R01AI161015

Novel Stem Cell Immunotherapy for MDR-Tuberculosis - Abstract

Tuberculosis (TB) kills around 2 million people each year and is a major cause of mortality from a single infectious disease worldwide. The emergence of multidrug-resistant TB (MDR) is now a major problem in more than 60 countries around the world. MDR-TB is therefore a disease where novel intervention strategies, including 'therapeutic vaccines', are required to supplement the available drug regimen.

A characteristic feature of lung tuberculosis is the granuloma, which is a collection of immune cells including T cells, neutrophils, dendritic cells (DCs), mesenchymal stem cells (MSCs), and macrophages (Ms) surrounding a central core of Mycobacterium tuberculosis (MTB) infected macrophages (Ms). Granulomas restrict the growth of MTB and continuously recruit immune cells. Macrophages are, in turn, the major phagocytic cells that kill MTB.

We have discovered two novel mechanisms through which MTB can be killed during tuberculosis. First, we found that human pro-inflammatory M1-Ms expressed nitric oxide (NO) and up-regulated autophagy to kill MTB, whereas anti-inflammatory M2-Ms allowed the growth of MTB due to a decrease in NO synthesis and autophagy. Secondly, we discovered that the 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 the BCG vaccine and MTB infected or conditioned human mesenchymal stem cells epigenetically program naïve 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.

Methodist Hospital

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Houston, Texas 77030 United States

Single Zip Code

Advancing Vaccine Science to Improve Tuberculosis Treatment Outcomes for People Living With or Without HIV (R01 Clinical Trial Not Allowed) (RFA-AI-20-010)

Amendment Since initial award the total obligations have increased 299% from $959,375 to $3,825,440.