Streptococcal preparation OK-432: a new maturation factor of monocyte-derived dendritic cells for clinical use.
For vaccinations based on dendritic cells (DCs), maturation of DCs is critical to the induction of T-cell responses. We tested the efficacy of streptococcal preparation OK-432 as a Good Manufacturing Practice (GMP)-grade maturation agent. OK-432 is currently used in Japan as a cancer immunotherapy drug. Immature monocyte-derived dendritic cells (imMo-DCs) isolated from human peripheral blood monocytes stimulated with granulocyte-macrophage colony stimulating factor and interleukin-4 were exposed to maturation factors, i.e., lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF-alpha) plus prostaglandin E2 (PGE2), and OK-432 for 2 days. OK-432 increased expression of activation- and maturation-related molecules such as HLA-DR, CD80, CD83, and CD86 in imMo-DCs at levels similar to that of TNF-alpha plus PGE2, and higher than that of LPS. All agents examined induced allogeneic T-cell proliferation at a similar level. Only OK-432 caused significant production of interleukin-12 (IL-12) p70 and interferon gamma (IFN-gamma) at both the mRNA and protein levels in imMo-DCs. Neutralizing antibody against IL-12 p70 blocked IFN-gamma secretion from OK-432-stimulated Mo-DCs. IL-12 p70 produced by OK-432-stimulated imMo-DCs induced secretion of IFN-gamma by CD4+ T cells. OK-432 and LPS activated nuclear factor kappa B (NF-kappaB) in imMo-DCs. Both secretion of IL-12 p70 and IFN-gamma and activation of NF-kappaB induced by OK-432 were suppressed when imMo-DCs were pretreated with cytochalasin B. These results indicate that uptake of OK-432 by imMo-DCs is an early critical event for IL-12 p70 production and that NF-kappaB activation induced by OK-432 also contributes partially to IL-12 p70 production. In conclusion, OK-432 is a GMP-grade maturation agent and may be a potential tool for DC-based vaccine therapies.
Kuroki
Hideo
H
Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
Morisaki
Takashi
T
Matsumoto
Kotaro
K
Onishi
Hideya
H
Baba
Eishi
E
Tanaka
Masao
M
Katano
Mitsuo
M
D002478:Cells, Cultured; D003571:Cytochalasin B / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology*; D004789:Enzyme Activation; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008213:Lymphocyte Activation; D009000:Monocytes / Q000276:immunology*; D010844:Picibanil / Q000493:pharmacokinetics*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology; D000097782:NF-kappaB-Inducing Kinase
D003571:Cytochalasin B; D007371:Interferon-gamma; D018664:Interleukin-12; D010844:Picibanil; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase