Delivery of Insulin Peptide, Vitamin D3, TGF-b1 & GM-CSF in Type-1 Diabetes
胰岛素肽、维生素 D3、TGF-b1 的输送
基本信息
- 批准号:8297512
- 负责人:
- 金额:$ 31.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-04-01 至 2017-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAntigen TargetingAntigen-Presenting CellsAntigensAutoantigensAutoimmune DiseasesAutoimmune ResponsesBeta CellBiocompatible MaterialsBiological FactorsBiological ProductsBloodBolus InfusionCell Surface ReceptorsCell surfaceCellsCholecalciferolDataDendritic CellsDevelopmentDiabetes MellitusDoseDrug FormulationsEncapsulatedEndosomesEngineeringEnvironmentGenerationsGoalsGranulocyte-Macrophage Colony-Stimulating FactorHomingITGAX geneImmuneImmune responseImmune systemImmunityImmunosuppressionIn VitroInbred NOD MiceInjectableInjection of therapeutic agentInsulinInsulin-Dependent Diabetes MellitusIntravenousLifeLocationLymphMaintenanceModificationOrganParticle SizeParticulatePatientsPeptidesPhagocytesPharmaceutical PreparationsPharmacologic SubstancePhenotypePopulationPreventionProcessProteinsRecruitment ActivityRegulatory T-LymphocyteResearchShippingShipsSiteSubcutaneous InjectionsSurfaceSystemT cell responseT-LymphocyteTestingTherapeuticTimeTissuesTreatment CostVaccinationVaccinesWorkbasecell typechemokineconditioningcontrolled releaseeconomic impactextracellularin vivoinnovationmonocytenovelparticlepreventreceptorrelease factorresponsetargeted delivery
项目摘要
DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) develops as a result of insufficient insulin being produced due to a self-destructive immune response against insulin producing beta cells. Although a number of factors are known to promote advantageous immune cell responses in experimental systems for T1D, systemic intravenous delivery of these agents often results in significant harmful off-target effects due to the uncontrolled dosing of bystander cells, tissues and organs. This project focuses on the targeted in vivo delivery of pro-tolerance factors and insulin antigen, in particulate form, targeted to a key immune cell type, dendritic cells (DCs). Dendritic cells, critical for maintenance and initiation of immunity to foregn antigens and tolerance to self-antigens, are phagocytic, antigen presenting cells. This makes DCs an ideal recipient for the targeted delivery of agents provided in particulate form. Moreover, exogenous conditioning of DCs with certain immunomodulatory agents has been shown to induce a pro-tolerance DC phenotype as well as ameliorate T1D. Vaccination with DC-targeting microparticles (MPs) holds promise to correct T1D autoimmune responses, critically, without the costly ex vivo manipulations required of DC-based cellular therapy. This enables the potential for widespread use. Micron-sized biodegradable polymeric particles are phagocytosable, which effectively promotes delivery of encapsulated factors to intracellular sites of DCs over non-phagocytes. These phagocytosable particles can be further targeted to DCs by surface immobilizing molecules targeting DC receptors. Larger (but still small enough to be injectable), non-phagocytosable biodegradable polymeric particles provide controlled release of encapsulated factors to the local extracellular environment at the subcutaneous injection site. Encapsulated factors in these large particles consist of bioactive factors for which DCs have the cognate cell-surface receptors. The objective of this proposal is to engineer a subcutaneously injectable dual MP vaccine system consisting of i.) Phagocytosable DC-targeting MPs delivering antigen and immunomodulatory factor (insulin and vitamin D3) to intracellular sites; and ii.) Non-phagocytosable MPs to deliver, extracellular, factors (GM- CSF and TGF-b1) for DC recruitment and tolerance induction. We expect to effect a pro-tolerogenic DC phenotype and promote induction of regulatory T-cells, suppression of auto-reactive T-cells, and prevent and reverse diabetes in non-obese diabetic (NOD) mice. We hypothesize that the combination of the multiple components in the dual MP system will more effectively provide robust, durable antigen-specific immune suppression than single-component formulations, either in MPs or in soluble form. Aim 1 is to formulate the dual MP system, test it in vitro by characterizing DC phenotype (activated, immature or tolerogenic) and T-cell response (stimulation, Th1, Th2, Treg, or Th17). Aim 2 is to evaluate the ability of the dual MP formulation in vivo, aiming to prevent and reverse diabetes in NOD mice. This novel and innovative approach holds promise for correcting autoimmune responses in T1D and represents a simple, clinically translatable system.
描述(由申请人提供):1型糖尿病(T1 D)是由于针对产生胰岛素的β细胞的自毁性免疫反应导致胰岛素产生不足而发生的。尽管已知许多因素在T1 D的实验系统中促进有利的免疫细胞应答,但由于旁观者细胞、组织和器官的不受控制的给药,这些药剂的全身静脉内递送通常导致显著有害的脱靶效应。该项目的重点是在体内靶向递送促耐受因子和胰岛素抗原,以颗粒形式,靶向一种关键的免疫细胞类型,树突状细胞(DC)。树突状细胞是吞噬性的抗原呈递细胞,对维持和启动对外来抗原的免疫以及对自身抗原的耐受性至关重要。这使得DC成为以颗粒形式提供的试剂的靶向递送的理想受体。此外,已显示用某些免疫调节剂对DC进行外源性调节可诱导促耐受DC表型以及改善T1 D。用DC靶向微粒(MP)进行疫苗接种有望纠正T1 D自身免疫反应,关键是,无需基于DC的细胞疗法所需的昂贵的离体操作。这使得广泛使用的潜力。 可生物降解的聚合物颗粒是可吞噬的,这有效地促进了包封因子递送到DC的细胞内位点而不是非吞噬细胞。这些可吞噬颗粒可以通过靶向DC受体的表面固定分子进一步靶向DC。较大(但仍足够小以可注射)的不可吞噬的生物可降解聚合物颗粒在皮下注射部位提供包封因子到局部细胞外环境的受控释放。这些大颗粒中的包封因子由DC具有同源细胞表面受体的生物活性因子组成。本提案的目的是设计一种皮下注射双重MP疫苗系统,该系统由i.)将抗原和免疫调节因子(胰岛素和维生素D3)递送至细胞内位点的可吞噬DC靶向MP;和ii.)非吞噬性MP递送细胞外因子(GM-CSF和TGF-β 1)用于DC募集和耐受诱导。我们期望在非肥胖糖尿病(NOD)小鼠中实现促致耐受性DC表型并促进调节性T细胞的诱导、自身反应性T细胞的抑制以及预防和逆转糖尿病。我们假设,在双重MP系统中的多个组分的组合将比MP或可溶形式的单组分制剂更有效地提供稳健、持久的抗原特异性免疫抑制。目的一是构建MP双元系统,通过表征DC表型(活化的、未成熟的或致耐受性的)和T细胞应答(刺激、Th 1、Th 2、Treg或Th 17)来体外测试MP双元系统。目的2是评价MP双重制剂在体内的能力,旨在预防和逆转NOD小鼠中的糖尿病。这种新颖和创新的方法有望纠正T1 D的自身免疫反应,并代表了一种简单的,临床上可翻译的系统。
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(3)
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Benjamin George Keselowsky其他文献
Benjamin George Keselowsky的其他文献
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