CpG DNA: A potent signal for growth, activation, and maturation of human dendritic cells

Abstract

DNA molecules containing unmethylated CpG-dinucleotides in particular base contexts (''CpG motifs'') are excellent adjuvants in rodents, but their effects on human cells have been less clear. Dendritic cells (DCs) form the link between the innate and the acquired immune system and may inf luence the balance between T helper 1 (Th1) and Th2 immune responses. We evaluated the effects of CpG oligodeoxynucleotides alone or in combination with granulocytemacrophage colony-stimulating factor (GMCSF) on different classes of purified human DCs. For primary dendritic precursor cells isolated from human blood, CpG oligonucleotides alone were superior to GMCSF in promoting survival and maturation (CD83 expression) as well as expression of class II MHC and the costimulatory molecules CD40, CD54, and CD86 of DCs. Both CD4-positive and CD4-negative peripheral blood dendritic precursor cells responded to CpG DNA which synergized with GMCSF but these DCs showed little response to lipopolysaccharide (LPS). In contrast, monocyte-derived DCs did not respond to CpG, but they were highly sensitive to LPS, suggesting an inverse correlation between CpG and LPS sensitivity in different subsets of DCs. Compared with GMCSF, CpG-treated peripheral blood DCs showed enhanced functional activity in the mixed lymphocyte reaction and induced T cells to secrete increased levels of Th1 cytokines. These findings demonstrate the ability of specific CpG motifs to strongly activate certain subsets of human DCs to promote Th1-like immune responses, and support the use of CpG DNA-based trials for immunotherapy against cancer, allergy, and infectious diseases.The vertebrate immune system has the ability to recognize the presence of bacterial DNA on the basis of recognition of so-called CpG motifs, unmethylated cytidine-guanosine dinucleotides within a specific pattern of flanking bases (1). It is known from the literature that CpG oligonucleotides are excellent adjuvants in murine models. CpG DNA is as potent as the complete Freund's adjuvant regarding the induction of B cell and T cell responses, but it is less toxic and it induces a T helper 1 (Th1) response (2, 3). Alum, the adjuvant that is used routinely in human vaccination, induces the less favorable Th2 response. CpG is more effective than alum, and the combination of CpG and alum shows synergy in mice (4, 5). CpG oligonucleotides enhance the efficacy of immunization with tumor antigen in a murine B cell lymphoma model (2), induce antigen-specific cytotoxic T cell responses (5, 6), and have utility in the immunotherapy of allergy, infectious disease, and cancer disease models (7-9). Furthermore, the presence of immunostimulatory DNA sequences in plasmids has been shown to be required for effective intradermal gene immunization (10).Dendritic cells (DCs) form the link between the innate and the acquired immune system by presenting antigens and by their expression of pattern recognition receptors that detect microbial molecules in their local environment. The use of DCs as a cellular adju...

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