JP2016522164A - Tl1a機能および関連するシグナル経路の抑制による線維症および炎症の緩和および回復 - Google Patents
Tl1a機能および関連するシグナル経路の抑制による線維症および炎症の緩和および回復 Download PDFInfo
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Abstract
Description
慢性大腸炎の誘導及び治療
C57BL/6JマウスをJackson Laboratoryから購入した。慢性のデキストラン硫酸ナトリウム(DSS)大腸炎が記載されるように導入された。10養子移植モデルにおいて、大腸炎は、Rag1−/−マウスに、WTマウスから分離された500,000のCD4+CD45RBhiのナイーブなT細胞の腹腔内注入により誘導された。ハムスター抗マウスTl1a Ab(12F6A,TEVA,North Wales,Pennsylvania)は、Tl1aの機能を抑制し、20または80mg/kgで投与され、または対照免疫グロブリン(Ig)G(Leinco Technologies,St.Louis,Missouri)が80mg/kg投与量で、慢性のDSSの15日目及び養子移植モデルの29日目で開始し、1週間に2回マウスに腹腔内に注入された(図1A)。ベースラインの対照(Rag Co or WT Co)は、ナイーブなT細胞のDSS治療または養子移植前に分析されたマウスであった。治療前(Pre−Tx)対照は、慢性のDSSモデルの14日目及び養子移植モデルの28日目で分析されたマウスであった。治療群は、慢性のDSSモデルについて28日目に及び養子移植モデルについて56日目に分析されたマウスであった(図1A)。全てのマウスは、Cedars−Sinai Medical Center(CSMC)の動物施設(Animal Facility)で、特定の病原体フリー条件下で維持された。本研究は、米国国立衛生研究所の実験動物の実験についてのガイドに従って厳密に行われた。動物実験は、CSMC動物実験委員会により承認された(プロトコル3813)。
疾患活動性の指標、ミエロペルオキシダーゼ、巨視的及び病理組織学的分析
疾患活動性の指標(DAI)スコアが、DSSモデルについて一日おきに、養子移植モデルについて1週間に2回、記載されるように測定された。ミエロペルオキシダーゼ活性が、製造元(Enzo Life Sciences,Plymouth Meeting,PA)のプロトコルに従ってミエロペルオキシダーゼ蛍光検出キットを用いて評価された。炎症の巨視的証拠が確立された分類を用いて盲検でスコア付けされた。組織サンプルは、CSMCヒストロジーコア(Histology−Core)により、処理されてヘマトキシリン−エオジン(H&E)により染色された。シリウスレッド染色が、製造元(IHC World,Woodstock,MD)のプロトコルに従ってNovaUltraのシリウスレッド染色キットを用いて行われた。免疫蛍光染色法が、10%ホルマリンで固定された4μM凍結切片で行われ、1:100希釈でα−SMA Ab及び1:2000希釈でα−ビメンチンAb(Covance,San Diego,CA)により、ロバα−ウサギIgG及びヤギα−トリIgY(Abcam,Cambridge,MA)二次Abにより染色された。病理組織学的スコアは、記載されるように、2人の訓練された動物病理学者(DQS及びJC)により盲検の態様で付与された。マウスあたりの腸の領域あたりに5以上の異なる視野の観察が、200の倍率で組織学的スコア及びコラーゲン沈着を測定するために、Leica TCS SP分光共焦点顕微鏡を用いて630の倍率で繊維芽細胞/筋線維芽細胞数をカウントするために使用された。
Dr3−/−マウスの作成
