The most common cause of death among patients with cystic fibrosis (CF) is prolonged purulent bronchitis caused by Pseudomonas aeruginosa, resulting in eventual respiratory failure. Antibiotic therapy has been unsuccessful in eradicating Pseudomonas lung infection among these patients. Accordingly, alternative clinical strategies for prevention or treatment of Pseudomonas respiratory infection in CF patients are essential. Recent work in our laboratory has demonstrated that active immunization of guinea pigs with lipopolysaccharide Pseudomonas vaccine produces significant protection against subsequent experimentally induced chronic Pseudomonas pneumonia. This lung protection was manifested by reduced numbers of Pseudomonas in the lungs of vaccinees and also reduced pulmonary histopathology. The present proposal is designed to expand these studies. Specifically, a variety of immunizing regimens will be evaluated to determine the most feasible yet protective method for active immunization with LPS Pseudomonas vaccine. Also, immunologic methods will be studied to evaluate prospective systems of monitoring the degree of pulmonary protection after vaccination. Further, an evaluation of the mechanisms by which LPS vaccine confers pulmonary protection will be carried out. Specifically, humoral and cellular immune responses, plus intrapulmonary immune events will be evaluated. And finally, the adverse and/or beneficial effects of glucocorticosteroid administration during chronic Pseudomonas lung infection will be assessed; and the interaction of LPS immunization and steroids in this model will be determined. It is our intent that these studies provide the requisite pre-clinical data necessary for determining the feasibility and planning the methodology for a clinical trial of prophylactic Pseudomonas immunization among cystic fibrosis patients.
