Näkökohtia rokotteista ja vaikutuksesta APOBEC järjestelmään

https://www.ncbi.nlm.nih.gov/pubmed/25953029

Immunol Cell Biol. 2015 Nov;93(10):868-76. doi: 10.1038/icb.2015.53. Epub 2015 May 8.

Modulating APOBEC expression enhances DNA vaccine immunogenicity.

Almeida RR^1,2, Raposo RA³, Coirada FC¹, da Silva JR⁴, de Souza Ferreira LC⁴, Kalil J^1,2,5, Nixon DF³, Cunha-Neto E^1,2,5.

Abstract

DNA vaccines have failed to induce satisfactory immune responses in humans. Several mechanisms of double-stranded DNA (dsDNA) sensing have been described, and modulate DNA vaccine immunogenicity at many levels. We hypothesized that the immunogenicity of DNA vaccines in humans is suppressed by APOBEC (apolipoprotein B (APOB) mRNA-editing, catalytic polypeptide)-mediated plasmid degradation. We showed that plasmid sensing via STING (stimulator of interferon (IFN) genes) and TBK-1 (TANK-binding kinase 1) leads to IFN-β induction, which results in APOBEC3A mRNA upregulation through a mechanism involving protein kinase C signaling. We also showed that murine APOBEC2 expression in HEK293T cells led to a 10-fold reduction in intracellular plasmid levels and plasmid-encoded mRNA, and a 2.6-fold reduction in GFP-expressing cells. A bicistronic DNA vaccine expressing an immunogen and an APOBEC2-specific shRNA efficiently silenced APOBEC2 both in vitro and in vivo, increasing the frequency of induced IFN-γ-secreting T cells. Our study brings new insights into the intracellular machinery involved in dsDNA sensing and how to modulate it to improve DNA vaccine immunogenicity in humans.

PMID:

25953029

DOI:

10.1038/icb.2015.53

[Indexed for MEDLINE]