Novel Stem Cell Immunotherapy for MDR-Tuberculosis

耐多药结核病的新型干细胞免疫疗法

• 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
• 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

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.

摘要 结核病（TB）每年造成约200万人死亡，是单次结核病死亡的主要原因。 全球性传染病。耐多药结核病（MDR）的出现现在是一个主要问题， 世界上60多个国家。因此，耐多药结核病是一种疾病， 包括“治疗性疫苗”，以补充现有的药物方案。的特性 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（M β）围绕中心核心 结核分枝杆菌（MTB）感染的巨噬细胞（M.肉芽肿限制了 结核分枝杆菌和不断招募免疫细胞。巨噬细胞是主要的吞噬细胞， 干掉山地车我们发现了两种新的机制，通过这种机制，MTB可以在结核病期间被杀死。 首先，我们发现人类促炎性M1-M β细胞表达一氧化氮（NO），并上调了 自噬杀死MTB，而抗炎的M2-M β细胞允许MTB的生长，由于自噬减少， NO合成和自噬。其次，我们发现，卡介苗和结核杆菌感染， 间充质干细胞（MSC）重编程幼稚人巨噬细胞成为M1表型 更活跃的是杀死山地车有趣的是，使用幼稚的自体MSC的I期试验已经改善了 耐多药结核病患者的健康。在这项提案中，我们将利用我们的新发现， 通过干细胞介导的免疫疫苗的巨噬细胞活化如下。具体目标- 1：研究BCG疫苗和MTB感染或调节的分子机制 人间充质干细胞表观遗传编程幼稚人巨噬细胞。具体目标2： 研究条件化MSCs在实验性肝损伤中的体内治疗和预防作用。 结核我们将分析输注的MSC清除细菌和恢复肺功能的能力。 功能MSC已用于300多项临床输血试验以控制癌症， 自身免疫性疾病和炎症。我们将开发一种新的干细胞治疗方法 接种疫苗以控制耐多药结核病。