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

基本信息

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
项目类别：
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

项目摘要

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) 患者中，对结核分枝杆菌 (Mtb) 感染的有害免疫反应支配有益免疫，导致结核分枝杆菌复制失控、肺肉芽肿和进展结核病。 Mtb 诱导的免疫抑制途径促进肺部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介导杀灭结核分枝杆菌。因此，深入了解结核病期间的免疫抑制机制是对于开发新型免疫调节疗法至关重要，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治疗。最近的研究表明，结核分枝杆菌感染后，一群未成熟的骨髓细胞被招募到肺部有助于结核病期间的免疫抑制。这些细胞被称为骨髓源性抑制细胞（MDSC），首次在癌症中被描述为负调节肿瘤微环境并抑制 NK 细胞和 T 细胞的细胞毒功能。有趣的是，MDSC 的积累与结核病病理学相关，这些细胞内也可携带 Mtb。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 MDSC 会阻止针对 Mtb 的有益先天性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来感染。我们进一步假设消耗 MDSC 感染 Mtb 的小鼠将增强肺部对 Mtb 的免疫反应，并显着改善结核病治疗功效。我们开发了一种通用且有效的方法，通过新型多价消耗肺部的 MDSC 合成纳米颗粒抗体 (SNAb) 通过抗体样特异性靶向并消耗 MDSC 杀伤机制。在此 MPI-R01 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，埃默里大学）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）研究 MDSC 在结核病进展和病理学中的作用，以及调节结核免疫的作用，以及探索 MDSC 作为 TB HDT 的靶点。我们将研究以下具体目标：目标 1. 评估使用 SNAb 消耗 MDSC 如何影响结核病进展。目标 2. 研究 MDSC 如何抑制对 Mtb 感染的免疫反应。目标 3. 检验 MDSC 消耗将增强抗结核治疗的疗效。总之，这些研究将增进我们对 MDSC 如何抑制结核病免疫力，并提供对 MDSC 作为辅助 HDT 目标的见解。