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

项目总结 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 由于病毒/细菌感染(如新冠肺炎)、创伤、脓毒症、 肺炎，或输血。ALI/ARDS在美国仍然是一个严重的健康负担， 发病率和死亡率(30-40%)。过去的干预研究主要集中在早期阶段。 支持性护理，如通风，作用有限。尽管进行了几次调查，但没有有效的 治疗ALI/ARDS有药物治疗方法。从机制上讲，ALI/ARDS是由长期的 巨噬细胞的持久激活和中性粒细胞的渗透是由于其表型向亲 炎症状态。在没有ALI的情况下，肺泡巨噬细胞(AMɸ)主要存在于抗炎中 表型，协助构建过程。一旦感觉到病原体，AMɸ就会表现出促炎作用 分泌高水平促炎细胞因子的表型，可导致不受控制的细胞因子 暴风雨。我们假设急性肺部炎症可以通过重新编程巨噬细胞来解决。 通过新的药物疗法有效治疗ALI。在这个假设的驱动下，这个项目的目标是 设计一种创新的基于巨噬细胞的药物疗法(MARE)，用于ALI的靶向免疫调节。 肉类整合巨噬细胞对ALI免疫环境的炎症靶向和治疗能力 调制。肉是由包裹着一种生物材料的巨噬细胞组成的，这种生物材料携带着一对协同作用 在巨噬细胞和中性粒细胞抗炎程序中发挥强大作用的细胞因子 表型。已经计划了两个独立的具体目标。在目标1中，我们将开发、优化和 能够将巨噬细胞和中性粒细胞编程为抗炎表型的肉类 在试管中。在这个目标中，我们将确定最佳的集中度、比率和时间要求 IL-4和IL-10结合以编程巨噬细胞和中性粒细胞。然后我们将组装和优化 肉类概括了这些在体外对巨噬细胞和中性粒细胞调节的最佳要求。在目标2中， 我们将评估肉类在解决急性炎症和ALI方面的疗效。为了实现这一目标，我们将 在临床前期小鼠模型中评估肉类向肺组织输送协同细胞因子的能力 ALI，以及ii)肉在调节发炎的肺部免疫环境方面的表现。最终， 我们将研究肉类在减轻ALI和恢复正常肺功能方面的疗效。《少年派》 (早期调查员)已经组建了一个具有互补专业知识的团队来实施这一项目。如果 成功，肉类将革命性地改变ALI的治疗方式，并通过解锁打开临床研究的新领域 ALI细胞免疫疗法未实现的应用。

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.