Streptococcal preparation OK432 promotes functional maturation of human monocyte-derived dendritic cells

Abstract.

Streptococcal preparation OK432 is an immunomodulatory agent extensively used as adjuvant therapy for gastric cancer in Japan. OK432 augments the cytotoxic activity of various effector cells such as lymphocytes, macrophages and (natural killer) NK cells and induces the production of multiple cytokines. Dendritic cells (DC) are professional antigen-presenting cells (APC) that can be used for cancer vaccine therapy. In the present study, we investigated the effect of OK432 on the activation of DC. Here we report that OK432 induced phenotypic and functional maturation of human monocyte-derived DC. In vitro culture of immature DC generated from adherent peripheral blood mononuclear cells (PBMC) using granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) with OK432 at various doses (0.01 to 0.1 KE/ml) for 2 days resulted in increased cell surface expression of CD80, CD83, CD86 and ICAM-1 in a dose-dependent manner. The expression of CD83, a selective marker of mature DC, on DC activated by OK432 (OK-DC) was maximally enhanced after 3 days of incubation. Assay of cytokine production in OK-DC after 2 days in culture revealed that OK432 was a strong inducer of IL-12 and interferon-gamma (IFN-γ). OK432 efficiently augmented the primary allogeneic T-cell responses by DC. This distinct phenotypic profile and allostimulatory capacity of OK-DC was stable for at least 48 h of additional culture in the absence of any cytokines. Moreover, the antiviral cytotoxic T lymphocytes (CTL) response in vitro was also enhanced by the addition of OK432 to the cultures. These findings suggest that OK432 is a potent stimulator of DC, and that stimulated DC are strong inducers of the T helper 1 (Th1)-type response. We conclude that OK-DC are likely candidates for use as an adjuvant for DC-based cancer immunotherapy.