Antitumor Effect of OK-432–Derived DNA
| Autor: | Masato Okamoto, Yoichiro Moriya, Motoo Saito, Shizuo Akira, Mitsunobu Sato, Akiko Sasai, Yoshiki Ryoma, Tetsuya Oshikawa, Tomoyuki Tano, Shin Kan |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Cytotoxicity
Immunologic DNA Bacterial Cancer Research Streptococcus pyogenes medicine.medical_treatment Immunology Antineoplastic Agents Biology Peripheral blood mononuclear cell Picibanil Mice Immune system Cell Line Tumor medicine Animals Humans Immunology and Allergy Pharmacology Interleukin TLR9 Neoplasms Experimental Immunotherapy DNA Methylation Th1 Cells Molecular biology Toll-Like Receptor 9 Toll-Like Receptor 4 CpG site Mutation DNA methylation CpG Islands |
| Zdroj: | Journal of Immunotherapy. 29:143-150 |
| ISSN: | 1524-9557 |
| DOI: | 10.1097/01.cji.0000189028.18288.6f |
| Popis: | OK-432 is a Streptococcus-derived immunotherapeutic agent for malignancies. Our group has tried to identify the effective components of OK-432 and has succeeded in isolating a lipoteichoic acid-related preparation designated as OK-PSA, which is a strong inducer of T helper 1 (T(H)1) cells, and elicits an anticancer effect via Toll-like receptor (TLR) 4. Conversely, bacterial DNA with unmethylated CpG motifs can stimulate a T(H)1-type host response via TLR9. The unmethylated CpG DNA contained in OK-432 may play a role in its anticancer effect. In the current study, we investigated the effect of OK-432-derived DNA (OK-DNA) in augmenting the anticancer immune response. Analysis of OK-DNA with the restriction enzymes Hpa II and MspI revealed that OK-DNA contained unmethylated CpG motifs. OK-DNA induced TH1-type cytokines such as interferon-gamma, tumor necrosis factor-alpha, interleukin (IL)-12, and IL-18 and augmented killer cell activities in vitro on human peripheral blood mononuclear cells, whereas the methylated OK-DNA did not. Cytokines were also produced by OK-DNA-stimulated splenocytes derived from wild-type mice but not from TLR9-deficient mice. In the in vivo study, peritumoral administration of OK-DNA resulted in a significant inhibition of tumor growth in syngeneic tumor-bearing wild-type and TLR4-deficient mice but not in TLR9-deficient mice. The antitumor effect of OK-432 in TLR9-deficient mice was significantly but partially reduced compared with that in wild-type mice, whereas the effect of OK-432 was almost completely eliminated in TLR4-deficient mice. These findings suggest that unmethylated CpG DNA in OK-432 functions as an active component in OK-432-induced anticancer immunity via TLR9. |
| Databáze: | OpenAIRE |
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