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.

项目摘要/摘要开发免疫工程技术以选择性刺激和扩展调节t（Treg）细胞体内将是自身免疫性疾病治疗和移植医学的变革性。广泛的有证据表明，采用转移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性活性以对抗疾病。但是，后勤和制造业并发症以及与离体扩展的T细胞有关的安全问题阻碍了临床采用这种方法。因此，有未满足的医疗需要激活现成的非细胞平台抗原特异性Treg细胞直接在患者中表现出免疫抑制。白介素2（IL-2）细胞因子有力地激活Treg细胞，并被证明是采用Treg细胞转移的有前途的替代方法。然而， IL-2同时刺激效应细胞的激活，从而导致有害的脱靶效应和毒性。共同用某些抗周期代因子抗体优先激活并扩展Treg的IL-2复合物。过度效应细胞，但人们对细胞因子/抗体复合物的关注阻碍了治疗这种方法的发展。此外，IL-2处理可诱导Treg细胞的非特异性扩张，并具有有限的治疗上抗原特异性细胞的富集。该建议旨在开发一个强大而多功能的平台，以激活抗原特异性Treg细胞并同时抑制致病性自动反应性T细胞的功能。这项技术合成了第一次，三种设计方法：（1）选择性递送IL-2向Treg细胞；（2）刺激抗原特异性 Treg细胞使用人工抗原呈递细胞（AAPC）；（3）免疫抑制的局部释放药物以防止效应T细胞激活。新型平台（表示Tolapc）包括涂有纳米颗粒带有自肽的主要组织相容性复合物（MHC）以及稳定的单链融合格式 IL-2/抗体复合物，有选择地促进Treg膨胀。这些粒子也经过设计免疫抑制药物雷帕霉素的受控释放。 tolapc将在体外和体内表征评估可以抑制致病性自反应效应T细胞的Treg细胞的选择性扩张。他们会的也可以在小鼠的自身免疫性疾病研究中对治疗进行治疗。作为模型系统，TOLAPC活动将在1型糖尿病（T1D）中进行评估，这是一种慢性自身免疫性疾病，对全球健康的威胁日益增加发病率每年以3％的惊人速度上升。 TOLAPC平台的模块化将允许准备扩展到自身免疫性疾病治疗和通过移植耐受性的众多应用替代抗原特异性。总体而言，我们的目标免疫调节纳米技术将成为强大而通用的工具，用于偏向免疫激活以实现治疗相关结果。