title: Passive transfer of interferon-γ over-expressing macrophages enhances resistance of SCID mice to Mycobacterium tuberculosis infection.
abstract: Infection with Mycobacterium tuberculosis (M.tb) is associated with increased deaths worldwide. Alveolar macrophages (AMs) play a critical role in host defense against infection with this pathogen. In this work we tested the hypothesis that passive transfer of normal AMs, IFN-γ activated AMs, or macrophages transduced to over-express IFN-γ into the lungs of immunosuppressed SCID mice, where resident macrophages are present but not functional, would enhance alveolar immunity and increase clearance of pulmonary M.tb infection. Accordingly, SCID mice were infected with M.tb intratracheally (I.T.), following which they received either control macrophages or macrophages overexpressing IFN-γ (J774A.1). The extent of M.tb infection was assessed at 30days post-M.tb infection. SCID mice administered macrophages over-expressing IFN-γ showed a significant decrease in M.tb burden and increased survival compared to J774A.1 control macrophages or untreated mice. This was further associated with a significant increase in IFN-γ and TNF-α mRNA and protein expression, as well as NF-κB (p65) mRNA, in the lungs. The increase in IFN-γ and TNF-α lung levels was inversely proportional to the number of M.tb organisms recovered. These results provide evidence that administration of macrophages overexpressing IFN-γ inhibit M.tb growth in vivo and may enhance host defense against M.tb infection.
authors.affiliation: Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States. Electronic address: rajamouli.pasula@va.gov.
authors.forename: Rajamouli
authors.initials: R
authors.lastname: Pasula
authors.affiliation: College of Public Health, The Ohio State University, Columbus, OH, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Martin
authors.affiliation: Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
authors.forename: Banu Rekha
authors.initials: BR
authors.lastname: Kesavalu
authors.affiliation: Research Service, VA Medical Center - Nebraska/Western Iowa, Omaha, NE, United States; Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, United States.
authors.forename: Maher Y
authors.initials: MY
authors.lastname: Abdalla
authors.affiliation: Research Service, VA Medical Center - Nebraska/Western Iowa, Omaha, NE, United States; Departments of Internal Medicine and Microbiology and Immunology, University of Nebraska Medical Center, Omaha, NE, United States; Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, United States.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Britigan
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D060467:Disease Resistance; D004198:Disease Susceptibility; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008264:Macrophages / Q000637:transplantation*; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010587:Phagocytosis; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: Alveolar macrophages; Gene therapy; Immunodeficiency; Lung; Mycobacterium tuberculosis; Reconstitution