Antigen loaded particles for tolerance induction

用于耐受诱导的负载抗原的颗粒

• 批准号: 9056589
• 负责人: STEPHEN D MILLER
• 金额: $ 53.83万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9056589
• 关键词: Acute Disease; Address; Adverse effects; Allergic Disease; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apoptotic; Artificial nanoparticles; Autoantigens; Autoimmune Diseases; Biocompatible; Biodistribution; CD4 Positive T Lymphocytes; Cell Transplants; Cells; Clinic; Clinical; Clinical Trials; Collaborations; Coupled; Development; Disease; Disease remission; Elements; Encapsulated; Epitopes; Ethylenes; Experimental Autoimmune Encephalomyelitis; Food; Funding; Glycolic-Lactic Acid Polyester; Goals; Graft Rejection; Health; Hypersensitivity; Immune; Immune Tolerance; Immune response; Immune system; Immunosuppression; Infiltration; Inflammation; Inflammatory; Infusion procedures; Interferon Type II; Intravenous; Laboratories; Liver; Maintenance; Memory; Methodology; Modeling; Molecular; Multiple Sclerosis; Mus; Myelin; Particulate; Peptides; Peripheral Blood Mononuclear Cell; Phase I Clinical Trials; Physiologic pulse; Polystyrenes; Population; Prevention; Proteins; Protocols documentation; Regenerative Medicine; Regulation; Regulatory T-Lymphocyte; Relapse; Reporting; Site; Specificity; Spleen; Splenocyte; System; T cell anergy; T cell response; T cell therapy; T memory cell; T-Lymphocyte; Technology; Testing; Therapeutic; Tissues; Translations; Vaccines; Work; anergy; autoreactive T cell; base; carboxylate; cell killing; clinically relevant; cost; crosslink; design; food antigen; in vivo; innovation; macrophage; maleic acid; man; monocyte; mouse model; multiple sclerosis patient; multiple sclerosis treatment; nanoparticle; novel; particle; prevent; response; scavenger receptor; surfactant; tool; trafficking; uptake

 DESCRIPTION: The undesired destruction of healthy cells by the immune system results in the loss of tissue function and complicates strategies to restore tissue function. The current standard therapy for autoimmune disease involves generalized immunosuppression, which is in most cases is not clinically efficacious and leads to numerous undesired side effects. Dr. Stephen Miller, (co-PI) pioneered an approach in which splenocytes were cross-linked with specific auto antigens, and their delivery to the spleen induced tolerance specifically to the auto antigen. This approach was recently adapted for a clinical trial in multiple sclerosis (MS) patients, and was the first-in-man study to report the induction antigen specific tolerance. However, the use of cellular carriers for tolerance induction in the clinical arena is challenging due to the considerable ex-vivo laboratory manipulation that is required, which is expensive, increases the number of donor cells needed and introduces further opportunity for technical error. Our long-term goal is to develop a particle-based platform that can be an off-the-shelf product for induction of tolerance to specific antigens to inhibit the specific undesired immune response while not altering the remaining elements of the immune response. We have demonstrated that antigen-loaded particles delivered intravenously can induce tolerance for the prevention and treatment of experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. With the goal of moving this technology toward the clinic, we propose to extend these studies to address fundamental questions about the particle design and their mechanisms of action, and also critical questions regarding the ability to target the variety of antigens and cell populations underlying disease. Specific Aim 1 will investigate the particle design parameters and identify the cellular mechanisms by which particles injected intravenously are able to modulate inflammation and induce antigen specific tolerance. Our results suggest the liver as a critical site involved in tolerance induction from the particles, which distinguishes it from the previous work with antigen-coupled splenocytes. We propose to investigate the particle composition and size to distinguish i) the impact of the carrier on immune cell polarization, ii) te efficacy of antigen presentation, and iii) in vivo trafficking of the particles. Specific Aim 2 wil determine the cellular and molecular mechanisms by which Ag-PLG tolerance is induced and maintained in naïve, activated, and memory T cells. We propose to test the ability to induce tolerance with particles encapsulating multiple peptides/proteins and to examine the separate and combined contributions of anergy and Tregs to the induction and maintenance of tolerance. Successful completion of these studies would identify particles that are novel, safe, efficient and clinically relevant tools to inhibit antigen-specific T-cells for therapy of autoimmune diseases. This innovative approach has far reaching implications for decreasing specific immune responses in applications such as autoimmune disease, rejection of transplanted cells, and allergies to food antigens or airborne particulates.

 描述：免疫系统对健康细胞的意外破坏会导致组织功能丧失，并使恢复组织功能的策略变得复杂。当前自身免疫性疾病的标准疗法涉及全身免疫抑制，这在大多数情况下在临床上并不有效，并且会导致许多不良副作用。 Stephen Miller 博士（联合 PI）开创了一种方法，其中脾细胞与特定的自身抗原交联，并且将它们递送到脾脏诱导特异性针对自身抗原的耐受性。 抗原。这种方法最近适用于多发性硬化症 (MS) 患者的临床试验，并且是报告诱导抗原特异性耐受性的首次人体研究。然而，在临床领域使用细胞载体进行耐受诱导具有挑战性，因为需要大量的离体实验室操作，这是昂贵的，增加了所需供体细胞的数量，并进一步引入了技术错误的机会。我们的长期目标是开发一种基于颗粒的平台，该平台可以成为一种现成产品，用于诱导对特定抗原的耐受性，从而抑制特定的不需要的免疫反应，同时不改变免疫反应的其余要素。我们已经证明，静脉注射的载有抗原的颗粒可以诱导耐受性，以预防和治疗实验性自身免疫性脑脊髓炎（EAE）（多发性硬化症的小鼠模型）。为了将这项技术推向临床，我们建议扩展这些研究，以解决有关颗粒设计及其作用机制的基本问题，以及有关针对多种抗原和潜在疾病的细胞群的能力的关键问题。具体目标 1 将研究颗粒设计参数并确定静脉注射颗粒能够调节炎症和诱导抗原特异性耐受的细胞机制。我们的结果表明肝脏是参与颗粒耐受诱导的关键部位，这使其与众不同 来自之前对抗原偶联脾细胞的研究。我们建议研究颗粒组成和大小，以区分 i) 载体对免疫细胞极化的影响，ii) 抗原呈递的功效，以及 iii) 颗粒的体内运输。具体目标 2 将确定在幼稚 T 细胞、活化 T 细胞和记忆 T 细胞中诱导和维持 Ag-PLG 耐受性的细胞和分子机制。我们建议测试封装多种肽/蛋白质的颗粒诱导耐受的能力，并检查无反应性和 Tregs 对诱导和维持耐受的单独和组合贡献。成功完成这些研究将鉴定出新颖、安全、高效和 抑制抗原特异性 T 细胞以治疗自身免疫性疾病的临床相关工具。这种创新方法对于减少自身免疫性疾病、移植细胞排斥以及对食物抗原或空气颗粒过敏等应用中的特异性免疫反应具有深远的影响。