Journal
HUMAN VACCINES & IMMUNOTHERAPEUTICS
Volume 10, Issue 12, Pages 3711-3721Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/21645515.2014.980682
Keywords
dendritic cells; gene expression profile; heparan sulfate; humoral immune response; toll-like receptor signaling pathway; vaccine adjuvant
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Funding
- National High Technology Research and Development Program (863 Program) of China [2012AA02A406]
- National Natural Science Foundation of China (NSFC) [31301044]
- Innovation Team Project of Yunnan province of China [2011CI140]
- Applied and Fundamental Research program of Yunnan Province [2013FA025, 2013FZ133]
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The traditional vaccine adjuvant research is mainly based on the trial and error method, and the mechanisms underlying the immune system stimulation remaining largely unknown. We previously demonstrated that heparan sulfate (HS), a TLR-4 ligand and endogenous danger signal, effectively enhanced humoral and cellular immune responses in mice immunized by HBsAg. This study aimed to evaluate whether HS induces better humoral immune responses against inactivated Hepatitis A or Rabies Vaccines, respectively, compared with traditional adjuvants (e.g. Alum and complete Freund's adjuvant). In order to investigate the molecular mechanisms of its adjuvanticity, the gene expression pattern of peripheral blood monocytes derived DCs (dendritic cells) stimulated with HS was analyzed at different times points. Total RNA was hybridized to Agilent SurePrint G3 Human Gene Expression 8 x 60 K one-color oligo-microarray. Through intersection analysis of the microarray results, we found that the Toll-like receptor signaling pathway was significantly activated, and NF-kB, TRAF3 and IRF7 were activated as early as 12 h, and MyD88 was activated at 48 h post-stimulation. Furthermore, the expression of the surface marker CD83 and the co-stimulatory molecules CD80 and CD86 was up-regulated as early as 24 h. Therefore, we speculated that HS-induced human monocyte-derived DC maturation may occur through both MyD88-independent and dependent pathways, but primarily through the former (TRIF pathway). These data provide an important basis for understanding the mechanisms underlying HS enhancement of the immune response.
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