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: 10890900
• 负责人: KRISHNENDU ROY
• 金额: $ 9.05万
• 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/10890900
• 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 结核病患者对结核分枝杆菌(Mtb)感染的有害免疫反应 主宰有益免疫，导致结核分枝杆菌复制失控、肺肉芽肿和进展 对结核病的威胁。结核分枝杆菌诱导的免疫抑制通路促进肺病理和组织损伤 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- 调解杀死结核分枝杆菌。因此，深入了解结核病的免疫抑制机制是 对开发新的免疫调节疗法至关重要，这种疗法可以打破致病反应的平衡 以及保护性免疫和更好的细菌清除。因此，针对宿主的治疗(HDT) 免疫抑制途径与抗结核抗生素相结合有可能改善结核病的治疗。 最近的研究表明，在结核分枝杆菌感染后，一群未成熟的髓系细胞被招募到肺中 导致结核病期间的免疫抑制。这些细胞被称为髓系抑制细胞(MDSCs)， 在癌症中首次被描述为负向调节肿瘤微环境，抑制NK细胞和T细胞 细胞的细胞毒功能。有趣的是，MDSCs的积聚与结核病的病理相关，这些 细胞内也可以携带结核分枝杆菌。然而，与癌症相比，MDSCs在结核病中的功能较差 明白了。我们假设mdscs阻止对结核分枝杆菌有益的先天和获得性免疫反应。 感染通过抑制T细胞、NK细胞和巨噬细胞的功能来实现。我们进一步假设正在枯竭的MDSCs 在感染结核杆菌的小鼠中将增强对结核杆菌在肺部的免疫反应，并显著改善结核病的治疗 功效。 我们已经开发了一种通用而有效的方法来通过新的多价药物来耗尽肺中的MDSCs 合成纳米抗体(SNAbs)通过类抗体特异性靶向和消耗MDSCs 杀戮机制。在MPI-R01的应用中，我们结合了结核病发病机制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方面的专业知识(Roy，佐治亚理工学院) 探讨骨髓间充质干细胞在结核病疾病发展和病理过程中的作用，以及对结核病免疫的调节作用 探讨MDSCs作为结核病HDT治疗靶点的可能性。我们将调查以下具体目标：目标1.评估 使用SNAbs消耗MDSCs如何影响结核病的进展。目标2.研究MDSCs是如何抑制 对结核分枝杆菌感染的免疫反应。目的3.验证MDSCs耗尽将增强 抗结核治疗的疗效。总之，这些研究将促进我们对MDSCs如何抑制 对结核病的免疫力，并提供对MDSCs作为附属HDTS目标的洞察。