Particle-Assisted Control over Macrophage-Neutrophil interactions (Pac-Man)
Particle-Assisted Control over Macrophage-Neutrophil interactions (Pac-Man)
批准号:
10725989
负责人:
Kara Lorraine Spiller
金额:
$20.0万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-07-01 至 2025-05-31
关键词:
AddressAdoptive Cell TransfersAdoptive TransferAllogenicAnti-Inflammatory AgentsApoptoticAutologousBehaviorBiocompatible MaterialsCell TherapyCellsCuesDataDexamethasoneDiseaseDoseDrug Delivery SystemsFibrosisFlow CytometryGene Expression ProfilingGenerationsGoalsHistologyHumanImmuneImmune responseIn SituIn VitroInflammationInflammatoryInjuryKnowledgeMacrophageMechanicsMediatingMediatorMusMusclePatientsPharmaceutical PreparationsPhenotypePreventionProcessProliferatingPunch BiopsyRegulatory T-LymphocyteSeriesSiteSkeletal MuscleSourceT-Cell ActivationT-LymphocyteTestingTherapeuticTimeTissuesTraumabiodegradable polymercell typehigh rewardhigh riskimprovedin vitro testingin vivoin vivo Modelinnovationlimb lossmanufacturing costmouse modelneutrophilnovel strategiesparticlepreventquadriceps muscleregenerativerepair modelrepairedresponsesatellite celltissue repairuptakevolumetric muscle losswound healing
中文摘要
项目摘要
容积性肌肉丧失(VML)是一种由于创伤或疾病对骨骼肌造成的衰弱损伤
导致丧失能力的纤维化和肢体功能丧失。我们和其他人已经确认了延迟的通关
凋亡的中性粒细胞通过对卫星细胞和巨噬细胞的有害作用成为纤维化的主要介导者
行为。因为巨噬细胞是伤口愈合的关键调节细胞,也是清除
中性粒细胞凋亡巨噬细胞疗法是一种很有前途的治疗方法
方法,但受到两个主要挑战的限制:1)巨噬细胞是高度可塑性的细胞,快速转移
对微环境提示作出反应的表型。因此,需要一种策略来控制它们的表型。
在给药后的原位,以防止它们对促炎信号做出反应而改变表型
在受伤的地方。2)高昂的制造成本和监管障碍阻碍了自体(患者-
来源)巨噬细胞,特别是因为需要非常高的数量,但同种异体(供体来源)
巨噬细胞可诱导强烈的T细胞介导的不良免疫反应。我们开发了一种创新的
生物材料介导的巨噬细胞治疗策略,同时应对这两个挑战。
在这个策略中,被称为巨噬细胞-中性粒细胞相互作用的粒子辅助控制(Pac-Man),
巨噬细胞首先在体外被装载有聚合物可生物降解的微粒,这些微粒会缓慢释放
地塞米松细胞内,从而从内到外控制巨噬细胞表型
对受伤部位进行管理。地塞米松之所以被选为地塞米松是因为它能产生抗炎/促炎作用
巨噬细胞的再生表型,增加其对凋亡细胞的吞噬作用,并抑制其
激活T细胞的能力。因此,地塞米松在给药后的细胞内释放
巨噬细胞到损伤部位有望使它们清除有害的中性粒细胞,化解炎症,并
抑制T细胞活化,防止同种异体细胞排斥。在目标1中,细胞的功能表型
过继转移的Pac-Man巨噬细胞将随着时间的推移在体外和体内使用
流式细胞术,基因表达谱,以及它们与凋亡的中性粒细胞的相互作用的分析。对……的影响
肌肉修复将通过组织学和功能机械测试进行评估。在目标2中,使用
一种异基因细胞来源将在体外和体内使用来自混合捐赠者的原代人类免疫细胞进行测试
以及来自不同品系的小鼠。该项目将推进一种创新的现成、翻译细胞疗法,以
增强对凋亡细胞的清除,这将对治疗纤维化损伤具有变革性,如
VML和其他许多人。
英文摘要
Project Summary
Volumetric muscle loss (VML) is a debilitating injury caused by trauma or disease to skeletal muscle that
leads to incapacitating fibrosis and loss of limb function. We and others have identified delayed clearance of
apoptotic neutrophils as a primary mediator of fibrosis via detrimental effects on satellite cell and macrophage
behavior. Because macrophages are critical regulators of wound healing and also the primary cell type that clear
apoptotic neutrophils in a process called efferocytosis, macrophage cell therapy is a promising therapeutic
approach, but is limited by two main challenges: 1) Macrophages are highly plastic cells that rapidly shift
phenotype in response to microenvironmental cues. Therefore, a strategy is needed to control their phenotype
in situ following administration, to prevent them from changing phenotype in response to pro-inflammatory cues
at the site of injury. 2) High manufacturing costs and regulatory hurdles prevent the use of autologous (patient-
derived) macrophages, especially because very high numbers are required, but allogeneic (donor-derived)
macrophages elicit a strong T cell-mediated adverse immune response. We developed an innovative
biomaterial-mediated macrophage cell therapy strategy that simultaneously addresses both of these challenges.