Dr3標的ベクターのクローニング及びDr3+/−ファウンダーマウスの作成はgenOway(genOway,Lyon,France)とのコラボレーションで行われた。簡潔には、エクソン1の上流1.5kb及びエクソン8の下流3kbを含むDr3の内在性位置が、C57BL/6JマウスからゲノムDNAを用いてPCR増幅により生成され、pCR4−TOPOベクターにクローニングされた(Invitrogen,Carlsbad,CA)。その後、2つのloxP部位が隣接するDr3エクソン2から5に挿入された(図5A)。FRT部位により隣接されるポジティブ選択ネオマイシン遺伝子が、標的ベクターを作成するためにエクソン1と2の間のイントロンに挿入された(図5A)。クローニングプロセスのそれぞれのステップが限定解析及びシーケンシングにより検証された。Dr3遺伝子標的構造は、直線化され、エレクトロポレーションによりC57BL/6Jバックグラウンドで、genOway所有の胚性幹(ES)細胞にトランスフェクトされた。相同組換え体がG418により選択され、サザンブロット解析により確認された。正しい5及び3’組換えESクローンは、C57BL/6J胚盤胞にマイクロインジェクトされ、偽妊娠のC57BL/6Jマウスに導入された。雄のキメラの子孫が、生殖細胞系突然変異マウスを得るために繁殖され、その後、ネオマイシンカセットを取り除くためにFlpe欠損マウス種へと繁殖され、その後、loxPに隣接する配列を切除するためにCre欠損マウスへと繁殖され(図5A)、サザンブロットにより確認され、C57BL/6Jの遺伝的背景が維持された。
発現の分析
総RNAがRNeasy Microarray Tissue Miniキット(Qiagen,Valencia,CA)を用いて分離され、逆転写ポリメラーゼ連鎖反応(RT−PCR)がRT2 HT First Strandを用いて行われ、遺伝子発現が、製造元のプロトコルに従って、RT2 Custom Fibrosis Array CAPM11248(Qiagen,Valencia,CA)キットを用いて測定された。サイトカインの濃度は、複合的な免疫測定、製造元のプロトコルに従って、マウスTh1/Th2/Th17/Th22 13plexキットFlowCytomix(eBioscience,San Diego,CA)を用いてアッセイされた。検証されたDr3 qPCRアッセイMm.PT.51.17321439、Il31Ra qPCRアッセイMm.PT.56a.32787326及びβアクチンqPCRアッセイMm.PT.39a.22214843が、IDT Technologies (Skokie,IL)から購入された。
細胞の分離、培養、細胞内のサイトカインの発現、及びフローサイトメトリー
粘膜固有層の単核細胞(LPMC)、腸間膜リンパ節(MLN)、及び脾細胞の分離と培養、並びにそれらのその後の抗CD28及び抗CD3εによる刺激が行われた。発明者らは、LPMCの分離のために結腸全体及び回腸の端部10cmを使用した。マウスの原発性結腸繊維芽細胞が、37℃で15分間、1mMのDTT(Fisher Scientific,Tustin,CA)で、その後、37℃で30分間5mMのEDTA(Promega,Madison,WI)を含む1mMのDTTでインキュベートされた結腸から分離された。残っている結腸の組織は、1×HBSS(Corning Cellgro,Swedesboro,NJ)でリンスされ、刻まれ、その後、DMEM(Corning Cellgro,Swedesboro,NJ)中の1.5mg/mLのコラゲナーゼII(Worthington,Lakewood,NJ)、0.3mg/mLのDNaseI及び3mg/mLのヒアルロニダーゼ(Sigma,St. Louis,MO)で、30分間37℃で消化された。分離された細胞は、10%FCS、ペニシリン/ストレプトマイシン(100IU/mL)、ファンギゾン(0.5μg/mL)が添加されたDMEMで培養された。原発性腸繊維芽細胞はパッセージ2で使用された。細胞は、LSRIIフローサイトメーターで取得され(BD Biosciences,San Jose,CA)、FlowJo分析ソフトウェアを用いて分析された。
エクスビボの腸の繊維芽細胞の増殖及びアポトーシスアッセイ
原発性腸繊維芽細胞が分離され、製造元の指示に従ってCellTrace Violet
