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: 9763439
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763439
• 关键词: Abbreviations; Acetals; Acids; Address; Adoptive Transfer; Affect; Aftercare; American; Animal Model; Anti-inflammatory; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Autoimmune Process; 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，因为它与耐受性的产生有关，使用 由聚合物乙酰化葡聚糖 (Ac-DEX) 制成的纳米/微粒 (Ps)。之前我们已经展示过 封装髓磷脂碱性蛋白 (MBP) 的 Ac-DEX 颗粒治疗可降低临床评分 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。 我们继续这项研究，并阐明了 Ac-DEX 颗粒封装了蛋白脂质蛋白 (PLP) 和 雷帕霉素 (Rapa) 在 EAE SJL 复发和缓解模型中的临床评分完全降低至基线 疾病发作后给予。这两种 EAE 模型的临床评分降低程度为 Ac-DEX 颗粒系统比其他已发表的抗原特异性 EAE 治疗中观察到的效果更大 使用粒子系统。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 是向吞噬细胞递送药剂的理想选择，因为它对酸敏感并且具有显着的 吞噬体在低酸（~pH 5）下降解增加。除此之外，它还具有可调节的衰减 速率范围从几小时到几个月不等，这是与常用聚酯（例如聚酯纤维）不同的独特范围。 聚（乳酸-乙醇酸）（PLGA））的降解时间约为数月。此外，Ac-DEX 是独一无二的 来自聚酯，因为其降解产物的 pH 值为中性，并且没有可能改变局部 pH 值或损坏敏感有效负载。我们已经证明 Ac-DEX 颗粒的降解率会影响 传统疫苗的抗体和细胞反应，并假设产生耐受性的类似效应。 因此，我们假设Ac-DEX颗粒通过诱导Tregs来促进抗原特异性免疫耐受 Ac-DEX 的环状缩醛覆盖会影响降解率并调节免疫突触。我们 有三个具体目标来解决这一假设。目标 1 侧重于聚合物和颗粒的配方。 MS 代表抗原和模型抗原 OVA 都将被封装。粒子参数 尺寸和负载等将被确定。将制造具有各种环状缩醛覆盖率的 Ac-DEX 聚合物 在很长一段时间内降解。目标 2 侧重于体外和体内研究，以了解免疫 突触及其与粒子降解时间的关系。评估指标将生成 诱导性 T 调节细胞 (iTreg)。此外，我们将使用延迟型超敏反应来优化系统 (DTH) 炎症模型。颗粒降解与耐受性产生之间的关系为 优化。在目标 3 中，优化的配方将在 MS 模型和 Tregs 表达中进行评估 将进行其他免疫学表征。这项工作的总体目标是评估Ac- DEX 颗粒系统作为多发性硬化症的抗原特异性治疗，并了解释放的影响 耐受剂（例如抗原和Rapa）对抗原特异性免疫耐受的产生。