Abstract
Dendritic cells are potent activators of the immune system and have a key role in linking innate and adaptive immune responses. In the current study we have used ex vivo pulsed bone marrow dendritic cells (BMDC) in a novel adoptive transfer strategy to protect against challenge with Bacillus anthracis, in a murine model. Pre-pulsing murine BMDC with either recombinant Protective Antigen (PA) or CpG significantly upregulated expression of the activation markers CD40, CD80, CD86 and MHC-II. Passive transfusion of mice with pulsed BMDC, concurrently with active immunisation with rPA in alum, significantly enhanced (p<0.001) PA-specific splenocyte responses seven days post-immunisation. Parallel studies using ex vivo DCs expanded from human peripheral blood and activated under the same conditions as the murine DC, demonstrated that human DCs had a PA dose-related significant increase in the markers CD40, CD80 and CCR7 and that the increases in CD40 and CD80 were maintained when the other activating components, CpG and HK B. anthracis were added to the rPA in culture. Mice vaccinated on a single occasion intra-muscularly with rPA and alum and concurrently transfused intra-dermally with pulsed BMDC, demonstrated 100% survival following lethal B. anthracis challenge and had significantly enhanced (p<0.05) bacterial clearance within 2 days, compared with mice vaccinated with rPA and alum alone.
Highlights
Dendritic cells (DCs) are potent activators of the adaptive immune system [1] and are critical for host defence against pathogens
An alternative approach is to activate DCs in situ through the ligation of their cell surface receptors with monoclonal antibody conjugated to the antigen of interest, which has been shown to be an efficacious method of enhancing adaptive immune responses to pathogens [5]
DCs were stimulated ex vivo, with vaccine antigens (rPA or heat-killed (HK) B. anthracis spores) or adjuvant (CpG) and the upregulation of costimulatory markers was assessed by flow cytometry
Summary
Dendritic cells (DCs) are potent activators of the adaptive immune system [1] and are critical for host defence against pathogens. DCs alter their phenotype and home to lymph nodes where they initiate and polarise an adaptive immune response by presentation of peptides on MHC-II molecules to CD4+ T cells or by cross-priming on MHC-I molecules to CD8+ T cells [3]. Their ability to induce antigen-specific T cell and antibody responses and their ability to be cultured in vitro has enabled DCs to be trialled as cellular vaccines, both for infectious diseases and in cancer, resulting in either tumour or infectious disease regression or eradication [4]. An alternative approach is to activate DCs in situ through the ligation of their cell surface receptors with monoclonal antibody conjugated to the antigen of interest, which has been shown to be an efficacious method of enhancing adaptive immune responses to pathogens [5]
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