Activation of NK cell-mediated protective immunity for the systemic treatment of ALD

激活 NK 细胞介导的保护性免疫以全身治疗 ALD

• 批准号: 10453261
• 负责人: DOUGLAS Edmund FELDMAN
• 金额: $ 43.52万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-11 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10453261
• 关键词: Acceleration; Acute; Alcohol consumption; Alcoholic Liver Diseases; Alcoholism; Alcohols; Antibodies; Antibody Therapy; Automobile Driving; Blocking Antibodies; Cell-Mediated Cytolysis; Cells; Cessation of life; Chronic; Cirrhosis; Clinical Trials; Combined Modality Therapy; Data; Detection; Development; Disease; Disease Progression; Economics; Engineering; Event; FCGR3B gene; FDA approved; Fc Receptor; Fibrosis; Foundations; Goals; Hepatic Stellate Cell; Immune; Immune Evasion; Immune response; Immunity; Immunologic Surveillance; Immunosuppression; Immunotherapy; In Vitro; Infiltration; Innate Immune System; Kupffer Cells; Link; Liver; Liver Failure; Liver Fibrosis; Lymphocyte; Macrophage; Mediating; NK Cell Activation; Natural Killer Cells; Outcome; Pathogenicity; Patients; Play; Pluripotent Stem Cells; Public Health; Quality of life; Research Proposals; Resistance; Resolution; Risk Factors; Role; Series; Shapes; Signal Transduction; Testing; Therapeutic; Translating; Translations; Treatment Efficacy; United States; adverse outcome; antibody test; bench to bedside; cellular engineering; cytotoxic; design; effective therapy; efficacy evaluation; efficacy testing; fibrogenesis; immune cell infiltrate; immune checkpoint blockade; improved; in vivo; induced pluripotent stem cell; insight; liver function; liver injury; manufacture; monocyte; mouse model; preclinical study; programs; resistance mechanism; restoration; treatment response; treatment strategy

Summary Chronic and acute (binge) alcohol drinking are major public health and economic problems worldwide and prominent risk factors for the development of alcoholic liver disease (ALD), a lethal and incurable condition. Currently there are no FDA-approved therapies for any stage of ALD, underscoring the urgent need for the approval of new treatments. The activation of hepatic stellate cells (HSC) and liver-resident macrophages (Kupffer cells, KC) represent key initiating events in ALD and are central to the onset of fibrosis and liver injury that results in cirrhosis and liver failure. Fully activated HSC, which emerge pathogenically in the liver following chronic heavy alcohol consumption, evade immune attack by natural killer (NK) cells, driving fibrogenesis and liver injury. Here, we seek to determine whether blockade of NK inhibitory checkpoints can overcome immune evasion by fully activated HSC. We will also test antibody-directed cellular cytotoxicity (ADCC) as an approach to trigger NK attack and elimination of activated KC and infiltrating Ly- 6C+ monocyte-derived macrophages, which constitute a parallel fibrogenic hub in ALD, both as a monotherapy and in combination with NK checkpoint blockade. Finally, we interrogate whether NK cells manufactured from inducible pluripotent stem cells (iNK), and engineered to express a chimeric CD16 antibody receptor designed to prime and sensitize NK cytolytic attack, can potentiate the therapeutic efficacy of ADCC. These studies will illuminate mechanisms of immune evasion in ALD, and establish NK checkpoint blockade, ADCC and engineered iNK cells as potentially breakthrough therapeutic strategies, bringing ALD into the list of diseases that benefit from the revolutionary power of immunotherapy. Insights gained from these studies can be directly translated from bench to bedside into clinical trials, leading to direct patient benefit.

概括 慢性和急性（暴饮）饮酒是主要的公共卫生和经济问题 在世界范围内，酒精性肝病（ALD）的发展的突出危险因素， 致命且无法治愈的情况。目前尚无 FDA 批准的针对任何阶段的治疗方法 ALD，强调了批准新疗法的迫切需要。 肝星状细胞 (HSC) 和肝脏巨噬细胞（库普弗细胞，KC）的激活 代表 ALD 的关键起始事件，并且是纤维化和肝损伤发生的核心， 导致肝硬化和肝功能衰竭。完全激活的 HSC，在致病性中出现 长期大量饮酒后的肝脏，逃避自然杀手（NK）的免疫攻击 细胞，驱动纤维形成和肝损伤。 在这里，我们试图确定 NK 抑制检查点的封锁是否可以克服 通过完全激活的 HSC 来逃避免疫。我们还将测试抗体定向的细胞毒性 (ADCC) 作为触发 NK 攻击并消除激活的 KC 和渗透 Ly-的方法 6C+ 单核细胞衍生的巨噬细胞，构成 ALD 中平行的纤维形成中心，两者都是 单一疗法并与 NK 检查点阻断相结合。最后，我们追问 NK 细胞是否由诱导性多能干细胞 (iNK) 制造，并经过改造 表达嵌合 CD16 抗体受体，旨在引发和敏化 NK 溶细胞攻击， 可以增强 ADCC 的治疗效果。 这些研究将阐明 ALD 中的免疫逃避机制，并建立 NK 检查点封锁、ADCC 和工程 iNK 细胞作为潜在的突破性治疗 战略，将 ALD 纳入受益于革命性力量的疾病清单 免疫疗法。从这些研究中获得的见解可以直接从实验室转化为 床旁进行临床试验，为患者带来直接利益。