title: Dendritic cells stimulated with a bacterial product, OK-432, efficiently induce cytotoxic T lymphocytes specific to tumor rejection peptide.
abstract: Dendritic cells (DCs) are potent antigen-presenting cells, which have recently been applied for cancer immunotherapy using epitope peptides. Accumulating results of the clinical trials of such a strategy suggest that maturity of the applied DCs has a significant impact on the outcome of the vaccination. Here we examined the effects of penicillin-killed Streptococcus pyogenes (OK-432) on DC maturation and functions including induction of CTLs. DCs generated from peripheral blood using granulocyte macrophage colony-stimulating factor and interleukin (IL)-4 showed immunophenotypes consistent with immature DCs (iDCs). These iDCs were further incubated with medium alone, tumor necrosis factor alpha, lipopolysaccharide, or OK-432. The immunophenotypical analysis showed DCs stimulated with OK-432 (OK-DCs) possessed significantly higher expression of CD83 compared with unstimulated DCs. Furthermore, OK-DCs showed significantly higher production of IL-12 and IFN-gamma compared with DCs with other stimulations. These results indicate that OK-432 stimulates iDCs to have a mature phenotype and to produce a significant amount of T-helper 1-type cytokines. To examine the potency of OK-DCs on the induction of specific CTLs, the tumor rejection peptide derived from carcinoembryonic antigen was used as a model antigen. The HLA-tetramer assay showed that potent CTL was induced with OK-DCs at high frequency. These results indicate that OK-432 efficiently stimulates DCs without interfering with the presentation of pulsed peptide. Furthermore, OK-432 does not activate nuclear factor kappaB through Toll-like receptor 2 or Toll-like receptor 4 in the indicator cell system; however, it induces IL-12 production through the beta(2) integrin system on DCs. These results strongly suggest that OK-432 could be applied to develop an efficient cancer vaccine using DCs pulsed with tumor rejection peptides.
authors.affiliation: Department of Surgery and Bioengineering, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Nakahara
authors.forename: Takuya
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Baba
authors.forename: Shinichi
authors.initials: S
authors.lastname: Asabe
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tahara
mesh_terms: D018821:CD18 Antigens / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D010844:Picibanil / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D018821:CD18 Antigens; D018984:Epitopes, T-Lymphocyte; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D016753:Interleukin-10; D018664:Interleukin-12; D010844:Picibanil; D007371:Interferon-gamma