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Influence of TLR-agonists on expression by antigen-presenting cells of the target protein antigen encoded in adenoviral vector


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Abstract

Replication-defective recombinant adenoviral vectors (rAd) represent one of the advantageous platforms for development of genetic vaccines. A target gene inserted into rAd is transcribed in cells of the vaccinated human, namely in macrophages and dendritic cells which are effective antigen-presenting cells (APC). The target antigen production is continued in the human organism during 2-3 weeks following administration of rAd, encoding the antigen. It induces intensive responses of T- and B-cells specific to the target antigen. Immune responses against the rAd-encoded target antigen can be enhanced with a use of immune adjuvants, in particular, agonists of Toll-like receptors which stimulate APC for production of pro-inflammatory cytokines and chemokines as well as expression of co-stimulatory receptors on the cell membrane. We hypothesized that a combined use o f TLR-agonists with the target antigen encoding rAd can enhance a production of the target antigen in APC, along with above mentioned immunostimulation effects. In this work we showed an immunoadjuvant effect of TLR4-agonist (Immunomax) administered in BALB/c mice during their immunization with the rAd-HA construct comprising gene of H1N1 Influenza virus hemagglutinin. Using in vitro cell cultures a direct stimulation of antigen-presenting dendritic cells by the TLR4-agonist was revealed which significantly enhanced the response of interferon-gamma secreting antigen-recognizing T cells. We examined expression of rAd-encoded protein antigens in dendritic cells and macrophages. Using cytoplasmic, membrane-bound and secretory target proteins, we showed that TLR4-agonist enhanced production of these three target proteins in APC. Both the number of APCs producing the antigen and the accumulation of the target protein in each antigen-producing cell were increased under influence of the TLR4-agonist. A comparison of Immunomax with agonists of other TLRs revealed that agonists of TLR2, TLR4, TLR5, TLR7, TLR8 and TLR9 enhanced, but the agonist of TLR3, unexpectedly, suppressed the expression of rAd-encoded target proteins.


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