Innate immunityの活性化による抗がん免疫療法

• Project/Area Number: 14030096
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Research Institute, Osaka Medical Center for Cancer and Cardiovascular Disaeses
• Principal Investigator: 瀬谷 司 大阪府立成人病センター, 研究所, 所長 (10301805)
• Project Period (FY): 2002
• Project Status: Completed (Fiscal Year 2002)
• Budget Amount: ¥6,100,000 (Direct Cost: ¥6,100,000); Fiscal Year 2002: ¥6,100,000 (Direct Cost: ¥6,100,000)
• Keywords: Toll-like receptor / 細胞障害性リンパ球(CTL) / 樹状細胞(DC) / NK細胞 / インターフェロンタイプ1 / スピルリナ / BCG / gene chip

Research Abstract

自然免疫、特にTLRのadjuvant receptorとしての側面を機能解析し、リンパ球系(獲得免疫、NKなど)との連携による抗がん免疫療法の確立を目指す。ヒトの各種Toll-like receptors(TLR)を活性化する種々の微生物成分(PAMP, pathogen-associated molecular pattern)を調製し、樹状細胞(DC)活性化を異なったモードで行う微生物成分(adjuvants)を得た。これらを用いてマウス移植がんの系で抗がん免疫療法への有効性をテストした。BCG-CWSはTLR2,TLR4を介してDCの活性化を誘起し、CTL(細胞傷害性Tリンパ球)を誘導することを証明した(Uehori et al., Infect Immun 2003 in press)。一方、spirulina (cyanobacteria)の熱水抽出物はNK(Natural killer)細胞を活性化することが判明した(Hirahashi et al., Int.Immunopharmac,2002)。これらのメカニスムを解明した。SpirulinaはDCのinterferon(IFN)type 1を発現誘導する。IFNはNKのIL-18R complex, NKG2Dの活性化誘起した。樹状細胞によるNK活性化はこの経路で起きると推定された。また、BCG-CWSはTLR4のagonistであるにも拘わらずIRF-3,IFN-betaを誘導せず、MyD88-dependent pathwayのみを活性化した。この経路で樹状細胞のCTL誘導が行われると想定された。PAMPとTLRの分子間相互反応、分子複合体解析を蛋白質の解析によって、樹状細胞の活性化の分子機構の一端を明らかにしうる。PAMP刺激によってヒト樹状細胞に誘導される遺伝子群約100を同定できた(Bebum et al., Infect. Immun. submitted)。機能、予後との関係を調べていく予定である。

