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.

摘要 慢性和急性(酗酒)是主要的公共健康和经济问题 酒精性肝病(ALD)发展的世界性和突出的危险因素， 致命的不治之症。目前还没有FDA批准的任何阶段的治疗方法 ALD，强调迫切需要批准新的治疗方法。 肝星状细胞(HSC)和驻肝巨噬细胞(Kupffer cell，KC)的激活 代表ALD中的关键启动事件，是肝纤维化和肝损伤发生的核心 导致肝硬变和肝功能衰竭。完全激活的HSC，在病理性地出现在 长期大量饮酒后的肝脏，逃避自然杀手(NK)的免疫攻击 细胞，导致肝纤维化和肝损伤。 在这里，我们试图确定NK抑制检查点的封锁是否可以克服 完全激活的HSC的免疫逃逸。我们还将测试抗体导向的细胞毒性。 (ADCC)作为一种触发NK攻击和消除激活的KC和浸润性Ly- 6C+单核细胞来源的巨噬细胞，它们构成了ALD中平行的纤维化中心，两者都是 单一疗法，并联合NK检查站封锁。最后，我们审问 NK细胞是否由可诱导的多能干细胞(墨水)制造，并经工程处理以 表达一种嵌合的CD16抗体受体，旨在启动和敏化NK细胞溶解攻击， 可增强ADCC的治疗效果。 这些研究将阐明ALD的免疫逃逸机制，并建立NK 检查点封锁、ADCC和工程墨水细胞作为潜在的突破性治疗 战略，将阿尔茨海默病列入受益于 免疫疗法。从这些研究中获得的见解可以直接从BASE转化为 在床边进行临床试验，直接造福于患者。