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

点击翻译按钮获取中文摘要

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.