Transient transgenic expression of gamma interferon promotes Legionella pneumophila clearance in immunocompetent hosts.
Gamma interferon (IFN-gamma) and T1-phenotype immune responses are important components of host defense against a variety of intracellular pathogens, including Legionella pneumophila. The benefit of intrapulmonary adenovirus-mediated IFN-gamma gene therapy was investigated in a nonlethal murine model of experimental L. pneumophila pneumonia. Intratracheal (i.t.) administration of 10(6) CFU of L. pneumophila induced the expression of T1 phenotype cytokines, such as IFN-gamma and interleukin-12 (IL-12). Natural killer cells were identified as the major cellular source of IFN-gamma. To determine if enhanced expression of IFN-gamma in the lung could promote pulmonary clearance of L. pneumophila, we i.t. administered 5 x 10(8) PFU of a recombinant adenovirus vector containing the murine IFN-gamma cDNA (AdmIFN-gamma) concomitant with L. pneumophila. We observed a 10-fold decrease in lung bacterial CFU at day 2 in the AdmIFN-gamma-treated group compared to controls (P < 0.01). Alveolar macrophages isolated from AdmIFN-gamma-treated animals displayed enhanced killing of intracellular L. pneumophila organisms ex vivo. Similar improvements in bacterial clearance were observed with i.t. recombinant IFN-gamma treatment. The transient transgenic expression of IL-12, a known inducer of IFN-gamma and promoter of T1-type immune responses, resulted in more modest improvement in bacterial clearance (sixfold reduction; P < 0.05). These results demonstrate that, even in immunocompetent hosts, exogenous administration or transient transgenic expression of IFN-gamma, and to a lesser extent IL-12, may be of potential therapeutic benefit in the treatment of patients with Legionella pneumonia.
Deng
J C
JC
Department of Medicine, Division of Pulmonary and Critical Care Medicine, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0360, USA.
Tateda
K
K
Zeng
X
X
Standiford
T J
TJ
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D007121:Immunocompetence; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D018664:Interleukin-12 / Q000096:biosynthesis; D016952:Legionella pneumophila / Q000276:immunology; D007877:Legionnaires' Disease / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D007962:Leukocytes / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008805:Mice, Inbred A; D008822:Mice, Transgenic; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D013997:Time Factors
D018664:Interleukin-12; D007371:Interferon-gamma