Transient transgenic expression of gamma interferon promotes Legionella pneumophila clearance in immunocompetent hosts

Gamma interferon (IFN-gamma) and T1-phenotype immune responses are importan t 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 mod el of experimental L. pneumophila pneumonia. Intratracheal (i.t.) administr ation 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 ce lls were identified as the major cellular source of IFN-gamma. To determine if enhanced expression of IFN-gamma in the lung could promote pulmonary cl earance of L. pneumophila, we i.t. administered 5 X 10(8) PFU of a recombin ant adenovirus vector containing the murine IFN-gamma cDNA (AdmIFN-gamma) c oncomitant with L. pneumophila. We observed a 10-fold decrease in lung bact erial CFU at day 2 in the AdmIFN-gamma -treated group compared to controls (P < 0.01). Alveolar macrophages isolated from AdmIFN-gamma -treated animal s displayed enhanced killing of intracellular L. pneumophila organisms ex v ivo. Similar improvements in bacterial clearance were observed with i.t. re combinant IFN-T treatment. The transient transgenic expression of IL-12, a known inducer of IFN-gamma and promoter of T1-type immune responses, result ed in more modest improvement in bacterial clearance (sixfold reduction; P < 0.05). These results demonstrate that, even in immunocompetent hosts, exo genous administration or transient transgenic expression of IFN-gamma, and to a lesser extent IL-12, may be of potential therapeutic benefit in the tr eatment of patients with Legionella pneumonia.