Principal Investigator/Program Director (Last, first, middle): ABSTRACT Title: MESENCHYMAL STEM CELL NICHE FOR TUBERCULOSIS Tuberculosis is the leading cause of death in mankind due to infections and more than 8 million new cases occur each year with 2 million deaths per year. Emergence of multi-drug resistance (MDR) and extraordinarily resistant (XDR) Mycobacterium tuberculosis (MTB) isolates has rendered the control of tuberculosis very difficult. A third of human population is infected with latent MTB from which active cases arise. Paradoxically, HIV-1 infection can deplete CD4 T cells and enhance co-infection due to tuberculosis and death rate. There is extensive lung damage during ongoing tuberculosis, tuberculosis during HIV infection, and in particular during MD/XDR tuberculosis. Urgent methods are required to repair and restore lung function and concurrently eradicate Mycobacterium tuberculosis (MTB) from the lungs of humans with and without HIV infection. Phase I studies show that transfusion of mesenchymal stem cells (MSCs; aka.stem cells) into patients with MDR/XDR patents was safe and there was partial clinical improvement in lung function and systemic immunity. Human bone marrow derived MSCs are unique because they can be grown in large numbers in vitro and infused back into humans from both allogenic and autologous sources. We made a new discovery that rapamycin-activated stem cells internalized and killed MTB in vitro through enhanced autophagy. We now propose that such `conditioned stem cells' can be transfused into patients with MDR-XDR tuberculosis to obtain enhanced killing of MTB and concurrent restoration of lung function. Since the cell biological basis of stem cell mediated infection control remains unclear, we propose the following studies to optimize stem cell administration into humans for immunotherapy of tuberculosis.
SPECIFIC AIM - 1: Investigate the mechanisms of receptor mediated phagocytic uptake, cytokine and oxidant responses of MTB by human mesenchymal stem cells.
SPECIFIC AIM -2: Investigate the mechanisms of inducing and maintaining autophagy in mesenchymal stem cells to develop immunotherapeutic methods. Rationale: We discovered that in vitro conditioned mesenchymal stem cells killed mycobacteria including BCG and MTB. Since autologous MSCs have been transfused in a phase I study and found relatively safe, we will assess the cell biology of stem cells prior to transfusion by analyzing mechanisms of MTB uptake into stem cells and correlate with cytokines and growth factors. We will analyze various surface receptors, phagocytic phenomena and associated oxidant synthesis to understand how stem cells can be conditioned to kill MTB. Since autophagy killed MTB within stem cells, we will evaluate the multiple mechanisms of inducing autophagy and their effects on stem cells. Impact of the project: The prevalence of MDR/XDR tuberculosis and HIV infection renders the control of both TB and HIV difficult. Lung damage in tuberculosis is well established. Thus, newer methods fo immunotherapy is urgently required. Once stem cell biology is investigated and understood, we anticipate that that `conditioned and improved' stem cells can be transfused into patents for effective control for infection in the lungs. The availability of large numbers of stem cells, the expertise to analyze the cell biology of stem cells suggest that this proposal will have lasting impact on immunotherapy for lung specific disease. Performance sites for research: Principal Investigator: Chinnaswamy Jagannath, Ph.D. Professor, Dept. of Pathology and laboratory Medicine, University of Texas Health Sciences Center, 6431, Fannin, Houston, Texas 77030 USA PHS 398 (Rev. 09/04) Page
NARRATIVE Title: MESENCHYMAL STEM CELL NICHE FOR TRUBERCULOSIS Tuberculosis is the leading cause of death in mankind due to infections and more than 8 million new cases occur each year with 2 million deaths per year. Emergence of multi-drug resistance (MDR) and extraordinarily resistant (XDR) Mycobacterium tuberculosis (MTB) isolates has rendered the control of tuberculosis very difficult. A third of human population is infected with latent MTB from which active cases arise. Paradoxically, HIV-1 infection can deplete CD4 T cells and enhance co-infection due to tuberculosis and death rate. There is extensive lung damage during ongoing tuberculosis and in particular during MD/XDR tuberculosis and urgent methods are required to repair and restore lung function and concurrently eradicate Mycobacterium tuberculosis (MTB) from the lungs. Phase I studies show that transfusion of mesenchymal stem cells (MSCs; aka.stem cells) into patients with MDR/XDR patents was safe and there was partial clinical improvement in lung function and systemic immunity. Human bone marrow derived MSCs are unique because they can be grown in large numbers in vitro and infused back into humans from both allogenic and autologous sources. This proposal will identify the biological features of stem cells and methods to condition them so that eventually, they can be used for therapeutic transfusion into human patients with MDR-XDR tuberculosis, where treatment options are limited. Thus, the proposal has immense translational value. PHS 398 (Rev. 09/04) Page
