APC stimulated by CpG oligodeoxynucleotide enhance activation of MHC class I-restricted T cells.

Oligonucleotides containing unmethylated CpG motifs (cytosine-phosphorothioate-guanine oligodeoxynucleotide (CpG ODN)) are potent immunostimulatory agents capable of enhancing the Ag-specific Th1 response when used as immune adjuvants. We evaluated the cellular mechanisms responsible for this effect. Development of a CTL response was enhanced when mice were immunized with peptide-pulsed dendritic cells (DCs) treated with CpG ODN. However, in vitro, CpG ODN had no direct effect on highly purified T cells. In vitro, CpG ODN treatment of peptide- or protein-pulsed DCs enhanced the ability of the DCs to activate class I-restricted T cells. The presence of helper T cells enhanced this effect, indicating that treatment with CpG ODN does not obviate the role of T cell help. The enhanced ability of CpG ODN-treated DCs to activate T cells was present but blunted when DCs derived from IL-12 knockout mice were used. Fixation of Ag-pulsed, CpG ODN-treated DCs limited their ability to activate T cells. In contrast, fixation had little effect on DC activation of T cells when DCs were not exposed to CpG ODN. This indicates that production of soluble factors by DCs stimulated with CpG ODN plays a particularly important role in their ability to activate class I-restricted T cells. We conclude that CpG ODN enhances the development of a cellular immune response by stimulating APCs such as DCs, to produce IL-12 and other soluble factors.

Uses of granulocyte-macrophage colony-stimulating factor in vaccine development.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent cytokine capable of inducing differentiation, proliferation, and activation of a variety of immunologically active cell populations. In addition to its effects on stimulating granulocytic hematopoiesis, it also facilitates development of both humoral and cellular mediated immunity. Accordingly, strategies involving the use of GM-CSF as a vaccine adjuvant have attracted considerable attention. These strategies include the systemic administration of soluble GM-CSF with an immunogen, and also its use as part of gene therapy approaches to immunization. Because of the potency of this cytokine as an immune adjuvant, particular interest has focused on its use to overcome poorly immunogenic antigens such as those associated with intracellular infections and cancer. This review focuses on recent advances in the use of GM-CSF as a vaccine adjuvant.

CpG oligodeoxynucleotides enhance monoclonal antibody therapy of a murine lymphoma.

Bacterial DNA and synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine dinucleotides known as cytosine phosphorothioate guanine oligodeoxynucleotides (CpG ODN) can activate various immune-cell subsets, including cells that participate in antibody-dependent cell-mediated cytotoxicity (ADCC). Studies have shown that CpG ODN enhance the efficacy of antitumor monoclonal antibody (MoAb) therapy in the 38C13 murine B-cell lymphoma. We performed a series of in vivo experiments using this tumor model to better characterize combination therapy with MoAb and CpG ODN. CpG ODN enhanced the efficacy of MoAb therapy of lymphoma in a dose-dependent manner. This effect was seen whether the CpG ODN was given before or after the MoAb therapy, but was decreased when CpG ODN was given more than 2 days after MoAb therapy. Three doses of CpG ODN and MoAb were more effective than single doses. There was no obvious toxicity with multiple dosing. These studies confirm that immunostimulatory CpG ODN enhance the efficacy of MoAb therapy, and that multiple courses of combination therapy with CpG ODN can serve as an effective therapy for lymphoma. Further exploration of this potentially potent combination of treatments, including clinical evaluation, is indicated.