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Particle-Assisted Control over Macrophage-Neutrophil interactions (Pac-Man)

巨噬细胞-中性粒细胞相互作用的粒子辅助控制（吃豆人）

基本信息

批准号：
10725989
负责人：
Kara Lorraine Spiller
金额：
$ 20万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10725989
关键词：
Address Adoptive Cell Transfers Adoptive Transfer Allogenic Anti-Inflammatory Agents Apoptotic Autologous Behavior Biocompatible Materials Cell Therapy Cells Cues Data Dexamethasone Disease Dose Drug Delivery Systems Fibrosis Flow Cytometry Gene Expression Profiling Generations Goals Histology Human Immune Immune response In Situ In Vitro Inflammation Inflammatory Injury Knowledge Macrophage Mechanics Mediating Mediator Mus Muscle Patients Pharmaceutical Preparations Phenotype Prevention Process Proliferating Punch Biopsy Regulatory T-Lymphocyte Series Site Skeletal Muscle Source T-Cell Activation T-Lymphocyte Testing Therapeutic Time Tissues Trauma biodegradable polymer cell type high reward high risk improved in vitro testing in vivo in vivo Model innovation limb loss manufacturing cost mouse model neutrophil novel strategies particle prevent quadriceps muscle regenerative repair model repaired response satellite cell tissue repair uptake volumetric muscle loss wound healing

项目摘要

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.

项目总结