Immunomodulatory properties of live attenuated Bordetella pertussis vaccine candidate BPZE1
Abstract number: R2764
Fedele G., Bianco M., Debrie A., Locht C., Ausiello C.M.
Objectives: New vaccines against pertussis are needed to evoke long lasting protection and immunological memory starting from the first administration in neonates. A novel live attenuated B. pertussis vaccine strain, BPZE1, has been developed by eliminating or detoxifying three important B. pertussis virulence factors: pertussis toxin, dermonecrotic toxin and tracheal cytotoxin. With the aim to evaluate BPZE1 immunomodulatory properties in human pre-clinical models, we used an ex vivo model based on monocyte-derived (MD) dendritic cells (DC) challenged with BPZE1.
Methods: Human immature MDDC were obtained by culturing purified monocytes in the presence of GM-CSF and IL-4 for 6 days. MDDC were challenged with BPZE1 or its parental wild type counterpart, BPSM. After 48 h MDDC were harvested for immunophenotypic analysis and the supernatants collected for cytokine measurement by ELISA. Resistance of BPZE1-challenged MDDC to apoptosis was assessed by AnnexinV/Propidium Iodide staining. Chemokine-driven chemotaxis was also evaluated. Co-culture experiments with T lymphocytes were performed to assess antigen-presenting activity, T-helper cell polarizing ability and induction of functional suppressor T cells.
Results: BPZE1 is able to induce phenotypic maturation of human MDDC which are resistant to apoptosis. BPZE1-primed MDDC produce a broad spectrum of proinflammatory and regulatory cytokines, and very efficiently migrate in vitro in response to the lymphatic chemokine CCL21, due to the inactivation of the pertussis toxin enzymatic activity. BPZE1-primed MDDC acquire antigen-presenting capacity, drive a mixed Th1/Th17 polarization, and induce functional suppressor T cells. Suppressing activity requires cell contact rather than the production of soluble factors.
Conclusion: Our findings support the potential of BPZE1 as a novel live attenuated pertussis vaccine strongly activating the maturation of DC with full-blown activity. BPZE1-challenged DC acquire the capacity to survive death signals and migrate from the site of infection to the lymph nodes. BPZE1-committed DC have the ability to orchestrate a broad spectrum of Th1/Th17 responses, protective in experimental B. pertussis infection, and regulatory T cell responses, likely balancing each other to restore local homeostasis.
This work was supported by grant from EC project CHILDINNOVAC-HEALTH-F32007201502
|Session name:||Abstracts of 21st ECCMID / 27th ICC|
|Location:||Milan, Italy, 7 - 10 May 2011|
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