Synthetic Nanoparticle-antibody (SNAb) Based Depletion of Myeloid-Derived Suppressor Cells for TB Host-Directed Therapy

基于合成纳米颗粒抗体 (SNAb) 的骨髓源性抑制细胞耗竭，用于结核宿主定向治疗

• 批准号: 10673996
• 负责人: KRISHNENDU ROY
• 金额: $ 86.75万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-05 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673996
• 关键词: Activities of Daily Living; Antibiotic Therapy; Antibiotics; Antibodies; Antimycobacterial Agents; Antitubercular Agents; Antitubercular Antibiotics; Area; C3HeB/FeJ Mouse; CD8B1 gene; Cell physiology; Cells; Cytotoxic T-Lymphocytes; Data; Dioxygenases; Disease; Disease Progression; Drug resistance in tuberculosis; Equilibrium; Genetic Predisposition to Disease; HIV/TB; Immune; Immune Targeting; Immune response; Immunity; Immunology; Immunosuppression; Inflammation Mediators; Innate Immune Response; Lung; Macrophage; Malignant Neoplasms; Mediating; Mediator; Monitor; Monoclonal Antibodies; Mus; Mycobacterium tuberculosis; Myeloid Cells; Myeloid-derived suppressor cells; Natural Killer Cells; Nitric Oxide Synthase; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Persons; Population; Pulmonary Pathology; Reagent; Regulatory T-Lymphocyte; Relapse; Research; Resistance; Role; S100A8 gene; Structure of parenchyma of lung; T-Lymphocyte; Testing; Therapeutic; Time; Treatment Efficacy; Treatment Protocols; Tuberculosis; Work; adaptive immune response; arginase; cancer immunotherapy; immune function; immunoengineering; immunomodulatory therapies; immunopathology; improved; innovation; insight; mycobacterial; nanoparticle; nanotherapeutic; novel; novel therapeutics; prevent; pulmonary granuloma; recruit; response; small molecule inhibitor; targeted treatment; tool; tuberculosis immunity; tuberculosis treatment; tumor microenvironment

ABSTRACT In patients with tuberculosis (TB), detrimental immune responses to Mycobacterium tuberculosis (Mtb) infection dominate over beneficial immunity, resulting in uncontrolled Mtb replication, lung granulomas and progression to TB disease. Immunosuppressive pathways induced by Mtb promote lung pathology and tissue damage and prevent protective immune responses. This suboptimal lung microenvironment can also interfere with antibiotic- mediated killing of Mtb. Therefore, in-depth understanding of immunosuppressive mechanisms during TB is critical for developing novel immunomodulatory therapies that tip the balance away from pathogenic responses and towards protective immunity and better bacterial clearance. Thus, host-directed therapies (HDT) that target immunosuppressive pathways in conjunction with anti-TB antibiotics have the potential to improve TB treatment. Recent studies show that a population of immature myeloid cells that are recruited to the lung after Mtb infection contribute to immunosuppression during TB. These cells, termed myeloid-derived suppressor cells (MDSCs), were first described in cancer as negatively regulating tumor microenvironments and suppressing NK cell and T cell cytotoxic functions. Interestingly, accumulation of MDSCs correlates with TB disease pathology and these cells can also harbor Mtb intracellularly. However, in contrast to cancer, the functions of MDSCs in TB are poorly understood. We hypothesize that MDSCs prevent beneficial innate and adaptive immune responses to Mtb infection by suppressing T cell, NK cell and macrophage functions. We further hypothesize that depleting MDSCs in Mtb-infected mice will enhance immune responses to Mtb in the lung and significantly improve TB treatment efficacy. We have developed a versatile and effective approach to deplete MDSCs in the lung via novel multivalent synthetic nanoparticle antibodies (SNAbs) that specifically target and deplete MDSCs through antibody-like killing mechanisms. In this MPI-R01 application, we combine expertise in TB pathogenesis and immunology research (Rengarajan, Emory) with expertise in immuno-engineering and nanotherapeutics (Roy, Georgia-Tech) to investigate the role of MDSCs in TB disease progression and pathology, and regulating immunity to TB, and to explore MDSCs as targets of HDT for TB. We will investigate the following Specific Aims: Aim 1. Evaluate how depleting MDSCs using SNAbs impacts TB disease progression. Aim 2. Investigate how MDSCs suppress immune responses to Mtb infection. Aim 3. Test the hypothesis that depletion of MDSCs will enhance the efficacy of anti-TB treatment. Together, these studies will advance our understanding of how MDSCs suppress immunity to TB and provide insights into MDSCs as targets for adjunctive HDTs.

摘要 在结核病（TB）患者中，对结核分枝杆菌（Mtb）感染的有害免疫应答 控制有益免疫，导致不受控制的Mtb复制，肺肉芽肿和进展 结核病。由Mtb诱导的免疫抑制途径促进肺病理学和组织损伤， 防止保护性免疫反应。这种次优的肺部微环境也会干扰抗生素- 介导的Mtb杀伤。因此，深入了解结核病期间的免疫抑制机制， 对于开发新型免疫调节疗法至关重要， 以及保护性免疫和更好的细菌清除。因此，靶向宿主的治疗（HDT） 免疫抑制途径与抗结核抗生素结合具有改善结核治疗的潜力。 最近的研究表明，结核分枝杆菌感染后招募到肺部的未成熟髓系细胞群 有助于结核病期间的免疫抑制。这些细胞被称为髓源性抑制细胞（MDSC）， 在癌症中首次被描述为负调节肿瘤微环境并抑制NK细胞和T细胞 细胞毒性功能。有趣的是，MDSC的积累与TB疾病病理学相关，并且这些 细胞也可以在细胞内携带Mtb。然而，与癌症相比，结核病中MDSC的功能较差 明白我们假设MDSC阻止了对结核分枝杆菌的有益的先天性和适应性免疫应答， 通过抑制T细胞、NK细胞和巨噬细胞功能来感染。我们进一步假设， 将增强肺部对Mtb的免疫反应，并显着改善结核病治疗 功效 我们已经开发了一种通用的和有效的方法，通过新的多价的MDSC消耗肺中的MDSC。 合成纳米颗粒抗体（SNAb），其通过抗体样作用特异性靶向并消耗MDSC， 杀人机制在这个MPI-R 01应用中，我们联合收割机结合了结核病发病机理和免疫学方面的专业知识 研究（Rengarajan，Emory），具有免疫工程和纳米治疗学方面的专业知识（Roy，Georgia-Tech） 研究MDSC在TB疾病进展和病理学中的作用，以及调节对TB的免疫， 探索MDSC作为结核病HDT靶点。我们将研究以下具体目标：目标1。评价 使用SNAb耗竭MDSC如何影响TB疾病进展。目标二。研究MDSC如何抑制 对Mtb感染的免疫反应。目标3.检验MDSC的耗竭将增强 抗结核治疗的效果。总之，这些研究将促进我们对MDSC如何抑制 本发明提供了一种抗结核免疫力的新方法，并提供了MDSC作为预防性HDT靶点的见解。