Research Products

• [Publications] Hirahashi, Seya., et al.: "Activation of the human innate immune system by spirulina : Augmentation of interferon gamma production and NK cytotoxicity by oral administration of spirulina"Int.Immunopharmacology. 2. 423-434 (2002)
• [Publications] Kurita-Taniguchi, Seya., et al.: "Molecular assembly of CD46 with CD9,alpha3-beta1 integrin and protein tyrosine phosphatase SHP-1 in human macrophages through differentiation by GM-CSF"Molec.Immunol.. 38. 689-700 (2002)
• [Publications] Murakami, Seya., et al.: "Transgenic pigs expressing human decay? accelerating factor regulated by porcine MCP gene promoter"Mol.Reprod.Dev.. 61. 302-311 (2002)
• [Publications] Masuda Seya., et al.: "High levels of RAE-1 isoforms on mouse tumor cell lines assessed by the anti-pan-Rae-1 polyclonal antibody confers tumor cell cytotoxicity on mouse NK"Biochem.Biophys.Res.Commun.. 290. 140-145 (2002)
• [Publications] Matsumoto, Seya., et al.: "Establishment of a monoclonal antibody against human Toll-like receptor 3 that blocks double-stranded RNA-mediated signaling"Biochem.Biophys.Res.Commun.. 293. 1364-1369 (2002)
• [Publications] Seya T., M.Matsumoto: "Molecule in Focus : A lipoprotein of Mycoplasma fermentans confers host immune activation through Toll-like receptor 2"J.Biochem.Cell Biol.. 34. 901-906 (2002)
• [Publications] Seya, et al.: "Structural-functional relationship of pathogen-associated molecular patterns : lessons from BCG-cell wall skeleton and Mycoplasma lipoprotein M161Ag"Microbes Infect.. 4. 955-961 (2002)
• [Publications] Murabayashi, Seya., et al.: "Susceptibility of human dendritic cells to measles virus depends on their activation stages in conjunction with the level of CDw150:role of Toll stimulators in DC maturation and MV amplification"Microbes Infect.. 4. 785 (2002)
• [Publications] Mori, Seya. et al.: "Human herpesvirus 6 variant A but not variant B induces fusion-from-without in a variety of human cells through a human herpesvirus 6 entry receptor CD46"J.Virol.. 76. 6750-6761 (2002)
• [Publications] Nomura, Seya. et al.: "Mechanism of host cell protection from complement in murine cytomegalovirus (CMV) infection : Identification of a CMV-responsive element in the CD46 promoter region"Eur.J.Immunol.. 32. 2954-2964 (2002)
• [Publications] Begum, Seya. et al.: "Mycobacterium bovis BCG cell wall and LPS induce a novel gene, BIGM103, whose main frame encodes a 7-TM protein : identification of a new protein family"Genomics. 80. 630-645 (2002)
• [Publications] Hirano Seya et al.: "Isoform-specific ligation of human CD46 enhances interferon gamma-dependent nitric oxide production in macrophages"J.Biochem (Tokyo). 132. 83-91 (2002)
• [Publications] Fukui, Seya et al.: "Mapping the sites responsible for factor I-cofactor for cleavage of C3b and C4b on human C4b-binding protein by deletion mutageneis"J.Biochem (Tokyo). 132:. 719-728 (2002)
• [Publications] Kato Seya et al.: "A novel simple method to purify recombinant soluble complement receptor type 1 (sCR1) from CHO cell culture"Biotechnol.Bioprocess.Eng.. 7. 67-75 (2002)
• [Publications] Kitamura Seya et al.: "Prostasomal CD46 and the anti-measles-virus effect"Wenner-Gren International Series In Prostasomes, ed.By G.Ronquist and B.O.Nilsson, Portlamd Press. 81. 81-89 (2002)
• [Publications] Oshiumi, Seya et al.: "TICAM-1,an adaptor molecule that participates in Toll-like receptor 3-mediated interferon β-induction"Nature Immunol.. 4. 161-167 (2003)
• [Publications] Oshiumi, Seya et al.: "Prediction of the prototype of the human Toll-like receptor gene family from the Pufferfish Fugu. rubripes genome"Immunogenetics. 54:. 791-800 (2003)
• [Publications] Inoue, Seya et al.: "Disruption of the mouse CD46 caused an accelerated spontaneous acrosome reaction in sperm"Molec.Cell.Biol.. 23. 2614-2622 (2003)
• [Publications] Hazeki, Seya., et al.: "TLR-mediated tyrosine phosphorylation of paxillin via MyD88-dependent and independent pathways"Eur.J.Immunol. 33:. 740-747 (2003)
• [Publications] Uehori, Seya et al.: "Simultaneous blocking of human Toll-like receptor 2 and 4 suppresses myeloid dendritic cell activation induced by Mycobacterium bovis bacillus Calmette-Guerin(BCG) peptidoglycan (PGN)"Infect.Immun.. (in press). (2003)
• [Publications] Seya, T.: "Role of Toll-like receptors and their adapters in adjuvant immunotherapy for cancer"Anticancer Res.(review). (in press). (2003)
• [Publications] 押海裕之, 瀬谷司他: "RNA interference (RNAi)を用いた哺乳類細胞での遺伝子ノックアウト"臨床薬理(実験技術). 120. 91-95 (2002)
• [Publications] 瀬谷司: "抗がん免疫の成立における自然免疫の役割"医学のあゆみ. (印刷中).
• [Publications] 松本美佐子, 瀬谷司: "微生物成分を用いたヒト樹状細胞の制御"Molecular Medicine. (印刷中).
• [Publications] 赤沢隆, 松本美佐子, 瀬谷司: "アジュバントを利用した樹状細胞の活性化と癌免疫療法への応用"現代医学社. (印刷中).
• [Publications] 瀬谷司: "補体による異物認識機構"「産婦人科の実際」生殖免疫. (印刷中).
• [Publications] 瀬谷司, 押海裕之, 松本美佐子: "TICAM-1 Interferon-βを誘導する新規Toll-like receptorのアダプター分子"医学のあゆみ. (印刷中).