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.

总结 慢性和急性（狂欢）饮酒是主要的公共卫生和经济问题 酒精性肝病（ALD）的发展是世界范围内的主要危险因素， 致命且无法治愈的疾病目前没有FDA批准的治疗任何阶段的 ALD强调了批准新治疗方法的迫切需要。 肝星状细胞（HSC）和肝脏巨噬细胞（Kupffer细胞，KC）的活化 代表ALD的关键起始事件，是纤维化和肝损伤发作的核心， 导致肝硬化和肝功能衰竭完全激活的HSC，其致病性地出现在 肝脏慢性重度饮酒后，逃避自然杀伤细胞（NK）的免疫攻击 细胞，驱动纤维化和肝损伤。 在这里，我们试图确定阻断NK抑制性检查点是否可以克服 通过完全激活的HSC的免疫逃避。我们还将测试抗体导向的细胞毒性 （ADCC）作为触发NK攻击和消除活化的KC和浸润的Ly- 6C+单核细胞衍生的巨噬细胞，构成ALD中的平行纤维化枢纽，两者均为 单药治疗和与NK检查点阻断联合治疗。最后，我们审问 NK细胞是否由诱导性多能干细胞（iNK）制造，并被工程化以 表达嵌合CD 16抗体受体，其设计用于引发和敏化NK细胞溶解攻击， 可增强ADCC的治疗效果。 这些研究将阐明ALD的免疫逃避机制，并建立NK细胞 检查点阻断、ADCC和工程化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 床旁临床试验，导致直接的患者受益。