CPG DNA promotes the maturation and function of human monocyte-derived dendritic cells (modc) via indirect effects

Anissa S.H. Chan, David P. Pond, Angela Panoskaltsis-Mortari, Jianli Wang, Arthur M. Krieg, Bruce R. Blazar, Wei Chen

Research output: Contribution to journalArticle

Abstract

Bacterial DNA containing unmethylated CpG motifs are excellent immune adjuvants that preferentially induce Thl-responses. In this study, we examined the effect of CpG oligodeoxynucleotides (ODN) on the maturation and function of human CD14 MoDC. CpG ODNs have been shown to stimulate DC, NK cell and B cell activation and the release of proinflammatory cytokines. Adding the CpG ODN, 2006 (5 (Ig/ml), on days 0, 3,5, or 7 to GM-CSF/1L-4 driven MoDC cultures for 2-3 days had modest effects on MoDC generation and maturation. However, in MoDC cultures containing 5-15% NK and B cells, CpG 2006 resulted in a rapid activation and maturation of MoDC. Significant increases of cell surface expression of HLA-ABC, -DR, CD40, CD54, CD80, CD83, and CD86 were detected on the CpG 2006-treated as compared to non-treated MoDC controls. MLR responses induced by CpG 2006-treated MoDC were 1.8- to 3.3-fold greater than non-treated MoDC controls and 56- to 160-fold greater than that induced by peripheral blood mononuclear cells (PBMNC). To determine the potential mechanism of MoDC maturation, the effect of CpG 2006 on purified CD56 NK cells, CD19 B cells, and CD14" monocytes from normal donors (n=5) was analyzed. CpG 2006 induced rapid activation of bulk PBMNC in short-term (48 hrs) cultures with enhanced production of IFNa, IFNy, TNFa, IL-6, and IL-12p40 in culture supernatants. Supernatant from the CpG cultured cells added to day-7 MoDC cultures induced MoDC activation. Treating CD56 NK cells with CpG 2006 upregulated the cell surface expression of CD69, augmented cytolytic activity against human NK-sensitive and NK-resistant leukemia cell lines, and increased IFNy and TNFa production. CpG 2006 treatment of CD 19 B cells induced proliferation and increased IL-6 and TNFa production. In contrast, treating purified CD14 cells with CpG 2006 did not show enhanced cytokine production. Neither IL-18 nor IL-12p70 was detected in CpG-treated groups. Adding purified NK or B cells with CpG 2006 to immature MoDC derived from purified CD 14 cells reproduced the observed CpG-induced maturation effects on MoDC. In summary, the data demonstrate that a CpG ODN can promote the maturation and function of CD 14+ MoDC via indirect effects. The findings support the potential of using CpG ODN as an immune adjuvant for MoDCbased vaccines in immunotherapy trials.

Original languageEnglish (US)
JournalBlood
Volume96
Issue number11 PART II
StatePublished - Dec 1 2000

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