Novel Stem Cell Immunotherapy for MDR-Tuberculosis

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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.