(Invitrogen,Carlsbad,CA)により染色された。染色された細胞は、その後、10%FCS、ペニシリン/ストレプトマイシン(100IU/mL)、及びファンギゾン(0.5μg/mL)が添加されたDMEMで、100ng/mLのTl1aとともにインキュベートされた。48時間後、培養された腸の繊維芽細胞は、製造元の指示に従ってアネキシンV染色検出キット(eBioscience,San Diego,CA)を用いて染色された。アネキシンV染色後、繊維芽細胞は回収されて、洗浄され、2%パラホルムアルデヒドで固定され、BD LSRIIフローサイトメーターによりフローサイトメトリック分析に供され、FlowJoソフトウェアにより分析された。
統計的分析
データは平均±標準偏差(SD)として示される。2つの群間の比較は、カテゴリー変数についての両側のフィッシャー直接検定及び連続変数についてのスチューデントt検定により行われた。パラメータテスト及び非パラメータテストが試験の前提の遂行に応じて使用された。3つの群間の比較は、ANOVAを用いてなされ、その後、多重比較のためのターキーのHSD及びベーレンス−フィッシャーの検定の修正による対でのポストhoc分析が続いた。p<0.05が有意であると考えられた。
確立された慢性大腸炎の疾患活動性及び全体的な炎症を弱毒化したTl1aAb投与
慢性のマウスの大腸炎におけるTl1a機能を中和する効果が、ナイーブなCD4+CD45RBhi T細胞で養子性にトランスファーされた免疫不全のRag1−/−マウスにおけるTl1a Abを用いて評価された。20及び80mg/kgのTl1a Abまたは80mg/kgでアイソタイプ対照Ab(Iso Ab)が、大腸炎が確立されたときに(図1A)、トランスファー後29日目で開始し、1週間に2回投与された。6週目まで及び8週目で実験の最後にわたって継続して、Tl1a Abで治療されたマウスの疾患活動性の指標(DAI)がIso Abを受けたマウスよりも有意に低かった(図1B)。Iso Ab群と比較して、全体的な結腸の炎症が、両方の投与量でTl1a Abを受けたマウスにおいて有意に減少した(図1C)。また、腸間膜リンパ節(MLN)及び粘膜固有層(LP)から回収される単核細胞の数は、Iso Ab群と比較して、Tl1a Ab治療により減少した(図1D)。Tl1a 80−mg/kgAbで治療されたマウスでは、確立された大腸炎及び細胞浸潤の寛解が、重篤な全体的な結腸の炎症が少なくなること及びPre−Tx群よりもLP単核細胞(LPMC)有意に数が低減することにより実証された(図1C及びD)。
Tl1a Ab投与が確立されたマウスの大腸炎の病理組織学的な特徴を緩和した。
結腸の組織学的実験は、養子移植モデルにおけるIso Ab群と比較して、Tl1aAb治療による低減された細胞浸潤、ムチンの減損、陰窩膿瘍、及び構造上の変化により特徴づけられる低減された炎症を明らかにした(図2A及びB)。組織学的炎症の低減は、また、4週間目のPre−Tx群と比較して有意に低減し(図2A及びB)、部分的に回復された炎症を示した。一貫して、結腸のミエロペルオキシダーゼ(MPO)活性が、Iso Ab群と比較してTl1a Ab投与の両方の投与量で、及びPre−Tx群と比較して80−mg/kgのTl1a Abで有意に低減した(図2C)。Tl1a Ab投与による結腸のMPO活性における低減がRagベースライン対照(Rag Co)群と有意に異ならないレベルに達した場合に、大腸炎の粘膜の分解が示唆された(図2C)。
Tl1a Abは、Th−1及び−17免疫応答を阻害した。
2つの腸炎惹起性のモデルにおける確立されたマウスの大腸炎を低減する潜在的免疫メカニズムを評価するために、Ifnγ、Il13、及びIl17の発現が測定された。Tl1a Abは、養子移植モデルにおけるIso Ab群及びPre−Tx群の両方と比較してMLN及びLPMCにおけるCD4+Il17+T細胞の頻度を低減した(図3A及びB)。CD4+Ifnγ+T細胞は、同様に、Tl1a Abを20−mg/kgで投与したLPMCを除いてTl1a Ab治療の両方の投与量で低減され、Pre−Tx群と比較して有意な低減をもたらさなかった(図3A及びC)。更に、発明者らは、またMLN及びLPMCの両方で、Pre−Tx及びIso Ab群と比較して、Tl1a Ab治療によりIfnγ+及びIl17+ダブルポジティブCD4+T細胞を有意に低減したことを見出した(図3B及びC、右のパネル)。CD3/CD28により刺激されたMLN及びLPMC細胞を用いて、より低いIl17産生が、Iso Ab及びプレ治療群を受けたマウスと比較して、Tl1a Abにより治療されたマウスでみられた(図3D)。MLNを除いて、Tl1a Ab治療は、両方の投与量で、Iso Ab及びPre−Tx群と比較してより低いIfnγ分泌を導いた(図3E)。CD4+Il13+T細胞及びIl13産生のパーセンテージは、群間で有意に異ならなかった。慢性のDSS大腸炎モデルでは、CD4+Il17+、CD4+Ifnγ+及びCD4+Il17+Ifnγ+T細胞の低減が、Tl1a Ab治療によるMLN及びLPMCにおいて同様に観察された(図9AからC)。一貫して、Tl1a Ab治療は、CD3/CD28により刺激された、分離されたMLN及びLPMC細胞におけるIl17及びIfnγのより低い産生をもたらした(図9D及びE)。CD4+Il13+T細胞及びIl13産生のパーセンテージは、慢性のDSS大腸炎モデルにおける群間で異ならなかった。これらのデータは、Tl1a AbがTh−1及び−17炎症誘発免疫応答を低減することを示唆した。
Tl1a Abは確立された結腸の線維症を逆戻りさせた。
恒常的なTl1a発現を有するマウスは、これまでに、消化管線維症の増加を発達させることが示された。Tl1aシグナル伝達を抑制することが結腸の線維症を低減し得るのかどうかを評価するために、我々は、コラーゲン沈着の程度を測定するためにシリウスレッド染色を行った。発明者は、ベースラインRag Co群と比較して、ナイーブなT細胞がPre−Tx群においてトランスファーした後4週間までに増加したコラーゲン沈着をみつけた(図4A及びC)。コラーゲン沈着の程度は、対照Iso Abを受けたマウスにおいて8週目までにより多くなった。しかしながら、Tl1a Abによる治療は、Iso AbまたはPre−Tx群を受けたマウスと比較される場合に、コラーゲン沈着において有意な低減を導いた(図4A及びC)。とりわけ、コラーゲン沈着は、80mg/kgのTl1a治療が正常なRag Coマウスと比較された場合に、有意に異ならなかった(図4C)。慢性のDSSモデルにおいて、Tl1a Ab治療による、コラーゲン沈着における同様の低減が、Iso AbまたはPre−Tx群と比較して観察された(図4A及びC)。また、Tl1a治療は、WTベースライン対照と有意に異ならないレベルにコラーゲン沈着における低減を導いた(図4A及びC)。ともに、これらのデータは、Tl1aシグナル伝達を抑制することが、炎症の発症前と同様のレベルにコラーゲン沈着を逆戻りさせることを示唆した。
Tl1a−Dr3シグナル伝達を抑制することが、腸の繊維芽細胞及び筋線維芽細胞数を低減させた。
Tl1a Abによるコラーゲン沈着低減のメカニズムを研究することを開始するために、腸の繊維芽細胞及び筋線維芽細胞の出現頻度が測定された。腸の筋線維芽細胞は、腸の線維形成に伴われる細胞群である。ビメンチン陽性細胞は、繊維芽細胞であり、α平滑筋アクチン(αSMA)の共発現に関し、筋線維芽細胞を表す。データは、ナイーブなT細胞をトランスファーした4週間後に(Pre−Tx群)、繊維芽細胞及び筋線維芽細胞の数が増加することを示した(図4B及びD)。繊維芽細胞及び筋線維芽細胞の数は、Iso Abを受けたマウスで8週目までに更に増加した。しかしながら、Tl1a Abによる治療は、正常なRag Coと同様のレベルまで、繊維芽細胞及び筋線維芽細胞の数における低減を導いた(図4B及びD)。興味深いことに、80−mg/kgのTl1a Abを受けたマウスにおける筋線維芽細胞の低減は、Rag Coマウスと統計的に異ならないレベルに達し(図4B及びD)、線維形成の反転を示唆した。
