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1.
Cell Immunol ; 211(1): 43-50, 2001 Jul 10.
Article in English | MEDLINE | ID: mdl-11585387

ABSTRACT

Interferon-gamma is a pivotal cytokine in the protective response to tuberculosis. In its absence rampant bacterial growth results in tissue destruction and death. While macrophage activation is key, this pleiotropic cytokine has other secondary but significant roles. To investigate these roles, both intravenous and aerosol infection of the IFN-gamma gene disrupted (GKO) mouse was performed. For the first time we describe the very similar growth of bacteria, during the initial phase of infection, between control and GKO mice. During this initial phase, however, very different histopathologic consequences between control and GKO mice were observed. Key observations included an early increased accumulation of granulocytes and a much more rapid and pronounced interstitial pneumonia in the GKO mice. As infection developed, GKO mice mounted an antigen-specific response; however, lymphocyte activation was much more rapid in these mice. Of interest is the fact that this increased rapidity occurred prior to significant differences in bacterial number. Taken together these data support a role for IFN-gamma in limiting both initial cellular recruitment and acquired lymphocytic responses to mycobacterial infection. This role may be key in surviving the kind of chronic stimulatory disease caused by Mycobacterium tuberculosis.


Subject(s)
Interferon-gamma/genetics , Interferon-gamma/physiology , Lymphocyte Activation , Tuberculosis/immunology , Animals , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , Colony Count, Microbial , Disease Susceptibility , Inflammation/immunology , Inflammation/pathology , Liver/enzymology , Liver/pathology , Lung/enzymology , Lung/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Mycobacterium tuberculosis/isolation & purification , Nitric Oxide Synthase/biosynthesis , Nitric Oxide Synthase Type II , Tuberculin/pharmacology , Tuberculosis/microbiology , Tuberculosis/pathology
2.
Am J Respir Cell Mol Biol ; 24(2): 203-9, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11159055

ABSTRACT

The role of CD8 T lymphocytes in the immune response to Mycobacterium tuberculosis infection remains enigmatic, with persuasive reports of both cytolytic and noncytolytic (cytokine-mediated) responses to infection. To address the importance of the cytolytic mechanisms, mice with targeted disruptions for CD8 and perforin or with gene mutations in the CD95/ CD95L signaling pathway were exposed to pulmonary infection. All mice tested showed no differences in their ability to contain the growth of infection during the early phase of disease. As the chronic phase of the disease ensued, however, both CD8- and CD95/CD95L-deficient mice gradually lost their ability to limit bacterial growth. This was associated with a tendency toward pyogenic inflammation in the lung. This tendency was not seen in the perforin gene-disrupted mice. In CD8 gene-disrupted mice, the ability to generate interferon-gamma secreting T cells was unimpaired. Although these cells were capable of entering the lung they were unable to influence the increasing bacterial load in this organ.


Subject(s)
CD8-Positive T-Lymphocytes/physiology , Membrane Glycoproteins/metabolism , Mycobacterium tuberculosis/immunology , Tuberculosis, Pulmonary/immunology , fas Receptor/metabolism , Animals , CD4 Antigens/metabolism , CD4-Positive T-Lymphocytes/physiology , Chronic Disease , Enzyme-Linked Immunosorbent Assay , Fas Ligand Protein , Flow Cytometry , Immunity, Innate , Interferon-gamma/analysis , Ligands , Lung/immunology , Lung/microbiology , Lung/ultrastructure , Membrane Glycoproteins/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Mycobacterium tuberculosis/pathogenicity , Signal Transduction , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Pulmonary/pathology , fas Receptor/genetics
3.
Infect Immun ; 68(12): 6879-82, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11083808

ABSTRACT

The interleukin-12 and gamma interferon (IFN-gamma) pathway of macrophage activation plays a pivotal role in controlling tuberculosis. In the murine model, the generation of supplementary nitric oxide by the induction of the nitric oxide synthase 2 (NOS2) gene product is considered the principal antimicrobial mechanism of IFN-gamma-activated macrophages. Using a low-dose aerosol-mediated infection model in the mouse, we have investigated the role of nitric oxide in controlling Mycobacterium tuberculosis in the lung. In contrast to the consequences of a systemic infection, a low dose of bacteria introduced directly into the lungs of mice lacking the NOS2 gene is controlled almost as well as in intact animals. This is in contrast to the rapid progression of disease in mice lacking IFN-gamma or a key member of the IFN signaling pathway, interferon regulatory factor 1. Thus while IFN-gamma is pivotal in early control of bacterial growth in the lung, this control does not completely depend upon the expression of the NOS2 gene. The absence of inducible nitric oxide in the lung does, however, result in increased polymorphonuclear cell involvement and eventual necrosis in the pulmonary granulomas of the infected mice lacking the NOS2 gene.


Subject(s)
Lung/microbiology , Mycobacterium tuberculosis/growth & development , Nitric Oxide Synthase/genetics , Animals , DNA-Binding Proteins/physiology , Granuloma/etiology , Interferon Regulatory Factor-1 , Interferon-gamma/physiology , Lung/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Nitric Oxide Synthase Type II , Phosphoproteins/physiology , Tuberculosis, Pulmonary/etiology
4.
Tuber Lung Dis ; 80(6): 273-9, 2000.
Article in English | MEDLINE | ID: mdl-11162768

ABSTRACT

There is a tendency among tuberculosis patients to have reduced cellular responses to mycobacterial antigens and this loss has been associated with apoptosis of CD4 T cells. In order to determine the role of CD95 in mediating apoptosis of antigen-specific lymphocytes in tuberculosis, mice with a mutated CD95L molecule were infected systemically with virulent Mycobacterium tuberculosis. Both control and CD95L mutant mice exhibited the expected loss of response to mycobacterial antigens, with the only difference being a slight delay in the loss of the response in the mutant mice. The limited persistence of the response in the mutant mice suggests that, while antigen-specific cellular responses do decline in mice infected with mycobacteria, this decline is not dependent upon CD95L.


Subject(s)
Down-Regulation/physiology , Membrane Glycoproteins/genetics , T-Lymphocyte Subsets/immunology , Tuberculosis/immunology , fas Receptor/immunology , Animals , Apoptosis/physiology , Colony Count, Microbial , Colorimetry , Enzyme-Linked Immunosorbent Assay , Fas Ligand Protein , Flow Cytometry , Immunity, Cellular/physiology , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mutation , Mycobacterium tuberculosis/isolation & purification
5.
Comput Biomed Res ; 20(2): 193-207, 1987 Apr.
Article in English | MEDLINE | ID: mdl-3595100

ABSTRACT

We have developed a computer-administered history designed to directly interview hospitalized patients with pulmonary disease. A frame-based decision system is used to direct the history and to generate a one- to five-member differential diagnostic list based on this history. This system incorporates a cognitive model of question selection and a Bayesian scoring algorithm. Structures to control the choice of questions are embedded in the diagnostic frames and in a QUERY program that makes the final choice of questions. We have compared the behavior of this decision-driven approach with a history taken using a paper questionnaire. The paper-based history presents 182 questions to every patient and captured 75% of 85 pulmonary diseases in its differential lists. The decision-driven system asks 50.7 +/- 31.0 (mean +/- standard deviation) and captured 74% of 61 pulmonary diseases. Our experience suggests that the use of a computerized diagnostic knowledge base to direct the selection of pertinent questions can substantially reduce the number of questions necessary to collect a diagnostically useful patient history.


Subject(s)
Decision Making, Computer-Assisted , Medical History Taking , Artificial Intelligence , Diagnosis, Differential , Humans , Lung Diseases/diagnosis
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