Biomaterials to study tolerance immune induction kinetics

研究耐受免疫诱导动力学的生物材料

• 批准号: 10458635
• 负责人: Kristy M Ainslie
• 金额: $ 37.66万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-14 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458635
• 关键词: Abbreviations; Acetals; Acids; Address; Adoptive Transfer; Affect; Aftercare; American; Animal Model; Anti-Inflammatory Agents; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens; Autoimmune; Autoimmune Diseases; Biocompatible Materials; Biological Models; C57BL/6 Mouse; CD80 gene; Cardiotoxicity; Cell Communication; Cell physiology; Cells; Clinical; Cohort Effect; Communication; Data; Delayed Hypersensitivity; Dendritic Cells; Development; Dexamethasone; Dextrans; Disease; Dose; Encapsulated; Engineering; Evaluation; Experimental Autoimmune Encephalomyelitis; Experimental Models; FOXP3 gene; Formulation; Generations; Glycolates; Goals; Hepatotoxicity; Hour; IL2RA gene; ITGAM gene; ITGAX gene; Immune; Immune Tolerance; Immunologics; Immunologist; Immunosuppression; In Vitro; Infection; Inflammation; Interferon Type II; Interferons; Interleukin-10; Kinetics; Lipopolysaccharides; Major Histocompatibility Complex; Malignant Neoplasms; Measures; Mediating; Methods; Modeling; Molecular Sieve Chromatography; Multiple Sclerosis; Mus; Myelin Basic Proteins; Onset of illness; Ovalbumin; Particle Size; Particulate; Pathogenesis; Peptides; Periodicity; Phagocytes; Phagolysosome; Phagosomes; Pharmaceutical Preparations; Polyesters; Polymers; Proteins; Proteolipids; Publishing; Reading; Regulatory T-Lymphocyte; Relapse; Research; Research Personnel; Risk; Role; Signal Transduction; Sirolimus; Spleen; Splenocyte; System; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Time; Transforming Growth Factors; Vaccines; Work; attenuation; biodegradable polymer; central nervous system demyelinating disorder; clinically relevant; cytokine; design; effector T cell; experimental study; immunological synapse; in vivo; macrophage; mouse model; multiple sclerosis treatment; nano; nanoparticle; oligodendrocyte-myelin glycoprotein; particle; response; side effect

ABSTRACT We plan to explore the kinetics of the immune synapse, as it relates to generation of tolerance, using nano/microparticles (Ps) fabricated from the polymer acetalated dextran (Ac-DEX). Previously, we have shown attenuation of clinical score with treatment of Ac-DEX particles encapsulating myelin basic protein (MBP) and dexamethasone (DXM), using a C57Bl/6 mouse model of experimental autoimmune encephalomyelitis (EAE). We continued this research and illustrated that Ac-DEX particles encapsulating proteolipid protein (PLP) and rapamycin (Rapa) in a SJL relapse and remitting model of EAE completely reduced clinical score to baseline when given after disease onset. The degree of reduction of clinical score for both of these EAE models was greater for the Ac-DEX particles systems than observed in other published antigen-specific EAE treatments that used particle systems. Our particle system is unique because it relies on the highly tunable polymer Ac-DEX. Ac-DEX is ideal for delivery of agents to phagocytic cells because it is acid-sensitive and has significantly increased degradation in the low acid (~pH 5) of the phagosome. In addition to this it has tunable degradation rates that can range from hours to months, which is a unique range from commonly used polyesters (e.g. poly(lactic-co-glycolic acid) (PLGA)) that have degradation on the order of months. Moreover, Ac-DEX is unique from polyesters because its degradation products are pH neutral, and do not have the potential to shift the local pH or damage sensitive payloads. We have shown that Ac-DEX particles have degradation rates that affect both antibody and cellular response for traditional vaccine and hypothesize similar effects for generation of tolerance. Therefore, we hypothesize that Ac-DEX particles promote antigen specific immune tolerance by inducing Tregs and that the cyclic acetal coverage of Ac-DEX impact degradation rate and modulate the immune synapse. We have three specific aims to address this hypothesis. Aim 1 is focused on formulation of the polymer and particles. Both a MS representative antigen as well as the model antigen OVA will be encapsulated. Particle parameters like size and loading will be determined. Ac-DEX polymer with various cyclic acetal coverages will be fabricated to degrade over a broad range of times. Aim 2 focuses on in vitro and in vivo studies to understand the immune synapse and how that relates to particle degradation times. The metrics for evaluation will be generation of inducible T-regulatory cells (iTregs). Furthermore, we will optimize systems using a delayed type hypersensitivity (DTH) model of inflammation. The relationship between particle degradation and generation of tolerance will be optimized. In Aim 3, the optimized formulation will be evaluated in a model of MS and expression of Tregs, as well as other immunological characterizations will be carried out. The overall goal of this work is to evaluate the Ac- DEX particles systems as an antigen-specific treatment for MS and to understand the influence of release of tolerance agents (e.g. antigen and Rapa) on the generation of antigen specific immune tolerance.

