JP5362940B2 - 炎症性疾患治療用候補薬剤をスクリーニングするためのアッセイ - Google Patents
炎症性疾患治療用候補薬剤をスクリーニングするためのアッセイ Download PDFInfo
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Description
a)候補薬剤を腸細胞に接触させることと、
b)NF−κBファミリーの転写因子の核外移行或いは核内移行の変化、
NF−κBファミリーの転写因子の転写活性の破壊、
p65(RelA)の特異的ヒストンアセチル化、
腸細胞のサイトゾル内でのPPARγ/RelA複合体量の変化、及び
PPARγの核質内破壊から成る群から選択される、前記候補薬剤の作用を解析することを含む。
NF−κBファミリーの転写因子の核外移行の促進或いは核内移行の抑制、
NF−κBファミリーの転写因子の転写活性の破壊、
p65(RelA)の特異的ヒストンアセチル化、
腸細胞のサイトゾル内でのPPARγ/RelA複合体量の増加、及び
PPARγの核質内破壊から成る群から選択される少なくとも1つの作用を示す候補薬剤を選択する工程を更に含んでもよい。
NF−κBファミリーの転写因子の核外移行或いは核内移行、
NF−κBファミリーの転写因子の転写活性の破壊、
p65(RelA)の特異的ヒストンアセチル化、
腸細胞のサイトゾル内のPPARγ/RelA複合体量、又は
PPARγの核質内破壊を調節することができる剤の治療有効量を投与する工程を含む方法を提供する。
1)病原性/非病原性細菌への接触後のCaco−2細胞内での炎症性サイトカイン遺伝子の発現。データはcDNAマクロアレイ、リアルタイムPCR及びノーザンハイブリダイゼーション解析を用いて得た。
2)B.テタイオタオミクロンの抗炎症作用の生理学的妥当性のインビトロ(Caco−2トランスウェル培養)及びインビボ(最少量細菌叢ラット)での検証。
3)NF−κB及びAP−1シグナル変換経路の解析、並びにサイトゾル内でのRelAとPPARγとの関係の解析。
1)B.テタイオタオミクロンによる調節の主なターゲットはNF−κBであり、AP−1ではない。
2)B.テタイオタオミクロン及び腸炎菌(S. enteritidis)で処理した細胞内にはp65(RelA)が蓄積する(最長30分間検出した)。
3)B.テタイオタオミクロン存在下でのp65の転写作用の低下は、p65の核外排除(移行)の促進に起因し、この核外移行はLMB感受性である(即ち、crm−1仲介による)。
4)データは全て、B.テタイオタオミクロンに起因する、炎症性サイトカイン/ケモカインの発現の低下、IκBαの発現、PMNの補充、及びラットにおいてインビボで示された生理的低レベルの炎症に関連付けられる。
5)B.テタイオタオミクロンの存在下でPPARγはサイトゾルに局在する。
6)PPARγとp65がサイトゾル内に共存する場合、両者は物理的に結合する。
非病原性細菌による免疫抑制のメカニズムを更に調べるため、本発明者らは、先ず、抗炎症性サイトカインIL−10及びTGF−βについて検討した。IL−10遺伝子発現はB.テタイオタオミクロンを用いた処理には影響を受けなかった(データは図示せず)が、このことは構成タンパク質が関与する可能性を排除するわけではない。抗炎症性サイトカインTGF−βが関与する可能性を示すデータから多少の示唆が得られた。しかし、この短時間の検討の時間経過においてはデノボサイトカイン合成は恐らく十分に行われてないので、TGF−βが炎症反応をダウンレギュレートするように作用しているとすれば、TGF−βは長期の抗炎症作用に関与している可能性が高い。
RelAの調節におけるPPARγの重要性を更に調べるため、PPARγのドミナントネガティブ(DN)型(英国ケンブリッジ大学チャタージー(Chatterjee)教授の寄贈)(ガーネル(Gurnell)ら、2000年)を用いた。PPAR受容体内ではロイシンとグルタミン酸の保存性が高い。これらのアミノ酸残基はリガンド結合及び核コアクチベーターの補充において必須である。これらのアミノ酸残基の変異によって上記受容体のDN型が産生し、この受容体が持つコアクチベーターを補充する能力と2種類のコリプレッサー、即ち、レチノイド甲状腺受容体のサイレンシングメディエータ(SMRT)と核コリプレッサー(NcoR)を遊離する能力が低下する(ガーネル(Gurnell)ら、2000年)。DN PPARγを用いた免疫共沈降実験によって、SMRTがPPARγとインビボで相互作用すること、そして、変異したPPARγは強力な転写リプレッサーとなることが示された。ヒトPPARγのキメラ蛍光タンパク構造体と、シアン蛍光タンパク質(CFP)をカルボキシ末端ドメインに有するPPARγのドミナントネガティブ型とを先に報告されたクローン(ガーネル(Gurnell)ら、2000年)からPCR増幅によって調製した。YFPと結合したキメラRelAは、J シュミット博士(Dr. J Schmid)から寄贈された(シュミット(Schmid)ら、2000年)。発現の成功は、抗ヒトPPARγ及び抗ヒトRelA抗体を用いた一過性トランスフェクトHela細胞のウェスタンブロット解析によって確認した。
LPS特異的IgG及びIgA
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Claims (11)
- 腸細胞の炎症反応によって引き起こされる炎症性疾患の治療に使用するためのバクテロイデス・テタイオタオミクロンを含む剤。
- 炎症性疾患は、炎症性腸疾患、クローン病、過敏性腸症候群、関節リウマチ、免疫不全症候群、悪液質、多発性硬化症、ケラチノサイトの増殖、皮膚の過剰増殖及び炎症性障害、乾癬及び尋常性ざ瘡から成る群から選択されることを特徴とする請求項1に記載の剤。
- 炎症性疾患はクローン病であることを特徴とする請求項2に記載の剤。
- 食品や座薬を用いて患者に投与するために調剤されていることを特徴とする請求項1〜3のいずれか1項に記載の剤。
- 経口投与するために調剤されていることを特徴とする請求項1〜3のいずれか1項に記載の剤。
- 生菌の状態で投与するために調剤されていることを特徴とする請求項1〜5のいずれか1項に記載の剤。
- NF−κBの転写活性を変化させることが可能であることを特徴とする請求項1〜6のいずれか1項に記載の剤。
- 腸細胞のサイトゾル内でPPARγ/RelA複合体量を増加させることが可能であることを特徴とする請求項1〜7のいずれか1項に記載の剤。
- 哺乳動物の免疫系をホメオスタシスへ回復させ且つ維持させることが可能であることを特徴とする請求項1〜8のいずれか1項に記載の剤。
- 炎症性疾患が炎症性サイトカインの産生に伴う疾患であることを特徴とする請求項1〜9のいずれか1項に記載の剤。
- 腸細胞の炎症反応によって引き起こされる炎症性疾患の治療に使用するための薬剤の製造において、バクテロイデス・テタイオタオミクロンを含む剤を前記薬剤に含有させることを特徴とするバクテロイデス・テタイオタオミクロンを含む剤の使用。
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