Tl1a Ab治療による線維形成の反転
Tl1a Abによる確立された腸の線維症の反転の分子メカニズムを研究するために、コラーゲンの発現、線維形成性プログラムメディエータ(Tgfβ1、Ctgf、Igf1、Pten、及びIl31Ra)、及び細胞外マトリクス(ECM)リモデリングを伴う因子(Mmp及びTimp)が測定された。より低いレベルのコラーゲン発現が、養子移植及び慢性のDSSモデルの両方で見られた(本明細書の表1及び表2)。Tl1a Abによる線維形成性プログラムの正常化が、養子移植及び慢性のDSSモデルの両方で並びに養子移植モデルにおけるIgf1でTgfβ1及びIl31Raを含む前繊維性のメディエータのより低い発現により観察された(表1及び表2)。結合組織増殖因子(Ctgf)、Tgfβシグナル伝達の下流メディエータの発現が、養子移植モデルにおけるPre−Tx及びIso Ab群と比較して、Tl1a Ab投与により低減された。ECMリモデリングは、メタロプロテアーゼ(Mmp)及びメタロプロテアーゼの組織インヒビタ(Timp)の発現を測定することにより評価された。アイソタイプAb群と比較して、ECM劣化を伴う遺伝子の発現は、養子移植モデルにおけるTl1a Abにより治療されたマウス(Mmp2、Mmp3;表1)において、及び慢性のDSSモデル(Mmp2、Mmp3、Mmp13;表2)において低減された。とりわけ、Timpの発現は、養子移植モデル(Timp2,表1)において及び慢性のDSSモデル(Timp1、Timp2;表2)において、Tl1a治療により、より低くなった。これらの結果は、低減されたコラーゲン合成を導くTl1a Abによる線維形成性プログラムにおける低減があることを論証する。Mmp及びTimpの両方のより低い発現が、組織の損傷を誘導するよりもむしろ確立されたECMコンポーネントの増強された除去に寄与するかもしれない。このように、データは、Tl1a Abによる確立された繊維症の反転が、低減された線維形成性プログラム及びおそらくMmp及びTimpの両方の低減の最終結果であることを示唆する。
腸の繊維芽細胞がDr3を発現し、Tl1a刺激に反応する。
発明者らは、腸の繊維芽細胞が、直接Tl1aシグナル伝達に対して機能的に反応し得るのかどうかを調査した。Dr3のmRNAレベル、Tl1aの唯一の既知のレセプターが測定され、WTでは低レベルで発現されるが、Dr3欠損原発性腸繊維芽細胞では発現されないことをみいだした(図6A、上のパネル)。一貫して、免疫蛍光染色法は、Dr3は、WT原発性腸繊維芽細胞で発現されることを示した(図6A、下のパネル)。フローサイトメトリーを用いて、発明者らは、Dr3が、αSMA発現なしの繊維芽細胞と比較して、αSMAと供発現する繊維芽細胞で優先的に発現されることを見出した(図6B)。発明者らは、腸の繊維芽細胞がTl1a刺激に反応し得るかどうかを次に確認し、繊維芽細胞活性化のマーカーとしてコラーゲン(Col1a2)及びIl31レセプター(Il31Ra)を使用した。発明者らは、Tl1aが、エクスビボでマウスの原発性腸繊維芽細胞におけるCol1a2及びIl31Raの発現を投与量に依存して増加させ得ることを示した(図6C)。Tl1a刺激の特性は、エクスビボでDr3−/−マウスの腸の繊維芽細胞におけるCol1a2及びIl31Raの平滑末端化されたTl1a誘導により論証される(図6D)。これらのデータは、腸の繊維芽細胞がDr3を発現し、直接Tl1aシグナル伝達に機能的に反応し得ることを示す。
線維症メディエータの発現分析の結果
表1 養子移植大腸炎モデルにおける線維症メディエータの発現分析
ns=有意ではない
ns=有意ではない
TL1A−Dr3シグナル伝達を抑制することは、腸の繊維芽細胞及び筋線維芽細胞の数を低減した。−追加の結果
