Polymer-derived biomaterials for mRNA delivery to induce antigen-specific immune tolerance

用于 mRNA 递送以诱导抗原特异性免疫耐受的聚合物衍生生物材料

• 批准号: 10886168
• 负责人: Hao Cheng
• 金额: $ 35万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10886168
• 关键词: Adoptive Transfer; Adverse effects; Affect; Allergens; American; Animal Disease Models; Animal Model; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Area; Asthma; Autoimmune Diseases; Autoimmunity; Biocompatible Materials; Biodistribution; Bone Marrow; CD4 Positive T Lymphocytes; CD86 gene; COVID-19; Cells; Chemicals; Dendritic Cells; Disease; Disease Outcome; Encapsulated; Endothelial Cells; Epitopes; Esters; Experimental Autoimmune Encephalomyelitis; Fluorescence; Formulation; Glycolic-Lactic Acid Polyester; Hepatocyte; Hybrids; Hypersensitivity; Immune; Immune Targeting; Immune Tolerance; Immune response; Immune system; Immunologic Stimulation; Immunosuppression; In Vitro; Infection; Inflammatory; Inflammatory Response; Injections; Interleukin-10; Life; Ligand Binding; Lipids; Liver; Medical; Messenger RNA; Methods; Modeling; Mouse Protein; Multiple Sclerosis; Mus; Organ; Ovalbumin; Patients; Peptides; Persons; Pharmaceutical Preparations; Phenotype; Play; Polymers; Polynucleotides; Population; Predisposition; Process; Production; Proliferating; Proteins; RNA delivery; RNA vaccine; Regulatory T-Lymphocyte; Reporting; Research; Role; Set protein; T-Lymphocyte; Tail; Technology; Testing; Therapeutic; Transforming Growth Factor beta; Transgenic Organisms; Translating; Translations; Up-Regulation; Veins; Virus Diseases; Work; allergic airway inflammation; anergy; antigen-specific T cells; cell transformation; cytokine; design; ethylene glycol; exhaustion; extracellular; immune function; immunoreaction; immunoregulation; in vivo; insight; learning materials; mouse model; nanocarrier; nanomaterials; nanoparticle; nanopolymer; novel; pathogen; programs; response; restraint; small molecule; success

Project Summary The immune system protects people from pathogens. However, it sometimes generates abnormal immune reactions against harmless environmental antigens or patient’s own antigens, leading to allergy or autoimmune diseases, respectively. These hypersensitivity disorders affect millions of Americans and are life-threatening in severe conditions. Current therapeutic strategies often require lifelong treatment and/or broad immunosuppression, causing adverse effects. The induction of antigen-specific immune tolerance is a promising strategy to treat hypersensitivity without compromising immune protection because this strategy either specifically eliminate the disease-related immune cells or restrains their hypersensitive response, leaving the immune system intact. The tolerance may last lifelong once established. Although progress has been made in this area, technologies that induce efficient antigen-specific immune tolerance remain to be developed. The key to success in tolerance induction is the precise modulation of targeted immune cells. Compared to small drug molecules, a set of proteins translated from delivered messenger RNAs (mRNAs) in immune cells can work coordinately to transform the cells in a more precise manner. The success of COVID-19 mRNA vaccines has validated mRNA delivery as a platform for antigen-specific immune stimulation. However, mRNA delivery for inducing immune tolerance, an opposite effect as immune stimulation, has not been established. This is because most reported mRNA delivery nanocarriers cause inflammatory response and/or cannot target the right antigen- presenting cells (APCs) to initiate the process of tolerance induction. We have recently shown that our polymeric nanoparticle could efficiently target liver sinusoidal endothelial cells (LSECs), which are a type of APCs naturally helping the immune system maintain tolerance. We hypothesize that nanocarriers derived from this polymeric nanoparticle can co-deliver antigens and mRNAs encoding tolerogenic proteins to LSECs to induce antigen- specific immune tolerance. In our preliminary study, we demonstrated that such a nanocarrier can deliver mRNA to LSECs in mice for protein translation after systemic administration. We also demonstrated that the nanocarrier loaded with an antigen can inhibit the antigen-specific T cells from being restimulated after in vivo treatment of mice. We will test our hypothesis by 1) evaluating diverse nanocarrier formulations encapsulating antigen and mRNA in vitro; 2) investigating the biodistribution of selected nanocarriers and their tolerogenic potential in vivo; 3) demonstrating nanocarrier efficacy in animal disease models and elucidating the mechanism. Our proposed study is expected to have a broad scientific and societal impact by achieving antigen-specific tolerance via mRNA delivery.

项目概要 免疫系统保护人们免受病原体侵害。然而，它有时会产生异常的免疫 针对无害的环境抗原或患者自身抗原的反应，导致过敏或自身免疫 疾病，分别。这些过敏症影响着数百万美国人，并危及生命 条件恶劣。目前的治疗策略通常需要终身治疗和/或广泛治疗 免疫抑制，造成不良反应。诱导抗原特异性免疫耐受是一种有前途的方法 在不损害免疫保护的情况下治疗过敏的策略，因为该策略要么 特异性消除与疾病相关的免疫细胞或抑制其过敏反应，从而使 免疫系统完好无损。一旦建立耐受性，可能会持续终生。尽管已经取得了进展 在这一领域，诱导有效的抗原特异性免疫耐受的技术仍有待开发。关键 耐受诱导的成功在于对目标免疫细胞的精确调节。与小药相比 分子，一组从免疫细胞中传递的信使 RNA (mRNA) 翻译而来的蛋白质可以发挥作用 协调地以更精确的方式改造细胞。 COVID-19 mRNA 疫苗的成功 验证了 mRNA 递送作为抗原特异性免疫刺激的平台。然而，mRNA 递送 诱导免疫耐受（与免疫刺激相反的作用）尚未确定。这是因为 大多数报道的 mRNA 递送纳米载体会引起炎症反应和/或无法靶向正确的抗原 - 呈递细胞（APC）启动耐受诱导过程。我们最近表明我们的聚合物 纳米颗粒可以有效地靶向肝窦内皮细胞 (LSEC)，这是一种天然的 APC 帮助免疫系统保持耐受性。我们假设纳米载体源自这种聚合物 纳米颗粒可以将抗原和编码耐受原蛋白的 mRNA 共同递送至 LSEC，以诱导抗原- 特异性免疫耐受。在我们的初步研究中，我们证明了这种纳米载体可以传递 mRNA 全身给药后，将其转移到小鼠的 LSEC 中进行蛋白质翻译。我们还证明了纳米载体 负载抗原可以抑制抗原特异性T细胞在体内治疗后被再刺激 老鼠。我们将通过以下方式检验我们的假设：1）评估封装抗原和的不同纳米载体制剂 体外 mRNA； 2）研究所选纳米载体的生物分布及其体内耐受性潜力； 3）证明纳米载体在动物疾病模型中的功效并阐明其机制。我们提出的 通过 mRNA 实现抗原特异性耐受，该研究预计将产生广泛的科学和社会影响 送货。