Tuberculosis, a major health problem in developing countries, has reemerged in recent years in many industrialized countries. The increased susceptibility of immunocompromised individuals to tuberculosis, and many experimental studies indicate that T cell-mediated immunity plays an important role in resistance. The lymphokine interferon gamma (IFN-gamma) is thought to be a principal mediator of macrophage activation and resistance to intracellular pathogens. Mice have been developed which fail to produce IFN-gamma (gko), because of a targeted disruption of the gene for IFN-gamma. Upon infection with Mycobacterium tuberculosis, although they develop granulomas, gko mice fail to produce reactive nitrogen intermediates and are unable to restrict the growth of the bacilli. In contrast to control mice, gko mice exhibit heightened tissue necrosis and succumb to a rapid and fatal course of tuberculosis that could be delayed, but not prevented, by treatment with exogenous recombinant IFN-gamma.

https://rupress.org/jem/article-pdf/178/6/2249/1104362/2249.pdf

An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection.

The expression of protective immunity to Mycobacterium tuberculosis in mice is mediated by T lymphocytes that secrete cytokines. These molecules then mediate a variety of roles, including the activation of parasitized host macrophages, and the recruitment of other mononuclear phagocytes to the site of the infection in order to initiate granuloma formation. Among these cytokines, interferon gamma (IFN-gamma) is believed to play a key role is these events. In confirmation of this hypothesis, we show in this study that mice in which the IFN-gamma gene has been disrupted were unable to contain or control a normally sublethal dose of M. tuberculosis, delivered either intravenously or aerogenically. In such mice, a progressive and widespread tissue destruction and necrosis, associated with very high numbers of acid-fast bacilli, was observed. In contrast, despite the lack of protective immunity, some DTH-like reactivity could still be elicited. These data, therefore, indicate that although IFN-gamma may not be needed for DTH expression, it plays a pivotal and essential role in protective cellular immunity to tuberculosis infection.

https://rupress.org/jem/article-pdf/178/6/2243/1104512/2243.pdf

Disseminated tuberculosis in interferon gamma gene-disrupted mice.

Microbial pathogenesis in cystic fibrosis: mucoid Pseudomonas aeruginosa and Burkholderia cepacia.

Tumor necrosis factor-α is required in the protective immune response against mycobacterium tuberculosis in mice

This review summarizes recent evidence from knock-out mice on the role of reactive oxygen intermediates and reactive nitrogen intermediates (RNI) in mammalian immunity. Reflections on redundancy in immunity help explain an apparent paradox: the phagocyte oxidase and inducible nitric oxide synthase are each nonredundant, and yet also mutually redundant, in host defense. In combination, the contribution of these two enzymes appears to be greater than previously appreciated. The remainder of this review focuses on a relatively new field, the basis of microbial resistance to RNI. Experimental tuberculosis provides an important example of an extended, dynamic balance between host and pathogen in which RNI play a major role. In diseases such as tuberculosis, a molecular understanding of host-pathogen interactions requires characterization of the defenses used by microbes against RNI, analogous to our understanding of defenses against reactive oxygen intermediates. Genetic and biochemical approaches have identified candidates for RNI-resistance genes in Mycobacterium tuberculosis and other pathogens.

https://www.pnas.org/content/pnas/97/16/8841.full.pdf

Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens

Interferon-gamma-treated murine macrophages inhibit growth of tubercle bacilli via the generation of reactive nitrogen intermediates

Cystic fibrosis (CF) is characterized by a dramatic neutrophil recruitment and repeated Pseudomonas infections in the lungs. To evaluate cytokine releasability by airway epithelial cells in the context of CF, we studied primary nasal epithelial cells isolated from the upper airways and continuous epithelial cell lines from normal and CF subjects. Relatively low levels of interleukin (IL)-8, IL-6, and granulocyte/macrophage colony-stimulating factor (GM-CSF) were produced spontaneously by primary epithelial cells (< 50 pg/106 cells) and higher levels of colony-stimulating factor-1 (CSF-1) (1 to 2 ng/106 cells). Cells were stimulated with substances that are likely to be present in the inflamed lungs of CF patients—namely, the proinflammatory monokines IL-1 and tumor necrosis factor-α (TNFα) as well as neutrophil elastase and bacterial products from Pseudomonas (mucoid exopolysaccharide [MEP] and rhamnolipids). Both IL-1 and TNFα induced a dose-dependent release of IL-6 (5 to 10 ng/106 cells) and GM-CSF (2 ...

