polymorphonuclear leukocyte released elastase. During childhood, most cystic fibrosis AZD-5438 patients have recurrent lung infections with Staphylococcus aureus and Haemophilus influenzae. With increasing age, chronic lung infections with mucoid Pseudomonas aeruginosa become more prevalent, and up to 80% of all adult CF patients become chronically infected. Chronic lung infection in CF patients is manifested as an endobronchiolitis, with the bacteria located as microcolonies without penetrating the periluminal tissue. At this stage P. aeruginosa is rarely eliminated despite a pronounced antibody response to numerous antigens and an abundance of polymorphonuclear leukocytes in the bronchial secretions. Previously we described a chronic lung infection induced in normal rats by intratracheal administration of mucoid P.
aeruginosa embedded in seaweed alginate. The pathological and serological responses were similar to those observed in patients with CF. Alginate is a major virulence factor which provides protection from the host defense mechanisms by interfering with the clearance of P. aeruginosa as a result of its antiphagocytic properties. It has been shown that a subpopulation of antibodies Epothilone A against alginate are able to promote the uptake and killing of mucoid P. aeruginosa by Corresponding author. Mailing address: Department of Clinical Microbiology, Rigshospitalet, Afsnit 7806, Tagensvej 20, DK 2200 Copenhagen N, Denmark. Phone: 45 35327899. Fax: 45 35456831. human PMNs. Most commonly the initial colonizing strains in CF patients are nonmucoid, and a shift to a mucoid phenotype occurs with time.
However, evidence that the early colonizing strains also produces small amounts of alginate has accumulated. Furthermore, it has been found that elevated levels of opsonic anti alginate antibodies correlate with lack of detectable P. aeruginosa lung infection in a group of older CF patients. In this study we have used native alginate and a depolymerized alginate vaccine which is covalently coupled to toxin A. This has previously elicited antibodies which were cross reactive with heterologous alginate and which could be of importance in trying to prevent the subsequent chronic lung infection. Lipopolysaccharide plays an important role in the virulence of P. aeruginosa by activating complement and inducing production of cytokines.
Elevated levels of antibodies to LPS and toxin A have been found to correlate with survival from P. aeruginosa bacteremia. It has been shown that in CF patients, infection induced anti LPS antibodies against P. aeruginosa possessed affinities at least 100 fold less than those induced by vaccination with an octavalent O polysaccharide toxin A vaccine. By using a chronic lung infection model in rats, it has been shown that P. aeruginosa toxin A positive mutant strains causes parenchymal changes and bronchial inflammation, indicating the impor 3146 IMMUNIZATION WITH P. AERUGINOSA VACCINES 3147 tance of this virulence factor. The O PS toxin A vaccine, which in CF patients was able to raise high levels of antibodies to LPS and toxin A, was therefore included in the present study. In a recent study we found that subcutaneous immunization with P. aeruginosa whole cell sonicate on days 0, 14, and 21 elicited high immunoglobulin G and IgA