Antigen Loaded Particles for Tolerance Induction

用于耐受诱导的抗原负载颗粒

基本信息

批准号：
8200645
负责人：
STEPHEN D MILLER
金额：
$ 50.69万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
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/8200645
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 Therapy 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 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

项目摘要

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. PUBLIC HEALTH RELEVANCE: In autoimmune diseases, such as multiple sclerosis, the immune system attacks healthy cells resulting in the loss of tissue function, and also complicates strategies to restore cells that could provide that function. We propose to develop biodegradable, biocompatible particles that can induce tolerance and thereby specifically prevent the attack by cells of the immune system. 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 in regenerative medicine, 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不期望破坏导致组织功能的丧失，并使恢复组织功能的策略变得复杂。当前对自身免疫性疾病的标准疗法涉及普遍的免疫抑制，在大多数情况下，这不是临床上有效的，并且会导致许多不希望的副作用。斯蒂芬·米勒（Stephen Miller）博士（Co-Pi）开创了一种方法，其中将脾细胞与特定的自动抗原交联，并将其递送到脾脏引起的耐受性，专门针对自动抗原。由于所需的大量前体实验室操作，临床领域的耐受性诱导的使用是具有挑战性的，这很昂贵，这增加了所需的供体细胞数量，并引入了进一步的技术错误机会。我们的长期目标是开发一个基于粒子的平台，该平台可能是诱导特定抗原的耐受性以抑制特定不需要的免疫反应的同时不改变免疫反应的其余元素的耐受性。在此提案中，我们会开发出静脉输送后针对脾脏的颗粒，随后将通过“耐受性”抗原呈现细胞内化，以呈现抗原而无需T细胞激活，从而诱导耐受性而不是免疫反应。针对免疫系统的大多数策略都集中在诱导特定的免疫反应（疫苗）上，而该系统的目的是通过诱导对特定抗原的耐受性来相反。我们假设肽连接的颗粒将通过耐受性宿主出色的APC进行内部化，从而通过T细胞能量的坐标诱导和限制T细胞反应的调节性T细胞的激活来诱导免疫耐受性。我们选择了可以控制其物理性能以影响其分布的生物相容性和可生物降解的材料，并且可以通过功能组进行修饰以促进内在化，靶向特定的APC种群或受体，并可以释放生物活性蛋白以增强耐受性反应。将研究以下目的：具体目标1将研究以耐受性诱导中脾归巢和抗原表现的颗粒设计。具体目标2将研究介导与抗原连接颗粒相互作用的先天细胞机制，从而导致耐受性。具体目标3将研究颗粒引起的效应子灭活的机理T细胞功能，介导耐受性诱导，包括克隆缺失，能量/免疫偏差和Treg激活。这些研究的成功完成将确定新型，安全，有效且临床上相关的颗粒，以抑制抗原特异性T细胞以治疗自身免疫性疾病。这种创新的方法对应用具有降低特定免疫反应可能是有益的应用具有很大的影响，例如自身免疫性疾病，对移植细胞的排斥以及对食物抗原或空气寄生颗粒物的过敏。公共卫生相关性：在自身免疫性疾病中，例如多发性硬化症，免疫系统会攻击健康的细胞，从而导致组织功能的丧失，并使恢复可以提供该功能的细胞的策略复杂化。我们建议开发可生物降解的生物相容性颗粒，以诱导公差，从而特别防止免疫系统细胞的攻击。这种创新的方法对降低特定免疫反应可能是有益的应用具有很大的影响，例如自身免疫性疾病，在再生医学中对移植细胞的排斥以及对食物抗原或空中颗粒物的过敏。