結腸の筋線維芽細胞は、腸の線維形成をともなう細胞群である。Tl1aAbによるコラーゲン沈着低減の細胞メカニズムを研究するために、繊維芽細胞発現のビメンチン及び筋線維芽細胞共発現のビメンチン及びα平滑筋アクチン(αSMA)が、これらの細胞タイプの数を評価するために測定された。Pre−Tx及びIso Ab群の両方でナイーブなT細胞がトランスファーした後に、結腸の繊維芽細胞及び筋線維芽細胞の数が増加した(図11a)。しかしながら、Tl1aAbによる治療は、正常なRagCoと同様のレベルにまで繊維芽細胞及び筋線維芽細胞の数における低減を導いた(図11a)。
腸の繊維芽細胞はDr3を発現し、TL1A刺激に対して反応する。−追加の結果
腸の繊維芽細胞が直接的なTl1aシグナル伝達に対して機能的に反応するかどうかを測定するために、Dr3のmRNAレベルが測定されて、Dr3欠損原発性腸繊維芽細胞では検出できないが、WT(0.0018±0.001%βアクチン)では低いレベルで発現されることが分かった。フローサイトメトリックな分析が、Dr3がビメンチン+αSMA−繊維芽細胞またはビメンチン+αSMA+筋線維芽細胞(myoflbroblast)で発現されるかどうかを測定するために行われた。結果は、Dr3が、ビメンチン+αSMA−繊維芽細胞と比較して、ビメンチン+αSMA+筋線維芽細胞で優先的に発現することを示した。更に、筋線維芽細胞でのαSMAレベルと、最も高いαSMA発現との筋線維芽細胞でのDr3発現のより高い比率と、Dr3発現の直接的な相関関係があった(図13a)。更に、αSMA及びDr3により免疫染色された、ソートされたαSMA陽性の原発性腸繊維芽細胞は、WTにおけるDr3の供染色を示したが、Dr3欠損筋線維芽細胞では示されず、Dr3はαSMA陽性の原発性腸繊維芽細胞で発現されることを示した(図13b)。
全般
腸の線維狭窄は、とりわけ重篤なCrohn病の顕著な特徴である。所定のTNFSF15(遺伝子名TL1A)変異体を有する患者はTL1Aを過剰に発現し、小腸で狭窄を発症するより高いリスクを有する。更に、マウスにおける持続性のTl1a発現は、腸炎惹起性の状況下に小及び大腸を導く。発明者らは、確立されたマウスの結腸の線維症が、Tl1a抗体により逆戻りし得るかどうかを測定した。Tl1a抗体を中和する治療は、結合組織増殖因子(Ctgf)、Il31Ra、形質転換増殖因子(Tgf)β1及びインスリン様増殖因子1(Igf1)のより低い発現の結果として、もとの前炎症性のレベルに結腸の線維症を逆戻りさせた。更に、Tl1a抗体を中和またはデスドメインレセプタ3(Dr3)の欠失のいずれかによりTl1a機能を抑制することは、繊維芽細胞及び筋線維芽細胞、組織の繊維症を媒介する原発性の細胞タイプの数を低減させた。原発性腸筋線維芽細胞がDr3を発現し、コラーゲン及びIl31Ra発現を増加させることにより直接的なTl1aシグナル伝達に機能的に反応した。これらのデータは、組織線維症におけるTL1A−DR3シグナル伝達の直接的な役割、及びTL1A−DR3シグナル伝達の変調が消化管線維症を阻害することを論証した。
Claims (59)
- 対象における線維症の治療方法であって、
TL1A−DR3シグナル伝達機能抑制物質を1つ以上含む組成物を提供すること;及び
治療効果のある用量の組成物を前記対象へ投与することを含む、前記対象における線維症の治療方法。 - 前記組成物が1つ以上のTL1A遮断抗体を含む、請求項1に記載の方法。
- 前記組成物が1つ以上のDr3遮断抗体を含む、請求項1に記載の方法。
- 前記組成物が、TL1Aに直接結合することでTL1A機能を抑制する1つ以上の化合物を含む、請求項1に記載の方法。
- 前記組成物が、Ifngamma、IL17、Ctgf、及びIL31Raの抑制物質を1つ以上含む、請求項1に記載の方法。
- 前記組成物が、Tgfbeta1及びIgf1の抑制物質を1つ以上含む、請求項1に記載の方法。
- 前記組成物が、IL31シグナル伝達の抑制物質を1つ以上含む、請求項1に記載の方法。
- 治療効果のある用量の前記組成物を投与することで、前記線維症から炎症前のレベルまでの回復をもたらす、請求項1に記載の方法。
- 前記線維症が結腸の線維症である、請求項1に記載の方法。
