Combinatorial cytokine-coated macrophages for targeted immunomodulation in acute lung injury

组合细胞因子包被的巨噬细胞用于急性肺损伤的靶向免疫调节

• 批准号: 10648387
• 负责人: Zongmin Zhao
• 金额: $ 19.29万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10648387
• 关键词: Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Alveolar Macrophages; Animals; Anti-Inflammatory Agents; Area; Bacterial Infections; Biocompatible Materials; Biodistribution; Biological Assay; COVID-19; COVID-19 mortality; COVID-19 patient; Cause of Death; Cell Therapy; Cells; Cellular immunotherapy; Clinical Research; Data; Dependence; Diagnosis; Disease; Dose; Drug Kinetics; Engineering; Environment; Failure; Foundations; Goals; Health; Health Care Costs; Hospitalization; IL4 gene; Immune; Immunotherapy; In Vitro; Incidence; Inflammation; Inflammatory; Interleukin-10; Interleukin-4; Intervention; Intervention Studies; Investigation; Life; Lung; Macrophage; Macrophage Activation; Measures; Modeling; Morbidity - disease rate; Neutrophil Infiltration; Onset of illness; Pathway interactions; Patients; Performance; Pharmacotherapy; Phase; Phenotype; Pneumonia; Population; Process; Pulmonary Inflammation; Research Personnel; Resolution; Sepsis; Site; Standardization; Structure of parenchyma of lung; Supportive care; Symptoms; System; Therapeutic; Therapeutic Intervention; Time; Tissues; Transfusion; Trauma; Treatment Efficacy; United States; Ventilator; Viral; combinatorial; cytokine; cytokine release syndrome; design; effective therapy; efficacy evaluation; efficacy study; follow-up; immunomodulatory strategy; immunomodulatory therapies; immunoregulation; improved; in vivo; innovation; lung injury; monocyte; mortality; mouse model; nano; neutrophil; novel; pandemic disease; pathogen; pharmacologic; pre-clinical; prevent; programs; pulmonary function; targeted treatment; trafficking; ventilation

PROJECT SUMMARY Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), is a life- threatening disease that develops because of viral/bacterial infections (e.g. COVID-19), trauma, sepsis, pneumonia, or transfusion. ALI/ARDS remains a significant health burden in the United States with a high incidence and mortality rate (30-40%). Past interventional studies have mainly centered around early-stage supportive care such as ventilation which has limited utility. Despite several investigations, no effective pharmacological therapy exists for the treatment of ALI/ARDS. Mechanistically, ALI/ARDS is caused by the long- lasting activation of macrophages and infiltration of neutrophils due to their phenotypic shift towards the pro- inflammatory status. In the absence of ALI, alveolar macrophages (AMɸ) exist primarily in the anti-inflammatory phenotype, assisting in constructive processes. Upon sensing pathogens, AMɸ takes on an pro-inflammatory phenotype that secretes high levels of pro-inflammatory cytokines which can lead to an uncontrolled cytokine storm. We hypothesize that the acute pulmonary inflammation can be resolved by reprogramming macrophages by novel pharmacotherapies for effective treatment of ALI. Driven by this hypothesis, the goal of this project is to engineer an innovative macrophage-based pharmacotherapy (MEAT) for targeted immunomodulation in ALI. MEAT integrates macrophages’ inflammation targeting and therapeutic capabilities for ALI immune environment modulation. MEAT is composed of macrophages coated with a biomaterial that carries a pair of synergistic cytokines which can exert potent effects in programing macrophages and neutrophils to the anti-inflammatory phenotype. Two independent specific aims have been planned. In Aim 1, we will develop, optimize, and characterize MEAT capable of programming macrophages and neutrophils toward anti-inflammatory phenotypes in vitro. In this aim, we will determine the concentration-, ratio-, and temporal-requirements for optimal combination of IL-4 and IL-10 to program macrophages and neutrophils. We will then assemble and optimize MEAT to recapitulate these requirements for optimal macrophage and neutrophil modulation in vitro. In Aim 2, we will evaluate the efficacy of MEAT in resolving acute inflammation and thereby ALI. In this aim, we will evaluate i) MEAT’s capability to deliver synergistic cytokines to the lung tissues in the pre-clinical mouse model of ALI, and ii) the performance of MEAT in modulating the immune environment in inflamed lungs. Eventually, we will investigate the therapeutic efficacy of MEAT in alleviating ALI and restore normal lung functions. The PI (Early Stage Investigator) has assembled a team with complementary expertise to conduct this project. If successful, MEAT will revolutionize how ALI is treated and opens a new area for clinical research by unlocking unrealized applications of ALI cellular immunotherapies.

项目摘要 急性肺损伤（ALI）及其严重形式，急性呼吸窘迫综合征（ARDS）是一种生命 由于病毒/细菌感染（例如COVID-19），创伤，败血症， 肺炎或输血。在美国，ALI/ARDS仍然是巨大的健康烧伤 发病率和死亡率（30-40％）。过去的介入研究主要集中在早期 支持性护理，例如有限的通风。尽管进行了几次投资，但没有有效 存在用于治疗ALI/ARDS的药理疗法。从机械上讲，ali/ards是由长期引起的 巨噬细胞的持久激活和中性粒细胞的浸润，因为它们的表型转移向促进 炎症状态。在没有ALI的情况下，肺泡巨噬细胞（AMɸ）在抗炎 表型，有助于建设性过程。感知病原体后，AMɸ进行促炎症 表型可以使高水平的促炎细胞因子介绍可能导致不受控制的细胞因子 风暴。我们假设可以通过重新编程巨噬细胞来解决急性肺部炎症 通过新的药物疗法来有效治疗ALI。在这个假设的驱动下，该项目的目标是 设计基于创新的巨噬细胞药物疗法（肉），以在ALI中进行靶向免疫调节。 肉类整合巨噬细胞的注射靶向和针对ALI免疫环境的治疗能力 调制。肉是由涂有生物材料的巨噬细胞组成的，该生物材料带有一对协同作用 细胞因子可以在编程巨噬细胞和中性粒细胞中对抗炎作用执行潜在影响 表型。计划了两个独立的特定目标。在AIM 1中，我们将开发，优化和 表征能够对巨噬细胞和中性粒细胞编程抗炎表型的肉 体外。在此目标中，我们将确定最佳的浓度，比率和临时要求 IL-4和IL-10组合与中性粒细胞编程。然后，我们将组装和优化 肉类以概括这些要求，以便在体外进行最佳巨噬细胞和中性粒细胞调节。在AIM 2中， 我们将评估肉在解决急性炎症中的效率。在这个目标中，我们将 评估i）肉在临床前鼠标模型中向肺组织传递协同细胞因子的能力 Ali和II）在调节发炎的肺部免疫环境中的肉类性能。最终， 我们将研究肉在减轻ALI并恢复正常肺功能方面的治疗效率。 pi （早期调查员）已经组建了一个具有完善专业知识的团队来进行此项目。如果 成功，肉将彻底改变Ali的治疗方式，并通过解锁开放一个新的临床研究领域 Ali细胞免疫疗法的未实现应用。