Antibody Dependent Enhancement ofAcinetobacter baumanniiInfection in a Mouse Pneumonia Model
| Autor: | Ruth Olson, Janet M. Beanan, Shun Xin Wang-Lin, Thomas A. Russo, Joseph P. Balthasar, Ulrike MacDonald |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Pharmacology biology Virulence biology.organism_classification Microbiology Acinetobacter baumannii 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Immune system In vivo Monoclonal biology.protein Molecular Medicine Antibody-dependent enhancement Antibody Pathogen 030217 neurology & neurosurgery |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 368:475-489 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.118.253617 |
| Popis: | Acinetobacter baumannii has become a pathogen of increasing medical importance because of the emergence of multidrug-resistant strains and the high rate of mortality of infected patients. Promising animal study results have been reported recently with active and passive immunization against A. baumannii virulence factors. In the present study, a monoclonal IgG3 antibody, 8E3, was developed with specificity for the K2 capsular polysaccharide of A. baumannii, and its therapeutic potential was assessed. 8E3 enhanced macrophage-mediated bactericidal activity against the A. baumannii clinical strain AB899. However, 8E3 treatment (passive immunization) of AB899-infected mice led to a substantial increase in mortality and to substantial increases in bacterial load in blood, lung, and in splenic samples. In vitro investigations showed a large binding capacity in the supernatant of bacterial cultures, suggesting that shed capsule components act as a binding sink for 8E3. Investigations of 8E3 pharmacokinetics in mice demonstrated that unbound concentrations of the antibody dropped below detection limits within 24 hours after a 200 mg/kg dose. However, total concentrations of antibody declined slowly, with an apparent terminal half-life (t1/2) of 6.7–8.0 days, suggesting that the vast majority of 8E3 in blood is bound (e.g., with soluble capsule components in blood). We hypothesize that high concentrations of 8E3-capsule immune complexes act to inhibit bacterial clearance in vivo. To the best of our knowledge, this is the first demonstration of antibody-dependent enhancement of A. baumannii infection, and these observations highlight the complexity of antibody-based therapy for A. baumannii infections. |
| Databáze: | OpenAIRE |
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