Immune complexes from immunized mice and infected cystic fibrosis patients mediate murine and human T cell killing of hybridomas producing protective, opsonic antibody to Pseudomonas aeruginosa.

Abstract

We examined the basis for the absence in cystic fibrosis (CF) patients of opsonic antibodies to the mucoid exopolysaccharide (MEP) antigen surrounding Pseudomonas aeruginosa that infect these patients. Opsonic antibodies to MEP are found in sera of the minority of CF patients that remain noncolonized into the second to fourth decades of life and protect rodents from chronic P. aeruginosa endobronchial infections. High titers of nonopsonic antibodies to MEP are found in P. aeruginosa-infected CF patients. Immunization of mice with doses of MEP that provoke only nonopsonic antibodies elicited CD3 +, CD8 +, T cell receptor a# receptor +, major histocompatibility complex-unrestricted cytotoxic lymphocytes specific for hybridoma cells producing opsonic but not nonopsonic antibodies. Cytotoxicity was dependent on immune complexes on the surface of the T cells. Normal murine T cells could be activated by concanavalin A and sensitized with immune complexes for cytotoxic killing of hybridoma targets. CF patients infected with P. aeruginosa had serum immune complexes that sensitized concanavalin A-activated human T cells to kill murine hybridoma cells producing opsonic but not nonopsonic antibody. These results could explain the absence in infected CF patients of MEP-specific opsonins, an occurrence that accompanies the persistence of this infectious state. (J. Clin. Invest. 1993. 91:1079-1087 Key words: endobronchial infections * Fc receptors -immunosuppression * mucoid exopolysaccharide* phagocytosis.

Clinical Significance of Microbial Infection and Adaptation in Cystic Fibrosis

“…5). Finally, this exopolysaccharide may have immunomodulatory properties that lead to a dysregulated immune response (98,206,372,459). Interestingly, the selective pressure driving the formation of mucoid mutants is not constant or global; up to 70% of nonmucoid isolates from chronically infected CF patients carry mutations in the mucA gene, suggesting that these strains at one time were mucoid but had reverted to a nonmucoid phenotype (95).…”

Vaccines forPseudomonas aeruginosa: a long and winding road

“…Immunotherapeutic strategies that provide systemic opsonic antibodies to alginate can protect mice and rats from lung infection with mucoid P. aeruginosa encased in agar beads [47]. Alginate, however, is poorly immunogenic in humans [48], possibly because of pre-existing non-opsonic alginate-specific antibodies, which prevent the production of opsonic antibodies in animal models [49]. The role of such antibodies in the protection against initial colonization is not clear, especially in light of the fact that the early P. aeruginosa isolates from young CF patients are nearly always non-mucoid in vitro [44].…”

Microbial pathogenesis in cystic fibrosis: mucoid Pseudomonas aeruginosa and Burkholderia cepacia.

“…Alginate suppresses lymphocyte functions (272). When alginate is used in high doses (but not in low doses) for immunization in mice, it elicits CD3 ϩ CD8 ϩ major histocompatibility complex-unrestricted cytotoxic T cells that selectively kill hybridomas producing opsonic but not nonopsonic antibodies (345). This cytotoxic activity, which is dependent on the presence of immune complexes, may explain the finding that the dose and size of alginate polymer used for immunization studies in mice or human volunteers may be critical parameters determining whether an immunization protocol will elicit opsonic or nonopsonic antibodies (138,339).…”