In this strategy, referred to as Particle-Assisted Control over Macrophage-Neutrophil interactions (Pac-Man), the
macrophages are first loaded ex vivo with polymeric biodegradable microparticles that slowly release
dexamethasone intracellularly, thus controlling macrophage phenotype from the inside out following their
administration to sites of injury. Dexamethasone was selected because it causes an anti-inflammatory/pro-
regenerative phenotype in macrophages, increases their efferocytosis of apoptotic cells, and suppresses their
ability to activate T cells. Thus, the intracellular release of dexamethasone following administration of the
macrophages to sites of injury is expected to make them clear detrimental neutrophils, resolve inflammation, and
suppress T cell activation to prevent rejection of allogeneic cells. In Aim 1, the functional phenotype of the
adoptively transferred Pac-Man macrophages will be rigorously characterized over time in vitro and in vivo using
flow cytometry, gene expression profiling, and analysis of their interactions with apoptotic neutrophils. Effects on
muscle repair will be assessed using histology and functional mechanical testing. In Aim 2, the potential to use
an allogeneic cell source will be tested in vitro and in vivo using primary human immune cells from mixed donors
and mice from different strains. This project will advance an innovative off-the-shelf, translational cell therapy to
enhance clearance of apoptotic cells, which would be transformative for the treatment of fibrotic injuries such as
VML and many others.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Inflammation-related gene biomarkers in human diabetic foot ulcer healing
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批准号:10658986
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项目类别:
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资助金额:$46.45万
-
财政年份:2022
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负责人:Kara Lorraine Spiller
-
依托单位:
Immune Modulation & Engineering Symposium
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批准号:10392105
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项目类别:
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资助金额:$1.0万
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财政年份:2020
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负责人:Kara Lorraine Spiller
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依托单位:
Immune Modulation & Engineering Symposium
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批准号:10609295
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项目类别:
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资助金额:$1.6万
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财政年份:2020
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负责人:Kara Lorraine Spiller
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依托单位:
Understanding and Controlling Macrophage Behavior in Angiogenesis
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批准号:9340738
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项目类别:
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资助金额:$5.49万
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财政年份:2017
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负责人:Kara Lorraine Spiller
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依托单位:
Understanding and Controlling Macrophage Behavior in Angiogenesis
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批准号:9002582
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项目类别:
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资助金额:$39.13万
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财政年份:2016
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负责人:Kara Lorraine Spiller
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依托单位:
Understanding and Controlling Macrophage Behavior in Angiogenesis
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批准号:10889772
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项目类别:
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资助金额:$7.74万
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财政年份:2016
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负责人:Kara Lorraine Spiller
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依托单位:
Understanding and Controlling Macrophage Behavior in Angiogenesis
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批准号:10629777
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项目类别:
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资助金额:$7.74万
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财政年份:2016
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负责人:Kara Lorraine Spiller
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依托单位:
Understanding and Controlling Macrophage Behavior in Angiogenesis
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批准号:9198940
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项目类别:
-
资助金额:$39.13万
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财政年份:2016
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负责人:Kara Lorraine Spiller
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依托单位:
Understanding and Controlling Macrophage Behavior in Angiogenesis
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批准号:10296177
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项目类别:
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资助金额:$59.53万
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财政年份:2016
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负责人:Kara Lorraine Spiller
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依托单位:
Understanding and Controlling Macrophage Behavior in Angiogenesis
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批准号:10682565
-
项目类别:
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资助金额:$58.89万
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财政年份:2016
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负责人:Kara Lorraine Spiller
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依托单位:
Understanding and Controlling Macrophage Behavior in Angiogenesis
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批准号:10471405
-
项目类别:
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资助金额:$59.53万
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财政年份:2016
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负责人:Kara Lorraine Spiller
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依托单位: