JP2015091241A - 室内空気由来細胞外ベシクルを含む組成物及びその用途 - Google Patents
室内空気由来細胞外ベシクルを含む組成物及びその用途 Download PDFInfo
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Abstract
【解決手段】前記細胞外ベシクルを用いて炎症性呼吸器疾患及び肺癌などを診断、予防、及び/又は治療する方法。室内空気に存在する細胞外ベシクルを動物に投与して呼吸器疾患動物モデルを製造し、前記動物モデルを用いて呼吸器疾患に対する予防及び治療候補薬物の検索及び/又は発掘を可能とし、呼吸器疾患に対する予防及び/又は治療用ワクチン、呼吸器疾患の原因物質を診断する方法、呼吸器疾患の発生及び悪化を予防するための目的で室温空気中の細胞外ベシクルの活性を抑制し或いは細胞外ベシクルを除去する方法。
【選択図】図12
Description
本発明者らは、室内空気に細胞外ベシクルが存在するか否かを確認するために、室内粉塵から細胞外ベシクルを分離、同定する実験を行った。
本発明者らは、室内から採集した粉塵が哺乳動物で炎症性呼吸器疾患を引き起こすか否かを評価するための実験を行った。
前記実施例2の結果より、室内粉塵によって哺乳動物で好中球性肺炎症が誘発されることを確認した。これに関連し、本発明者らはその免疫学的メカニズムを解明するための実験を行った。
前記実施例1で室内粉塵、すなわち室内空気に細胞外ベシクルが存在することを確認したとともに、室内粉塵から分離した細胞外ベシクルによるinvitro先天免疫反応を評価した。このために、マウスマクロファージ(RAW264.7)に、室内粉塵から分離した細胞外ベシクルを処理した。
本発明者らは、実施例4で確認したin vitro先天免疫反応に加えて、室内空気に存在する細胞外ベシクルによるin vivo先天免疫反応を評価するための実験を図9の実験プロトコルに従って行った。
図11に示したプロトコルに従って、室内粉塵から分離した細胞外ベシクルによるinvivo後天免疫反応を評価する実験を行った。
前記実施例5及び実施例6の結果より、室内空気に存在する細胞外ベシクルによるinvivo先天免疫反応及び後天免疫反応の発生に、LPSを含有しているベシクルが重要であることが分かった。LPSはグラム陰性細菌の外膜に存在する物質であり、LPSを含有しているベシクルはグラム陰性細菌に由来することが自明である。
実施例7では室内空気に大腸菌由来細胞外ベシクルが存在することが分かった。これに基づいて、大腸菌由来細胞外ベシクルによるinvivo先天免疫反応を評価した。
実施例8で大腸菌由来ベシクルが用量依存的にTh17免疫反応を誘導するIL−6の分泌を誘導するという事実に基づいて、大腸菌由来ベシクルを反復的に投与して肺炎症を評価した。
実施例9で大腸菌由来細胞外ベシクルを3週間気道内に反復投与したとき、用量依存的に肺炎症が発生するという事実に基づいて、高用量のベシクルを4週間反復投与して構造的な変化を評価した。
本発明者らは、室内に生息するイエダニ(house dust mite、HDM)に細胞外ベシクルが存在するか否かを調べるために、イエダニから細胞外ベシクルを抽出して特性を解明する実験を行った。
実施例11ではイエダニ由来細胞外ベシクルが存在することが分かった。イエダニから分離した細胞外ベシクルによるinvivo先天免疫反応を評価した。このために、マウスマクロファージ(RAW264.7)にイエダニ由来細胞外ベシクルを処理した。
実施例11ではイエダニ由来細胞外ベシクルが存在することが分かり、実施例12ではイエダニ由来ベシクルによる免疫反応を確認することができた。これに基づいて、イエダニ由来細胞外ベシクルによるinvivo先天免疫反応を評価した。
実施例13ではイエダニ由来細胞外ベシクルによる免疫反応を確認することができた。これに基づいて、イエダニ由来細胞外ベシクルによるinvivo後天免疫反応を評価した。
