Important note: Information in this article was accurate in August 1999. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, August 30, 1999
Daniel J. DeNoon, Senior Editor
CW HENDERSON PUBLISHER -- A bacterial DNA motif greatly increases the growth, activation, and maturation of human dendritic cells.
Dendritic cells (DCs) are the body's key antigen- presenting cells (APCs). They represent the link between ancient innate immunity and the more complex acquired immune system. In response to unmethylated cytidine-guanosine dinucleotides (CpG motifs), DCs initiate T-helper type 1 (Th1) immunity. Th1 cell-mediated immune responses are particularly effective against viruses and tumor cells.
CpG dinucleotides are far more common in bacterial genomes than in vertebrate DNA and quickly are recognized as foreign invaders. These motifs therefore represent a potent new tool not only for use as vaccine adjuvants but also for ex vivo expansion and sensitization of DCs for the treatment of cancer and infectious diseases.
Previous studies showed that CpG motifs have extremely potent adjuvant effects in the mouse model (see Vaccine Weekly, June 28, 1999). Now researchers at the University of Iowa (with ties to CpG ImmunoPharmaceuticals Inc.) have shown that they have similar effects on human DCs.
"Our results suggest that treatment with the combination of CpG and DCs, with or without GMCSF [granulocyte-macrophage colony-stimulating factor], may be a promising immunotherapeutic strategy," wrote G. Hartmann and colleagues.
Hartmann et al. reported their findings in the Proceedings of the National Academy of Sciences ("CpG DNA: A Potent Signal for Growth, Activation, and Maturation of Human Dendritic Cells," PNAS, 1999;96:9305-10).
Human DCs can be obtained in three ways: from CD14(+) monocytes incubated with GMCSF and interleukin-4 (IL-4); from stem cells; and by isolation from the peripheral blood.
Hartmann et al. hypothesized that CpG motifs directly activate DCs. They exposed DCs derived from each of the above three methods to CpG with or without GMCSF.
In primary DCs isolated directly from human blood, CpG promoted survival, maturation, and expression of immunogenic molecules (class II MHC, CD40, CD54, and CD86). These effects were independent of, and synergistic with, GMCSF.
However, CpG had no effect on monocyte-derived DCs.
"We demonstrate that CpG DNA is a more potent stimulus than GMCSF for inducing primary blood DC survival, differentiation, activation, maturation, and the functional ability to produce a Th1-like cell response," Hartmann et al. wrote.
The authors suggested that blood-derived DCs activated with CpG have several therapeutic advantages over monocyte- or stem-cell-derived DCs:
"Our studies also suggest that systemic administration of CpG could enhance the availability of immature and mature DCs in the blood and in tissues, and so increase the efficacy of immunization," Hartmann et al. wrote.
"The findings ... support the use of CpG DNA-based trials for immunotherapy against cancer, allergy, and infectious diseases."
This study was supported by grants from the Deutsche Forschungsgemeinschaft, the U.S. Department of Veterans Affairs, the U.S. National Institutes of Health, and CpG ImmunoPharmaceuticals, Hilden, Germany and Wellesley, Massachusetts.
The corresponding author for this study is A.M. Krieg, Department of Internal Medicine, University of Iowa, 540 EMRB, Iowa City, IA 52242. Email: <amkrieg@blue.weeg.uiowa.edu>.
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