induces non-specific expansion of TReg cells, with limited enrichment of therapeutically superior antigen-specific cells. This proposal aims to develop a robust and versatile platform that activates antigen-specific TReg cells and simultaneously inhibits the function of pathogenic autoreactive T cells. This technology synthesizes, for the first time, three design approaches: (1) Selective delivery of IL-2 to TReg cells; (2) Stimulation of antigen-specific TReg cells using artificial antigen-presenting cells (aAPCs); and (3) Localized release of an immunosuppressive drug to prevent effector T cell activation. The novel platform, denoted TolAPC, comprises nanoparticles coated with self peptide-loaded major histocompatibility complex (MHC) as well as a stabilized single-chain fusion format of an IL-2/antibody complex that selectively promotes TReg expansion. These particles are also engineered for controlled release of the immunosuppressive drug rapamycin. TolAPCs will be characterized in vitro and in vivo to assess selective expansion of TReg cells that can suppress pathogenic self-reactive effector T cells. They will also be therapeutically evaluated in autoimmune disease studies in mice. As a model system, TolAPC activity will be assessed in type 1 diabetes (T1D), a chronic autoimmune disease that is a growing threat to global health with incidence rising at an alarming rate of 3% annually. The modularity of the TolAPC platform will allow for ready extension to a host of applications in autoimmune disease treatment and transplant tolerance through substitution of the antigen specificity. Overall, our targeted immunomodulatory nanotechnology will serve as a powerful and general tool for biasing immune activation to effect therapeutically relevant outcomes.

项目概要/摘要开发免疫工程技术以选择性刺激和扩增调节性 T (TReg) 细胞体内研究将为自身免疫性疾病治疗和移植医学带来变革。广泛的有证据表明，过继转移的 TReg 细胞，特别是抗原特异性 TReg 细胞，有效抑制致病性自身免疫活动，对抗疾病。然而，物流和制造与离体扩增 T 细胞相关的并发症和安全问题阻碍了临床采用这种方法。因此，对现成的非细胞平台的医疗需求尚未得到满足，该平台可以激活抗原特异性 TReg 细胞直接在患者体内表现出免疫抑制。白细胞介素 2 (IL-2) 细胞因子有效激活 TReg 细胞，并已被证明是过继性 TReg 细胞移植的有前途的替代方案。然而， IL-2 同时刺激效应细胞的激活，导致有害的脱靶效应和毒性。共同 IL-2 与某些抗细胞因子抗体复合物的施用优先激活和扩展 TReg 超过效应细胞，但对细胞因子/抗体复合物解离的担忧阻碍了治疗这种方法的发展。此外，IL-2 治疗可诱导 TReg 细胞非特异性扩增，治疗上优越的抗原特异性细胞的有限富集。该提案旨在开发一个强大且多功能的平台来激活抗原特异性 TReg 细胞同时抑制致病性自身反应性T细胞的功能。该技术综合了首次提出了三种设计方法：（1）将IL-2选择性递送至TReg细胞； (2) 抗原特异性刺激使用人工抗原呈递细胞 (aAPC) 的 TReg 细胞； (3)免疫抑制剂的局部释放阻止效应T细胞激活的药物。这种新颖的平台被称为 TolAPC，包含纳米颗粒涂层具有负载自肽的主要组织相容性复合物 (MHC) 以及稳定的单链融合形式选择性促进 TReg 扩增的 IL-2/抗体复合物。这些颗粒也被设计用于免疫抑制药物雷帕霉素的控制释放。 TolAPC 将在体外和体内进行表征评估可抑制致病性自身反应性效应 T 细胞的 TReg 细胞的选择性扩增。他们会也可以在小鼠自身免疫性疾病研究中进行治疗评估。作为模型系统，TolAPC 活动将在 1 型糖尿病 (T1D) 中进行评估，这是一种对全球健康构成日益严重威胁的慢性自身免疫性疾病发病率每年以3%的惊人速度上升。 TolAPC 平台的模块化将允许准备好扩展到自身免疫性疾病治疗和移植耐受中的许多应用抗原特异性的替代。总体而言，我们的靶向免疫调节纳米技术将作为用于偏向免疫激活以实现治疗相关结果的强大且通用的工具。