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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：
10247081
负责人：
Amanda Martinot
金额：
$ 25.02万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247081
关键词：
Ablation Affect Animal Model Antibodies Antiviral Agents 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 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 biological specimen archives cell type chemotherapy co-infection cytokine human model imaging platform immunopathology improved in vivo instrument macrophage monocyte mouse model multiplexed imaging mycobacterial necrotic tissue 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.

项目总结