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: 10462723
• 负责人: KRISHNENDU ROY
• 金额: $ 86.12万
• 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/10462723
• 关键词: Activities of Daily Living; Antibiotic Therapy; Antibiotics; Antibodies; 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; HIV; Immune; Immune Targeting; Immune response; Immunity; Immunology; Immunosuppression; Inflammation Mediators; Lung; Malignant Neoplasms; Mediating; Mediator of activation protein; 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; Time; Treatment Efficacy; Treatment Protocols; Tuberculosis; Work; adaptive immune response; arginase; base; cancer immunotherapy; immune function; immunoengineering; immunomodulatory therapies; immunopathology; improved; innovation; insight; macrophage; 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.

抽象的 在结核病（TB）的患者中，对结核分枝杆菌感染的有害免疫反应 主导有益免疫力，导致不受控制的MTB复制，肺肉芽肿和进展 结核病疾病。 MTB诱导的免疫抑制途径促进肺病理和组织损伤，以及 防止保护性免疫反应。这种次优的肺微环境也可以干扰抗生素 介导的MTB杀害。因此，对结核病期间免疫抑制机制的深入了解为 对于开发新型免疫调节疗法至关重要，使平衡远离致病反应 并寻求保护性免疫和更好的细菌清除率。因此，靶向宿主定向疗法（HDT） 与TB抗生素结合使用的免疫抑制途径有可能改善结核病治疗。 最近的研究表明，MTB感染后募集到肺部的未成熟髓样细胞群 在结核病期间有助于免疫抑制。这些细胞称为髓样衍生的抑制细胞（MDSC）， 在癌症中首先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的积累与结核病病理相关，这些相关 细胞还可以在细胞内携带MTB。但是，与癌症相反，MDSC在结核病中的功能很差 理解。我们假设MDSC可以防止对MTB的有益先天和适应性免疫反应 通过抑制T细胞，NK细胞和巨噬细胞功能感染。我们进一步假设耗尽MDSC 在MTB感染的小鼠中，将增强对肺中MTB的免疫反应，并显着改善TB治疗 功效。 我们已经开发了一种多功能有效的方法来通过新颖的多价耗尽肺中的MDSC 合成纳米颗粒抗体（SNABS），这些抗体特异性地靶向MDSC，通过抗体样 杀戮机制。在此MPI-R01应用中，我们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疗法方面的专业知识（Roy，Georgia-Tech） 研究MDSC在结核病疾病进展和病理学中的作用，并调节对结核病的免疫力 探索MDSC作为TB的HDT目标。我们将研究以下具体目标：目标1。评估 使用SNABS耗尽MDSC如何影响结核病疾病进展。目标2。调查MDSC如何抑制 对MTB感染的免疫反应。 AIM 3。检验以下假设，即MDSC的耗竭将增强 抗TB治疗的功效。这些研究将共同​​提高我们对MDSC如何抑制的理解 对结核病的免疫力，并提供对MDSC作为辅助HDT的目标的见解。