title: Human serum amyloid P functions as a negative regulator of the innate and adaptive immune responses to DNA vaccines.
abstract: The utility of DNA vaccines has been limited by their failure to elicit sufficiently potent immune responses in many human applications, whereas DNA vaccinations in mice have been very successful. However, the underlying mechanisms remain unknown. We hypothesize that serum amyloid P component (SAP), which has a species-specific, DNA-binding ability, contributes to the differences between human and mice and then limits DNA vaccine's efficacy in vivo. In our study, DNA vaccine-induced adaptive immune responses were also significantly decreased in the human SAP (hSAP) transgenic mice. Using human promonocytic cell line THP-1-derived macrophages as a cell model, we found that cells incubated with a hSAP-DNA complex showed significant defects in innate immune activations, whereas mouse SAP had similar, albeit very weak, activities. hSAP also significantly inhibited the functions of two identified DNA sentinels, high-mobility group B protein 1 and antimicrobial peptide LL37, and redirected DNA update to FcRs leading to endocytosis and endosomal degradation. We also found that a chemical SAP inhibitor strongly recovered the suppressed innate immune responses to DNA in the presence of human serum and enhanced the immunogenicity of DNA vaccines in vivo. Our data indicated that SAP is a key negative regulator for innate immune responses to DNA and may be partly responsible for the insufficient immune responses after DNA vaccinations in humans. SAP suppression may be a novel strategy for improving efficacy of human DNA vaccines and requires further clinical investigations.
authors.affiliation: Department of Medical Genetics, Second Military Medical University, Shanghai 200433, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Guo
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Huang
authors.forename: Jingli
authors.initials: J
authors.lastname: Shang
authors.forename: Shuhan
authors.initials: S
authors.lastname: Sun
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D000683:Serum Amyloid P-Component / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000276:immunology* / Q000592:standards
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D000683:Serum Amyloid P-Component; D019444:Vaccines, DNA