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In vivoにおける口腔レンサ球菌の抗腫瘍活性 [全文の要約]

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Title: In vivoにおける口腔レンサ球菌の抗腫瘍活性 [全文の要約]
Other Titles: In vivo anti-tumor activity of oral Streptococci
Authors: 原, 博志 Browse this author
Keywords: Stretococcus gordonii
Issue Date: 25-Mar-2014
Publisher: Hokkaido University
Abstract: 我々は,これまでにToll-like receptor 2 (TLR2)のリガンドであるリポペプチドFSL-1がin vivoにおいてTLR2依存的な抗腫瘍活性を示すこと,また,口腔レンサ球菌の全菌体の認識にTLR2が重要な役割を果たしていることを明らかにした.そこで,本研究では口腔レンサ球菌の全菌体のin vivoにおける抗腫瘍活性を検証した.8-9週齢のC57BL/6マウスの背部皮下にメラノーマB16F0を接種後,4日後及び9日後に,Streptococcus gordoniiの生菌あるいは死菌で免疫した.その結果,生菌ならびに死菌は共に腫瘍の増殖を有意に抑制した.さらに,2回目の免疫を行った翌日の脾臓ならびに所属リンパ節からリンパ球を採取し,ナチュラルキラー(NK)細胞と細胞傷害性T細胞(CTL)の傷害活性を調べた.生菌で免疫したマウスの脾臓ならびに所属リンパ節では有意に高いNK活性を示した.また,脾臓では有意に高いCTL活性を示したが,所属リンパ節では有意ではないが,活性化傾向を示した.さらに,2回目の免疫から6日後の所属リンパ節において,免疫抑制状態を惹起することが知られている制御性T細胞(Treg)ならびに骨髄由来抑制細胞(MDSC)の割合を調べた.その結果,生菌で免疫していた場合にTregならびにMDSCの割合が共に有意に減少していることがわかった.また,腫瘍周囲におけるTregの存在状況を調べたところコントロール群では移植腫瘍間や間質にTregが認められたが,生菌で免疫した群は認められなかった.以上の結果から,口腔レンサ球菌の一つであるStreptococcus gordoniiの全菌体はin vivoにおいて抗腫瘍活性を有しており,その活性発現にはNK細胞ならび4にCTLによる細胞傷害活性と, TregならびにMDSC数の減少による免疫力の亢進が関与していることが示唆された.
We have found that the microbial lipopeptide FSL-1, a Toll-like receptor 2(TLR2) ligand, has the TLR2-mediated anti-tumor activity in vivo. Therefore, we tested the anti-tumor activity in vivo of oral streptococci, because they are known to be recognized by TLR2. On day 0, B16F0 melanoma cells were implanted subcutaneously in the back of C57BL/6 mice of 8 - 9 weeks of age. Heat-killed and live cells of Streptococcus gordonii were injected into the back of the mice on day 4 and 9 after implantation. Both heat-killed and live S. gordonii significantly inhibited the growth of tumor. As a first step to clarify the mechanism by which they exhibit the anti-tumor activity, therefore, cytotoxic activities of lymphocytes of draining lymph nodes and spleens toward YAC-1 cells as a target (natural killer activity) or B16F0 melanoma cells as a target 25(tumor-specific cytotoxic Tlymphocyte activity) were measured on day 1 after second immunization. Natural killer activity was significantly higher in the draining lymph nodes and spleens of the immunized mice. Tumor-specific cytotoxic Tlymphocyte activity in spleen of the immunized mice was significantly higher, whereas that in the draining lymph nodes was higher, but not significant. Furthermore, the proportion of Myeloid-Derived Suppressor Cells (MDSC) and regulatory T cells (Treg) in the draining lymph nodes was measured by flow cytometry on day 6 after second immunization. The proportions of both MDSC and Treg were significantly reduced in the immunized mice. Furthermore, Treg was observed around stroma cells and/or transplanted tumor cells in the non-immunized mice, but not in the immunized mice. Taken together, whole cells of S. gordonii have the anti-tumor activity in vivo, in which cytotoxic activities of tumor-specific cytotoxic Tlymphocytes as well as natural killer cells and upregulation of anti-tumor immune response caused by reduction of the numbers of the immunosuppressor cells such as MDSC and Treg are involved.
Description: この博士論文全文の閲覧方法については、以下のサイトをご参照ください。
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Conffering University: 北海道大学
Degree Report Number: 甲第11261号
Degree Level: 博士
Degree Discipline: 歯学
Examination Committee Members: (主査) 教授 山崎 裕, 教授 柴田 健一郎, 教授 進藤 正信
Degree Affiliation: 歯学研究科(口腔医学専攻)
Type: theses (doctoral - abstract of entire text)
Appears in Collections:学位論文 (Theses) > 博士 (歯学)
課程博士 (Doctorate by way of Advanced Course) > 歯学院(Graduate School of Dental Medicine)

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