Antigen Loaded Particles for Tolerance Induction

用于耐受诱导的抗原负载颗粒

• 批准号: 8305475
• 负责人: STEPHEN D MILLER
• 金额: $ 50.59万
• 依托单位: NORTHWESTERN UNIVERSITY
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305475
• 关键词: Adverse effects; Allogenic; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apoptotic; Autoantigens; Autoimmune Diseases; Biocompatible; Biocompatible Materials; Biodistribution; Carbodiimides; Cell Transplants; Cell physiology; Cells; Clinical; Clonal Anergy; Clonal Deletion; Complex; Coupled; Data; Dendritic Cells; Elements; Eragrostis; Experimental Autoimmune Encephalomyelitis; FDA approved; Food; Goals; Graft Rejection; Graft Survival; Homing; Hydrophobicity; Hypersensitivity; Image; Immune; Immune Tolerance; Immune response; Immune system; Immunosuppression; Injection of therapeutic agent; Interleukin-10; Intravenous; Laboratories; Lead; Leukocytes; Link; Mediating; Methods; Modeling; Molecular; Multiple Sclerosis; Mus; Particle Size; Particulate; Pathway interactions; Peptides; Phosphatidylserines; Physiologic pulse; Population; Prevention; Proteins; Regenerative Medicine; Regulatory T-Lymphocyte; Relapse; Role; Signal Transduction; Spleen; Splenocyte; System; T cell anergy; T cell response; T cell therapy; T-Cell Activation; T-Lymphocyte; Tissues; To autoantigen; Transgenic Mice; Translations; Transplant Recipients; Vaccines; anergy; base; bench to bedside; cell killing; clinically relevant; copolymer; crosslink; cytokine; density; design; food antigen; functional group; in vivo; innovation; macrophage; novel; particle; physical property; prevent; receptor; receptor internalization; response; scavenger receptor; tool; uptake

DESCRIPTION (provided by applicant): 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 crosslinked with specific autoantigens, and their delivery to the spleen induced tolerance specifically to the autoantigen. 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. In this proposal, we develop particles that target the spleen following intravenous delivery, and would subsequently be internalized by 'tolerogenic' antigen presenting cells to present the antigens without T cell activation thereby inducing tolerance rather than an immune response. Most strategies targeting the immune system focus on inducing a specific immune response (vaccines), whereas this system aims to do the opposite by inducing tolerance to specific antigens. We hypothesize that peptide-linked particles will be internalized by tolerogenic host splendid APCs which subsequently induce immune tolerance through the coordinate induction of T cell energy and activation of regulatory T cells that limit T cell responses. We have selected biocompatible and biodegradable materials whose physical properties can be controlled to influence their distribution, and can be modified with functional groups to promote internalization, target specific APC populations or receptors, and can release bioactive proteins to enhance the tolerogenic response. The following aims will be investigated: Specific Aim 1 will investigate particle design for splenic homing and antigen presentation in tolerance induction. Specific Aim 2 will investigate the innate cellular mechanisms that mediate interactions with antigen-linked particles that lead to tolerance. Specific Aim 3 will investigate mechanisms of particle-initiated inactivation of effectors T cell functions mediating tolerance induction including clonal deletion, energy/immune deviation, and Treg activation. 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 applications in which decreasing specific immune responses could be beneficial, such as the autoimmune diseases, rejection of transplanted cells, and allergies to food antigens or airborne particulates.

描述（由申请人提供）：免疫系统对健康细胞的意外破坏导致组织功能丧失，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，其中脾细胞与特定自身抗原交联，并将其递送到脾脏诱导特异性针对自身抗原的耐受性。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。在该提案中，我们开发了静脉注射后靶向脾脏的颗粒，随后被“耐受性”抗原呈递细胞内化，在不激活 T 细胞的情况下呈递抗原，从而诱导耐受而不是免疫反应。大多数针对免疫系统的策略侧重于诱导特定的免疫反应（疫苗），而该系统的目的是通过诱导对特定抗原的耐受性来达到相反的效果。我们假设肽连接颗粒将被耐受性宿主辉煌 APC 内化，随后通过协调诱导 T 细胞能量和激活限制 T 细胞反应的调节性 T 细胞来诱导免疫耐受。我们选择了生物相容性和可生物降解的材料，其物理特性可以通过控制来影响其分布，并且可以用官能团进行修饰以促进内化，针对特定的APC群体或受体，并且可以释放生物活性蛋白以增强耐受性反应。将研究以下目标： 具体目标 1 将研究耐受诱导中脾归巢和抗原呈递的颗粒设计。具体目标 2 将研究介导与抗原相连的颗粒相互作用从而导致耐受的先天细胞机制。具体目标 3 将研究粒子引发的效应 T 细胞功能失活机制，介导耐受诱导，包括克隆删除、能量/免疫偏差和 Treg 激活。这些研究的成功完成将鉴定出新型、安全、有效且具有临床相关性的颗粒工具来抑制抗原特异性T细胞，从而治疗自身免疫性疾病。这种创新方法对于减少特异性免疫反应可能有益的应用具有深远的影响，例如自身免疫性疾病、移植细胞排斥以及对食物抗原或空气中颗粒物的过敏。