Intrapulmonary Tumor Necrosis Factor Gene Therapy Increases Bacterial Clearance and Survival in Murine Gram-Negative Pneumonia
- 10 April 1999
- journal article
- research article
- Published by Mary Ann Liebert Inc in Human Gene Therapy
- Vol. 10 (6), 899-909
- https://doi.org/10.1089/10430349950018300
Abstract
Tumor necrosis factor alpha (TNF) has been shown to be an essential cytokine mediator of innate immunity in bacterial pneumonia. To augment the expression of TNF within the lung, a recombinant adenoviral vector containing the murine TNF cDNA (Ad5mTNF) has been developed, and the intratracheal administration of this vector resulted in the dose- and time-dependent expression of TNF in the lung, but not systemically. Administration of Ad5mTNF resulted in significant airspace and peribronchial inflammation, with a predominant neutrophil influx by 2 days, and mononuclear cell infiltrates by 4 to 7 days posttreatment. Importantly, the administration of Ad5mTNF at a dose of 1 X 10 8 PFU significantly improved the survival of animals challenged concomitantly with Klebsiella pneumoniae, which occurred in association with enhanced clearance of bacteria from the lung and decreased dissemination of K. pneumoniae to the bloodstream. However, the delivery of higher doses of Ad5mTNF (5 X 10 8 PFU) was not beneficial and in fact the intratracheal administration of a similar dose of control vector (Ad5LacZ) actually enhanced Klebsiella -induced lethality by impairing clearance of K. pneumoniae from the lung. Our studies suggests that the transient transgenic expression of TNF within the lung dose dependently augments antibacterial host defense in murine Klebsiella pneumonia.Keywords
This publication has 27 references indexed in Scilit:
- Tumour immunotherapy using an adenoviral vector expressing a membrane-bound mutant of murine TNFαGene Therapy, 1997
- Neutralization of Macrophage Inflammatory Protein-2 Attenuates Neutrophil Recruitment and Bacterial Clearance in Murine Klebsiella PneumoniaThe Journal of Infectious Diseases, 1996
- Pulmonary Inflammation Induced by Incomplete or Inactivated Adenoviral ParticlesHuman Gene Therapy, 1995
- Adenovirus-Mediated Blockade Of Tumor Necrosis Factor In Mice Protects Against Endotoxic Shock Yet Impairs Pulmonary Host DefenseThe Journal of Infectious Diseases, 1995
- Inhibition of Interleukin-1-Induced Effects in Synoviocytes Transduced with the Human IL-1 Receptor Antagonist cDNA Using an Adenoviral VectorHuman Gene Therapy, 1995
- Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosisNature Genetics, 1994
- Phagocyte function and cytokine production in community acquired pneumonia.Thorax, 1994
- Recombinant Cytokines and Pulmonary Host DefenseThe American Journal of the Medical Sciences, 1993
- Divergent Efficacy of Antibody to Tumor Necrosis Factor- in Intravascular and Peritonitis Models of SepsisThe Journal of Infectious Diseases, 1991
- Shock and Tissue Injury Induced by Recombinant Human CachectinScience, 1986