Release of interleukin-8, interleukin-6, and colony-stimulating factors by upper airway epithelial cells: implications for cystic fibrosis.

We examined the importance of the cytokine tumor necrosis factor-alpha (TNF-alpha) in a mouse model of hypersensitivity pneumonitis (HP). Mice of the C57BL/6 strain were instilled intranasally 3 days/wk for 3 wk with 150 micrograms of the actinomycete Faenia rectivirgula (Micropolyspora faeni) to induce HP as a model of farmer's lung. This experimental model was associated with a progressive inflammation in the lungs of challenged mice, seen histologically as cellular infiltrates of large quantities of macrophages and lymphocytes and some neutrophils. The disease in challenged mice treated with a control rabbit serum was also associated with a substantial release of tumor TNF-alpha (up to 80 U/ml of TNF-alpha in the bronchoalveolar lavage [BAL] at 3 wk after beginning of treatment) and interleukin-1, which peaked at 1 wk (approximately 300 U/ml) and diminished thereafter. A very large increase in BAL cell number (11-fold increase versus saline controls) and an enhanced release potential for TNF-alpha by alveolar macrophages was also seen. Lung fibrosis was also evident in challenged animals, as demonstrated by a 2-fold increase in hydroxyproline levels. Infusion of challenged mice with a rabbit polyclonal antibody against TNF-alpha (2 mg/wk) completely abrogated the disease, as mice so treated had normal lung histology. Anti-TNF-alpha blocked cellular recruitment in the lungs (only a 2-fold increase at week 3); it also completely abolished TNF-alpha secretion in the BAL and drastically reduced interleukin-1 levels in this fluid. Anti-TNF-alpha also abolished lung index increases and lung fibrosis, with both parameters similar to that of saline-instilled mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor Necrosis Factor Plays an Essential Role in Determining Hypersensitivity Pneumonitis in a Mouse Model

Cytokine modulation of Mycobacterium tuberculosis growth in human macrophages

The progression of hypersensitivity pneumonitis (HP) was evaluated in mice repeatedly challenged with the actinomycete Faeni rectivirgula (Micropolyspora faeni) (90 or 180 µg), at the cellular level and at the mediator level. Instillation of F. rectivirgula by the intranasal route determined a granulomatous inflammation in the lungs of animals correlated with a dramatic increase (5- to 6-fold) in cellularity in the bronchoalveolar space and an increase in the percentage of lymphocytes. Disease in mice was also correlated with high spontaneous release of the cytokines interleukin-1 (IL-1) (60 U/ml), interleukin-6 (IL-6) (72 U/ml), and tumor necrosis factor-α (TNF-α) (56 U/ml) in the bronchoalveolar lavage (BAL) fluid, as well as by an enhanced capacity for cytokine release by macrophages upon stimulation with F. rectivirgula. It was also found that the pulmonary inflammation was correlated with a 60 to 70% increase in total lung weight after 4 wk and a significant lung fibrosis as seen by a 2-fold increase...

Michel Denis

Papers

Interferon-gamma-treated murine macrophages inhibit growth of tubercle bacilli via the generation of reactive nitrogen intermediates

Release of interleukin-8, interleukin-6, and colony-stimulating factors by upper airway epithelial cells: implications for cystic fibrosis.

Tumor Necrosis Factor Plays an Essential Role in Determining Hypersensitivity Pneumonitis in a Mouse Model

Cytokine modulation of Mycobacterium tuberculosis growth in human macrophages

Murine hypersensitivity pneumonitis: a study of cellular infiltrates and cytokine production and its modulation by cyclosporin A.