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Oral Administration of High Molecular Mass Poly--Glutamate Induces NK Cell-Mediated Antitumor Immunity¹

Tae Woo Kim^*, Tae Young Lee, Hyun Cheol Bae^*, Jeong Ho Hahm, Yang Hyun Kim, Chung Park, Tae Heung Kang^*, Chul Joong Kim, Moon Hee Sung^,¶ and Haryoung Poo^2,

^* Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Gyeonggi-Do, Korea; Mucosal Immunology Laboratory, System Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea; Bioleaders, Daejeon, Korea; College of Veterinary Medicine, Chungnam National University, Daejeon, Korea; and ^¶ Department of Bio and Nanochemistry, Kookmin University, Seoul, Korea

We analyzed the in vivo tumor regression activity of high molecular mass poly--glutamate (-PGA) from Bacillus subtilis sups. chungkookjang. C57BL/6 mice were orally administered 10-, 100-, or 2000-kDa -PGA or -glucan (positive control), and antitumor immunity was examined. Our results revealed higher levels of NK cell-mediated cytotoxicity and IFN- secretion in mice treated with higher molecular mass -PGA (2000 kDa) vs those treated with lower molecular mass -PGA (10 or 100 kDa) or -glucan. We then examined the effect of oral administration of 10- or 2000-kDa -PGA on protection against B16 tumor challenge in C57BL/6 mice. Mice receiving high molecular mass -PGA (2000 kDa) showed significantly smaller tumor sizes following challenge with the MHC class I-down-regulated tumor cell lines, B16 and TC-1 P3 (A15), but not with TC-1 cells, which have normal MHC class I expression. Lastly, we found that -PGA-induced antitumor effect was decreased by in vivo depletion of NK cells using mAb PK136 or anti-asialo GM1 Ab, and that was completely blocked in NK cell-deficient B6 beige mice or IFN- knockout mice. Taken together, we demonstrated that oral administration of high molecular mass -PGA (2000 kDa) generated significant NK cell-mediated antitumor activity in mice bearing MHC class I-deficient tumors.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A050562), and a grant from Korea Research Institute Bioscience and Biotechnology Initiative Program to H.P.

² Address correspondence and reprint requests to Dr. Haryoung Poo, Mucosal Immunology Laboratory, Korea Research Institute of Bioscience and Biotechnology, Daejon 305-600, Korea. E-mail address: haryoung{at}kribb.re.kr

³ Abbreviations used in this paper: -PGA, poly--glutamate; anti-ASGM1, anti-asialo GM1; DC, dendritic cell.

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