Novel Stem Cell Immunotherapy for MDR-Tuberculosis

摘要 结核病(TB)每年导致约200万人死亡，是单纯性结核病死亡的主要原因 世界范围内的传染病。耐多药结核病(MDR)的出现现在是 世界上60多个国家。因此，耐多药结核病是一种疾病，在那里，新的干预策略 包括“治疗性疫苗”在内的疫苗是现有药物方案的补充。一个特点 肺结核的特征是肉芽肿，肉芽肿是包括T细胞在内的免疫细胞的聚集， 中性粒细胞、树突状细胞、间充质干细胞(MSCs)和巨噬细胞(MФS)围绕中央核心 结核分枝杆菌感染巨噬细胞(MФS)。肉芽肿限制肿瘤的生长 结核分枝杆菌和持续招募免疫细胞。巨噬细胞反过来又是主要的吞噬细胞， 杀了MTB。我们发现了两种新的机制，通过它们可以在结核病期间杀死结核分枝杆菌。 首先，我们发现人类促炎性M1-MФS表达一氧化氮(NO)并上调 自噬杀灭结核分枝杆菌，抗炎M2-MФS允许结核分枝杆菌生长 在无合成和自噬方面。其次，我们发现，卡介苗和结核杆菌感染 间充质干细胞(MSCs)将原始的人巨噬细胞重新编程为M1表型 更能被激活来杀死结核杆菌。有趣的是，使用天真的自体骨髓间充质干细胞的I期试验有所改善 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来增加人类 通过干细胞介导的免疫治疗性疫苗激活巨噬细胞如下。具体目标-- 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幼稚的人类巨噬细胞进行表观遗传学编程。具体目标--2： 条件骨髓间充质干细胞在实验中的体内治疗和预防作用 肺结核。我们将分析输注的MSCs清除细菌和恢复肺的能力 功能。骨髓间充质干细胞已经用于300多项临床输血试验，以控制癌症， 自身免疫性疾病和炎症。我们将开发一种干细胞治疗的新方法 接种疫苗以控制耐多药结核病。

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.