Abstract
MF59 is an oil-in-water emulsion adjuvant approved for human influenza vaccination in European Union. The mode of action of MF59 is not fully elucidated yet, but results from several years of investigation indicate that MF59 establishes an immunocompetent environment at injection site which promotes recruitment of immune cells, including antigen presenting cells (APCs), that are facilitated to engulf antigen and transport it to draining lymph node (dLN) where the antigen is accumulated. In vitro studies showed that MF59 promotes the differentiation of monocytes to dendritic cells (Mo-DCs). Since after immunization with MF59, monocytes are rapidly recruited both at the injection site and in dLN and appear to have a morphological change toward a DC-like phenotype, we asked whether MF59 could play a role in inducing differentiation of Mo-DC in vivo. To address this question we immunized mice with the auto-fluorescent protein Phycoerythrin (PE) as model antigen, in presence or absence of MF59. We measured the APC phenotype and their antigen uptake within dLNs, the antigen distribution within the dLN compartments and the humoral response to PE. In addition, using Ovalbumin as model antigen, we measured the capacity of dLN APCs to induce antigen-specific CD4 T cell proliferation. Here, we show, for the first time, that MF59 promotes differentiation of Mo-DCs within dLNs from intranodal recruited monocytes and we suggest that this differentiation could take place in the medullary compartment of the LN. In addition we show that the Mo-DC subset represents the major source of antigen-loaded and activated APCs within the dLN when immunizing with MF59. Interestingly, this finding correlates with the enhanced triggering of antigen-specific CD4 T cell response induced by LN APCs. This study therefore demonstrates that MF59 is able to promote an immunocompetent environment also directly within the dLN, offering a novel insight on the mechanism of action of vaccine adjuvants based on emulsions.
Highlights
According to the statement of the World Health Organization reported in its web site, immunization via a vaccine, “is a proven tool for controlling and eliminating life-threatening infectious diseases and is estimated to avert between 2 and 3 million deaths each year
This study elucidates a new aspect of the mode of action of MF59 emulsion adjuvant, which until now was believed to promote the establishment of a transient “immunocompetent” environment at the injection site, resulting in the recruitment of Antigen presenting cells (APCs), which take up antigen and adjuvant and transport them to draining lymph node (dLN), where they trigger the immune response[11,12,13,14, 16, 25, 27]
This proposed mechanism of action for MF59 is still valid, our study demonstrates that at least an additional mechanism of MF59 adjuvant activity exists, by which MF59 promotes an “immunocompetent” environment that induces differentiation of antigen-loaded and activated monocytes toward dendritic cells (DCs) (Mo-DCs), directly in the dLN
Summary
According to the statement of the World Health Organization reported in its web site, immunization via a vaccine, “is a proven tool for controlling and eliminating life-threatening infectious diseases and is estimated to avert between 2 and 3 million deaths each year. After vaccination, in presence of an adjuvant, monocytes are recruited to the inflammation site and can differentiate into DCs, which mature, uptake the antigen and migrate into the dLNs where they can amplify the adaptive immune response, previously initiated by LN-resident DCs or by tissue-resident DCs which migrated earlier into the dLN[17]. Since after immunization with MF59 monocytes are the APCs more rapidly recruited both at the injection site and in the dLN[13], we asked whether MF59 could play a role in promoting differentiation of MoDCs in vivo
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