抽象的 我们计划探索免疫突触的动力学，因为它与耐受性有关 纳米/微粒（PS）由聚合物乙酰化葡萄糖（AC-DEX）制造。以前，我们已经表明 临床评分的衰减，用于封装髓磷脂碱性蛋白（MBP）和 地塞米松（DXM），使用实验性自身免疫性脑脊髓炎（EAE）的C57BL/6小鼠模型。 我们继续进行这项研究，并说明了封装蛋白质蛋白（PLP）和 雷帕霉素（RAPA）在SJL复发中，EAE的汇出模型将临床评分完全降低至基线 当疾病发作后。这两种EAE模型的临床评分降低程度是 在其他已发表的抗原特异性EAE治疗中，AC-脱核颗粒系统比观察到的要大得多 用过的粒子系统。我们的粒子系统是独一无二的，因为它依赖于高度可调的聚合物AC-DEX。 AC-DEX非常适合向吞噬细胞递送剂，因为它具有酸敏感，并且具有显着的 吞噬体的低酸（〜pH 5）降解增加。除此之外，它还具有可调的降解 从小时到几个月的速率，这是一个独特的范围，从常用的聚酯（例如 在几个月内降解的聚（乳酸 - 乙醇酸））。而且，AC-DEX是独一无二的 从polyesters出发，因为它的降解产物是pH中性的，并且没有可能移动局部的潜力 pH或伤害敏感有效载荷。我们已经表明，AC-脱位颗粒的降解速率都会影响这两者 传统疫苗的抗体和细胞反应，假设对耐受性产生的相似作用相似。 因此，我们假设AC-DEX颗粒通过诱导Treg促进抗原特异性免疫耐受性 并且AC-DEX的环状乙酰覆盖效果降解率并调节免疫突触。我们 有三个特定的目的来解决这一假设。 AIM 1专注于聚合物和颗粒的配方。 MS代表性抗原和模型抗原OVA都将封装。粒子参数 将确定大小和加载。将制造具有各种环状乙酰覆盖范围的AC-DEX聚合物 在广泛的次数中退化。 AIM 2专注于体外和体内研究以了解免疫 突触及其与粒子降解时间的关系。评估的指标将产生 可诱导的T调节细胞（ITREGS）。此外，我们将使用延迟类型高敏性优化系统 （DTH）炎症模型。粒子降解与耐受性产生之间的关系将是 优化。在AIM 3中，还将在MS的模型和Tregs的表达中评估优化的公式 将进行其他免疫学特征。这项工作的总体目标是评估AC- DEX颗粒系统作为MS的抗原特异性处理，并了解释放的影响 对抗原特异性免疫耐受性产生的耐受性剂（例如抗原和Rapa）。