Biomaterials to study tolerance immune induction kinetics
研究耐受免疫诱导动力学的生物材料
基本信息
- 批准号:10223121
- 负责人:
- 金额:$ 37.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AbbreviationsAcetalsAcidsAddressAdoptive TransferAffectAftercareAmericanAnimal ModelAnti-Inflammatory AgentsAntibodiesAntigen PresentationAntigen-Presenting CellsAntigensAutoimmuneAutoimmune DiseasesBiocompatible MaterialsBiological ModelsC57BL/6 MouseCD80 geneCardiotoxicityCell CommunicationCell physiologyCellsClinicalCohort EffectCommunicationDataDelayed HypersensitivityDendritic CellsDevelopmentDexamethasoneDextransDiseaseDoseEncapsulatedEngineeringEvaluationExperimental Autoimmune EncephalomyelitisExperimental ModelsFOXP3 geneFormulationGenerationsGlycolatesGoalsHepatotoxicityHourIL2RA geneITGAM geneITGAX geneImmuneImmune ToleranceImmunologicsImmunologistImmunosuppressionIn VitroInfectionInflammationInterferon Type IIInterferonsInterleukin-10KineticsLipopolysaccharidesMajor Histocompatibility ComplexMalignant NeoplasmsMeasuresMediatingMethodsModelingMolecular Sieve ChromatographyMultiple SclerosisMusMyelin Basic ProteinsOnset of illnessOvalbuminParticle SizeParticulatePathogenesisPeptidesPeriodicityPhagocytesPhagolysosomePhagosomesPharmaceutical PreparationsPolyestersPolymersProteinsProteolipidsPublishingReadingRegulatory T-LymphocyteRelapseResearchResearch PersonnelRiskRoleSignal TransductionSirolimusSpleenSplenocyteSystemT cell responseT-LymphocyteT-Lymphocyte SubsetsTechnologyTimeTransforming Growth FactorsVaccinesWorkattenuationbiodegradable polymercentral nervous system demyelinating disorderclinically relevantcytokinedesigneffector T cellexperimental studyimmunological synapsein vivomacrophagemouse modelmultiple sclerosis treatmentnanonanoparticleoligodendrocyte-myelin glycoproteinparticleresponseside effect
项目摘要
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.
摘要
我们计划探索免疫突触的动力学,因为它与耐受的产生有关,使用
由聚合物缩醛化葡聚糖(Ac-DEX)制造的纳米/微米颗粒(Ps)。此前,我们已经展示了
用包封髓磷脂碱性蛋白(MBP)的Ac-DEX颗粒治疗减轻临床评分,
地塞米松(DXM),使用实验性自身免疫性脑脊髓炎(EAE)的C57 B1/6小鼠模型。
我们继续这项研究,并说明Ac-DEX颗粒包封蛋白脂质蛋白(PLP)和
雷帕霉素(Rapa)在EAE的SJL复发和缓解模型中完全降低临床评分至基线水平
在发病后服用。这两种EAE模型的临床评分降低程度均为
Ac-DEX颗粒系统比在其他公开的抗原特异性EAE治疗中观察到的更大,
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对于将药剂递送至吞噬细胞是理想的,因为它是酸敏感的并且具有显著的细胞毒性。
在吞噬体的低酸(~pH 5)中的降解增加。除此之外,它还具有可调的降解能力,
速率的范围可以从数小时到数月,这是与常用聚酯(例如,
聚(乳酸-共-乙醇酸)(PLGA)),其具有数月量级的降解。此外,Ac-DEX是独一无二的
因为其降解产物是pH中性的,并且不具有改变局部
pH值或损伤敏感有效载荷。我们已经表明,Ac-DEX颗粒的降解速率影响两者
传统疫苗的抗体和细胞应答,并假设产生耐受性的类似效果。
因此,我们假设Ac-DEX颗粒通过诱导TcR来促进抗原特异性免疫耐受,
Ac-DEX的环缩醛覆盖影响降解速率并调节免疫突触。我们
有三个具体的目标来解决这个假设。目标1集中于聚合物和颗粒的配制。
MS代表性抗原以及模型抗原OVA都将被包封。粒子参数
将确定类似的尺寸和负载。将制备具有各种环状缩醛覆盖率的Ac-DEX聚合物
在很宽的时间范围内降解。目的2侧重于体外和体内研究,以了解免疫
以及它与粒子降解时间的关系。评估的指标将是
诱导型调节性T细胞(iT细胞)。此外,我们将使用迟发型超敏反应优化系统,
(DTH)炎症模型。颗粒降解和公差产生之间的关系将是
优化在目标3中,还将在MS模型和TdR表达中评价优化的制剂,
因为将进行其它免疫学表征。这项工作的总体目标是评估AC-
DEX颗粒系统作为MS的抗原特异性治疗,并了解
耐受剂(例如抗原和Rapa)对抗原特异性免疫耐受产生的影响。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Kristy M Ainslie其他文献
Kristy M Ainslie的其他文献
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{{ truncateString('Kristy M Ainslie', 18)}}的其他基金
Mechanistic evaluation of mast cell agonists combined with TLR, NOD and STING agonists.
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