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.

项目摘要 免疫系统保护人们免受病原体的侵害。然而，它有时会产生异常的免疫 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。这些超敏性疾病影响数百万美国人，并危及生命， 严峻的条件。目前的治疗策略通常需要终身治疗和/或广泛的治疗。 免疫抑制，引起不良反应。抗原特异性免疫耐受的诱导是一个很有前途的研究方向。 治疗超敏反应而不损害免疫保护的策略，因为该策略 特异性消除疾病相关的免疫细胞或抑制其过敏反应， 免疫系统完好一旦建立，耐受性可持续终身。虽然在这方面取得了进展， 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 成功诱导耐受性的关键是精确调节靶向免疫细胞。与小型药物相比 分子，一组蛋白质翻译从交付信使RNA（mRNA）在免疫细胞可以工作 协调地以更精确的方式变换细胞。新冠病毒mRNA疫苗的成功 作为抗原特异性免疫刺激的平台，验证了mRNA递送。然而，mRNA递送对于 诱导免疫耐受性（与免疫刺激相反的作用）尚未建立。这是因为 大多数报道的mRNA递送纳米载体引起炎症反应和/或不能靶向正确的抗原- 在免疫耐受的诱导过程中，免疫耐受细胞可以通过呈递细胞（APCs）来启动耐受诱导过程。我们最近发现，我们的聚合物 纳米颗粒可以有效地靶向肝窦内皮细胞（LSECs），这是一种天然的APC 帮助免疫系统保持耐受性。我们假设，从这种聚合物衍生的纳米载体 纳米颗粒可将抗原和编码致耐受性蛋白的mRNA共递送至LSEC以诱导抗原-免疫应答。 特异性免疫耐受在我们的初步研究中，我们证明了这样的纳米载体可以递送mRNA， 在全身给药后，小鼠中的LSEC用于蛋白质翻译。我们还证明了纳米载体 负载有抗原的免疫抑制剂可以抑制抗原特异性T细胞在体内治疗后被再刺激。 小鼠我们将通过1）评估包封抗原的不同纳米载体制剂， 2）研究所选纳米载体的生物分布及其体内致耐受性潜力; 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 这项研究预计将通过mRNA实现抗原特异性耐受，产生广泛的科学和社会影响。 交付.