室内空気に存在する細胞外ベシクルは、室内粉塵に存在する多様な細菌又はカビによって生成できる。本発明者らは、真空掃除機を用いて、特定住居地の寝具に存在する粉塵を収去した。真空掃除機のフィルター内に存在する粉塵を綺麗なガラス瓶に移して質量を測定した。室内粉塵5gを200mLのPBSが入っているビーカーに4℃で12時間溶かし、カーゼを用いてサイズの大きい物質を除去した。このときの粉塵液を1とし、濃度を1/10ずつ希釈して細菌とカビの成長が可能な培養液入りのプレート(plate)に粉塵液を塗抹した。一定の時間が経過した後、成長した細菌とカビを確認した。図28に示すように、室内粉塵に多様な細菌とカビが生息していることが分かった。
最近、本発明者らは、グラム陽性細菌としてのブドウ球菌が細胞外ベシクルを分泌することを最初に発見して報告した。室内空気に存在するグラム陽性細菌由来細胞外ベシクルによる呼吸器疾患の発生への役割を評価するために、ブドウ球菌培養液から、実施例1の方法でブドウ球菌から分泌される細胞外ベシクルを分離し、呼吸器疾患の病因に対する役割を評価した。
ブドウ球菌由来細胞外ベシクルによるin vivo免疫反応を評価するために、C57BL/6、6週齢雌マウス(各群当たり3匹)を使用した。PBSに溶かしたブドウ球菌由来細胞外ベシクル1μg、10μgをマウスの気道内に投与した群を実験群とし、PBSを気道内に投与した群を対照群とした。細胞外ベシクルを1回投与した後、翌日にマウスに対して初期肺炎症とサイトカインIL−6の量を測定した(図31の実験プロトコルを参照)。
前記実施例16のin vitro実験に加えて、先天免役反応の発生に対するブドウ球菌由来細胞外ベシクル内のタンパク質の役割をin vivo実験によって検証した。
実施例8の方法によって分離した大腸菌由来細胞外ベシクル1mgを1週間隔で3週間3回C57BL/6(雄、6週、グループ当たり10匹)の腹腔に注入した。毎注入6時間、24時間、7日後にマウスの血液を得て、血液内に存在する細胞外ベシクル特異的な抗体を測定した。大腸菌由来ベシクル200ngがコートされた黒色86ウェルプレートに、1%BSA/PBSで1:500希釈されたマウス血清を入れ、常温で2時間培養した後、ぺルオキシダーゼ(peroxidase)が結合したマウス抗体を介して観察した。
大腸菌由来細胞外ワクチンの効能を評価するために、大腸菌の感染による敗血症動物モデルを確立した。大腸菌1×106、1×108、1×1010CFUをC57BL/6(雄、6週、グループ当たり10匹)の腹腔内に注入して5日間8時間間隔でマウスの生存率を観察した。
大腸菌由来細胞外ベシクルによる炎症の発生に対するベシクルワクチンの効能を評価するために、実施例19の方法によって大腸菌由来細胞外ベシクル1μgを1週間隔で3回C57BL/6(雄、6週、グループ当たり5匹)の腹腔に注射して接種した後、大腸菌由来細胞外ベシクルを腹腔投与し、しかる後に、血液から炎症媒介体の分泌を測定した。
Claims (7)
- 室内空気に存在するイエダニ由来細胞外ベシクルを用いて好中球性肺炎症の存在を検出するためのin vitro方法。
- 前記の方法は室内空気に存在する細胞外ベシクルの遺伝物質の塩基配列を分析することを含む、請求項1記載の方法。
- 前記の方法は室内空気に存在する細胞外ベシクルのタンパク質を測定することを含む、請求項1又2に記載の方法。
- 前記の方法は、室内空気に存在する細胞外ベシクルに対する免疫反応を測定することを含む、請求項1〜3のいずれか1項に記載の方法。
- 前記の方法は気管支肺胞洗浄液(BAL fluid)における炎症細胞の数の増加を指標とすることを含む、請求項1〜4のいずれか1項に記載の方法。
- 前記の方法は気管支肺胞洗浄液(BAL fluid)におけるTNF−α及びIL−6の増加を指標とすることを含む、請求項1〜5のいずれか1項に記載の方法。
- 前記の方法は気管支肺胞洗浄液(BAL fluid)におけるIL−17量の増加を指標とすることを含む、請求項1〜6のいずれか1項に記載の方法。
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WO2011043538A2 (ko) | 2011-04-14 |
EP2486940A4 (en) | 2013-08-21 |
JP6293649B2 (ja) | 2018-03-14 |
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