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Myeloid-Derived Suppressor Cells in Tuberculosis Granuloma Structure and Function

结核肉芽肿中骨髓源性抑制细胞的结构和功能

基本信息

批准号：
10082741
负责人：
Amanda Martinot
金额：
$ 22.39万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10082741
关键词：
Ablation Affect Animal Model Antibodies Antiviral Agents Archives Bacillus Bacteria Biological Markers Blood Cell Count Cell Therapy Cell physiology Cells Chronic Clinical Communicable Diseases Coupled Data Development Disease Disease Progression Drug resistance in tuberculosis Effectiveness FOXP3 gene Fluorochrome Formalin Genetic Transcription Genetic Variation Goals Granuloma HIV HIV/TB Human Human Characteristics Image Immune Immune response Immunofluorescence Immunologic Immunophenotyping Immunosuppression In Vitro Individual Infection Infection Control Infiltration Interferon Type II Knowledge Liquid substance Lung Malignant Neoplasms Methodology Methods Modality Multidrug-Resistant Tuberculosis Mus Mycobacterium tuberculosis Myelogenous Myeloid Cells Myeloid-derived suppressor cells Necrosis Outcome Paraffin Embedding Pathology Patients Pattern Periodicity Pharmaceutical Preparations Pharmacology Phenotype Pleural Population Predisposition Reagent Regulatory T-Lymphocyte Research Resolution Role Specimen Stains Structure Structure of parenchyma of lung T-Cell Activation T-Lymphocyte Technology Tissue Embedding Tissue imaging Tissues Treatment outcome Tuberculosis Tuberculosis Vaccines Tumor-infiltrating immune cells Vaccine Design Visual alternative treatment antimicrobial cell type chemotherapy co-infection cytokine human model imaging platform immunopathology improved in vivo instrument macrophage monocyte mouse model multiplexed imaging mycobacterial novel pre-clinical programmed cell death protein 1 recruit response stem cells trafficking tuberculosis granuloma tuberculosis treatment vaccine immunotherapy

项目摘要

Project Summary There is a critical need for identification of factors contributing to TB-HIV co-infection outcomes and to prioritize new treatment modalities for treating drug-resistant TB in immune suppressed populations. Recently, it has been suggested that pharmacologic modulation of myeloid-derived suppressor cells (MDSC) may be an alternative to antimicrobial therapy for TB. MDSC are a transient immature myeloid cell population derived from a common progenitor cell, that have been shown to block T cell-activation by recruiting T-regulatory lymphocytes and inducing PD-1 expression on immune cells. In both cancer and chronic infectious diseases, MDSC have been associated with immune-suppression and dampening of the host’s immune response locally in tissue microenvironments, but the role of MDSC in Mycobacterium tuberculosis (Mtb) disease progression is unclear. In order to determine if MDSC are a useful target for adjunctive therapy for TB disease in immune suppressed populations, their role in TB disease needs to be elucidated. We hypothesize that MDSC contribute to local immune suppression in the lung during TB infection by influencing spatial infiltrates of immune cells and decreasing numbers and/or antimicrobial effectiveness of resident macrophage/monocyte populations within the granuloma. Myeloid derived suppressor cells (MDSC) have been associated with immune- suppression and dampening of the host’s immune response locally in tissue microenvironments, but the role of MDSC in Mycobacterium tuberculosis (Mtb) disease progression is unclear. We propose to determine if MDSC are a useful target for adjunctive therapy for TB disease by establishing numbers and localization patterns of MDSC in both human and mouse Mtb infected lung using a novel imaging platform, tissue cyclic immunofluorescence (t-CyCIF) to evaluate MDSC in the context of the granuloma. The long-term goal of our research is to establish the extent to which MDSC function and trafficking can be modulated pharmacologically to improve TB treatment outcomes. By determining the spatial co-localization of MDSC with other immune cells in human TB granulomas and establishing immune correlates of MDSC tissue localization with tuberculosis infection and control in Diversity Outbred (DO) mice we can evaluate MDSC as targets for host-directed therapy in TB treatment. In summary, we will use novel methodology, t- CyCIF, coupled with a mouse model of human genetic diversity, to generate new knowledge regarding the role of MDSC in TB disease. Methods to alter the expansion and infiltration of MDSC may aid TB vaccine design and immunotherapy to promote mycobacterial clearance in both HIV infected an uninfected patients.

项目概要迫切需要确定导致 TB-HIV 合并感染结果的因素并优先考虑新的治疗方式来治疗免疫抑制人群中的耐药结核病。最近，有人提出，骨髓源性抑制细胞（MDSC）的药理学调节可能是结核病抗菌治疗的替代方案。 MDSC 是一种短暂的未成熟骨髓细胞群来自共同的祖细胞，已被证明可以通过招募 T 调节性细胞来阻止 T 细胞激活淋巴细胞并诱导免疫细胞表达 PD-1。在癌症和慢性传染病中， MDSC 与免疫抑制和宿主局部免疫反应减弱有关在组织微环境中，但 MDSC 在结核分枝杆菌 (Mtb) 疾病进展中的作用是不清楚。为了确定 MDSC 是否是免疫结核病辅助治疗的有用靶点受抑制的人群，他们在结核病中的作用需要阐明。我们假设 MDSC 通过影响结核病的空间浸润，有助于结核感染期间肺部的局部免疫抑制免疫细胞和常驻巨噬细胞/单核细胞的数量和/或抗菌效力下降肉芽肿内的群体。骨髓源性抑制细胞 (MDSC) 与免疫相关在组织微环境中局部抑制和减弱宿主的免疫反应，但 MDSC 在结核分枝杆菌 (Mtb) 疾病进展中的作用尚不清楚。我们建议确定 MDSC 是否通过建立结核病的数量和定位模式，成为结核病辅助治疗的有用目标。使用新型成像平台组织循环在人和小鼠 Mtb 感染的肺部中进行 MDSC 免疫荧光 (t-CyCIF) 评估肉芽肿背景下的 MDSC。我们的长期目标研究的目的是确定 MDSC 功能和运输可以调节的程度药理学上可改善结核病治疗结果。通过确定空间共定位 MDSC 与人结核肉芽肿中的其他免疫细胞并建立 MDSC 的免疫相关性我们可以评估多样性远交 (DO) 小鼠中结核感染和控制的组织定位 MDSC 作为结核病治疗中宿主导向治疗的靶标。总之，我们将使用新颖的方法，t- CyCIF 与人类遗传多样性的小鼠模型相结合，产生有关其作用的新知识 MDSC 在结核病中的作用。改变 MDSC 扩张和浸润的方法可能有助于结核病疫苗的设计和免疫疗法可促进 HIV 感染者和未感染者的分枝杆菌清除。