Novel Stem Cell Immunotherapy for MDR-Tuberculosis

耐多药结核病的新型干细胞免疫疗法

基本信息

批准号：
10640122
负责人：
Janice J Endsley
金额：
$ 95.94万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
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：
2021-06-04 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640122
关键词：
Acid Fast Bacillae Staining Method Anti-Inflammatory Agents Antigen Presentation Pathway Antimycobacterial Agents Antitubercular Agents Attenuated Autoimmune Autoimmune Diseases Autologous Autophagocytosis BCG Vaccine Bacillus Bacteria Bone Marrow Bone Marrow Aspiration Cancer Control Cell Therapy Cell Transplantation Cells Characteristics Clinical Clinical Trials Coculture Techniques Collection Communicable Diseases Country DNA Disease Epigenetic Process Extreme drug resistant tuberculosis Gene Cluster Gene Expression Genes Granuloma Growth Health Hematopoietic stem cells Human Immune Immune response Immune system Immunotherapeutic agent Immunotherapy In Vitro Infiltration Inflammatory Infusion procedures Interferon Type II Interleukin-10 Interleukin-4 Intervention Lung Lysosomes Macrophage Macrophage Activation Malignant Neoplasms Mediating Mesenchymal Stem Cells Methods Modeling Molecular Multidrug-Resistant Tuberculosis Mus Mycobacterium tuberculosis Mycobacterium tuberculosis antigens Nitric Oxide Organism Pathology Patients Persons Phagocytes Phagosomes Pharmaceutical Preparations Phenotype Preventive vaccine Pulmonary Tuberculosis Regimen Sirolimus Spleen Stromal Cells T-Lymphocyte Therapeutic Transfusion Tuberculosis Up-Regulation Vaccine Therapy Vaccines Validation autoimmune inflammation bactericide cellular engineering chemokine cytokine immune function immunogenicity immunological status improved in vivo innovation lung repair lymph nodes mortality neutrophil novel phase 1 study phase I trial programs prophylactic pulmonary function pulmonary granuloma recruit repaired response stem cell therapy stem cells therapeutic vaccine transcriptome transcriptome sequencing tuberculosis drugs tuberculosis granuloma tuberculosis immunity

项目摘要

Abstract Tuberculosis (TB) kills around 2 million people each year and is a major cause of mortality from a single infectious disease worldwide. Emergence of multidrug-resistant TB (MDR) is now a major problem in more than 60 countries of the world. MDR-TB is therefore a disease, where novel intervention strategies including ‘therapeutic vaccines’ are required to supplement available drug regimen. A characteristic feature of lung tuberculosis is the granuloma, which is collection of immune cells including T cells, neutrophils, DCs, mesenchymal stem cells (MSCs) and macrophages (MФs) surrounding a central core of Mycobacterium tuberculosis (MTB) infected macrophages (MФs). Granulomas restrict the growth of MTB and continuously recruit immune cells. Macrophages are in turn, the major phagocytic cells which kill MTB. We discovered two novel mechanisms through which MTB can be killed during tuberculosis. First, we found that human pro-inflammatory M1-MФs expressed nitric oxide (NO) and up-regulated autophagy to kill MTB whereas, anti-inflammatory M2-MФs allowed the growth of MTB due to a decrease in NO synthesis and autophagy. Secondly, we discovered that, BCG vaccine and MTB infected mesenchymal stem cells (MSCs) reprogrammed naïve human macrophages to become M1 phenotype and more activated to kill MTB. Interestingly, Phase I trials using naïve, autologous MSCs have improved the health of MDR-TB patients. In this proposal, we will leverage our new findings to increase human macrophage activation through stem cell-mediated immunotherapeutic vaccine as follows. Specific Aim- 1: Investigate the molecular mechanisms through which, BCG vaccine and MTB infected or conditioned human mesenchymal stem cells to epigenetically program naive human macrophages. Specific Aim-2: Investigate the in vivo therapeutic and prophylactic effects of conditioned MSCs during experimental tuberculosis. We will analyze the ability of transfused MSCs to eradicate bacteria and restore lung function. MSCs have been used in more than 300 clinical transfusion trials to control cancer, autoimmune diseases and inflammation. We will develop a new method of stem cell therapeutic vaccination to control MDR-TB.

抽象的结核病 (TB) 每年夺去约 200 万人的生命，是单一疾病导致死亡的主要原因耐多药结核病 (MDR) 的出现现已成为世界范围内的一个主要问题。因此，世界上 60 多个国家的耐多药结核病是一种需要新干预策略的疾病。包括“治疗性疫苗”需要补充现有的药物治疗方案。肺结核的特征是肉芽肿，它是包括T细胞在内的免疫细胞的集合，中性粒细胞、DC、间充质干细胞 (MSC) 和巨噬细胞 (MФ) 围绕中央核心结核分枝杆菌 (MTB) 感染的巨噬细胞 (MФs) 限制了肉芽肿的生长。 MTB 并不断招募免疫细胞，而巨噬细胞是主要的吞噬细胞。杀死 MTB。我们发现了两种新的机制，可以在结核病期间杀死 MTB。首先，我们发现人类促炎性 M1-MФ 表达一氧化氮 (NO) 并上调自噬杀死 MTB，而抗炎 M2-MФs 由于 MTB 减少而允许 MTB 生长其次，我们发现，BCG疫苗和MTB感染。间充质干细胞 (MSC) 重新编程幼稚人类巨噬细胞，使其成为 M1 表型更有意义的是，使用天然自体 MSC 进行的 I 期试验已得到改善。在这项提案中，我们将利用我们的新发现来提高人类的健康水平。通过干细胞介导的免疫治疗疫苗激活巨噬细胞具体目标如下。 1：研究卡介苗和结核分枝杆菌感染或调节的分子机制人类间充质干细胞对初始人类巨噬细胞进行表观遗传编程特定目标 2：研究实验期间条件化 MSC 的体内治疗和预防作用我们将分析输注的间充质干细胞消灭细菌和恢复肺部的能力。 MSCs 已被用于 300 多项临床输血试验来控制癌症、我们将开发一种干细胞治疗的新方法。接种疫苗以控制耐多药结核病。