- 治療効果のある用量の前記組成物を投与することで、前記対象における腸炎症の抑制を更にもたらす、請求項1に記載の方法。
- 治療効果のある用量の前記組成物を投与することで、前記対象における線維芽細胞及び/または筋線維芽細胞の数を減少させる、請求項1に記載の方法。
- 治療効果のある用量の前記組成物を投与することで、前記対象における原発性腸筋線維芽細胞の数を減少させる、請求項1に記載の方法。
- 対象における疾患の治療方法であって、
IL31Raシグナル伝達抑制物質を含む組成物を提供すること;及び、
有効量の前記組成物を前記対象へ投与することを含む、前記治療方法。 - 前記疾患がTL1A関連疾患である、請求項13に記載の方法。
- 前記疾患が炎症性腸疾患(IBD)である、請求項13に記載の方法。
- 前記疾患が、前記小腸及び/または腸炎症において発生した狭窄と関係する、請求項13に記載の方法。
- 前記疾患が、小腸及び大腸の繊維性狭窄(fibrostenosis)である、請求項13に記載の方法。
- 前記疾患が線維症である、請求項13に記載の方法。
- 前記組成物が1つ以上のTL1A Abを含む、請求項13に記載の方法。
- 前記組成物が、IL31RA、Ifngamma、IL17、Ctgf、TgfB1、及び/またはIgf1シグナル伝達の抑制物質を1つ以上含む、請求項13に記載の方法。
- 治療効果のある用量の前記組成物を投与することで、前記対象における線維芽細胞及び/または筋線維芽細胞を減少させる、請求項13に記載の方法。
- 対象におけるTL1A関連疾患への感受性の診断方法であって、
前記対象から試料を得ること;
前記試料を試験して、健常者と比べて高レベルなIL31Ra発現が存在するかまたは存在しないかを判定すること;及び、
健常者と比べて高レベルなIL31RA発現の存在に基づいて、前記TL1A関連疾患に対する感受性を診断することを含む、前記対象におけるTL1A関連疾患への感受性の診断方法。 - 前記TL1A関連疾患が炎症性腸疾患(IBD)である、請求項22に記載の方法。
- 前記TL1A関連疾患が、前記小腸及び/または腸炎症において発生した狭窄と関係する、請求項22に記載の方法。
- 前記TL1A関連疾患が、小腸及び大腸の繊維性狭窄である、請求項22に記載の方法。
- 前記TL1A関連疾患が線維症である、請求項22に記載の方法。
- 健常者と比べて高レベルな、コラーゲン、IL31RA、Ifngamma、IL17、Ctgf、TgfB1、及び/またはIgf1の発現の存在を判定することを更に含む、請求項22に記載の方法。
- 対象におけるTL1A関連疾患の診断方法であって、
前記対象から試料を得ること;
前記試料を試験して、1つ以上の前記TL1A関連疾患と関連するリスクバリアント及び/またはマーカーが存在するかまたは存在しないかを判定すること;ならびに、
前記TL1A関連疾患と関連する1つ以上のリスクバリアント及び/またはマーカーの存在に基づいて、前記TL1A関連疾患を診断することを含む、前記対象におけるTL1A関連疾患の診断方法。 - 前記1つ以上のリスクバリアント及び/またはマーカーがIL31RAの高発現を含む、請求項28に記載の方法。
- 前記1つ以上のリスクバリアント及び/またはマーカーが、Ifngamma、IL17、Ctgf、TgfB1、及び/またはIgf1の高発現を含む、請求項28に記載の方法。
- 前記TL1A関連疾患が炎症性腸疾患(IBD)である、請求項28に記載の方法。
- 前記TL1A関連疾患が、前記小腸及び/または腸炎症において発生した狭窄と関係する、請求項28に記載の方法。
- 前記TL1A関連疾患が、小腸及び大腸の繊維性狭窄である、請求項28に記載の方法。
- 前記TL1A関連疾患が線維症である、請求項28に記載の方法。
- 1つ以上のTL1A抑制物質を投与することで前記TL1A関連疾患を治療することを更に含む、請求項28に記載の方法。
- TL1A抑制物質を投与することで前記TL1A関連疾患を治療することを更に含む、請求項28に記載の方法。
- 前記対象がヒトである、請求項28に記載の方法。
- Dr3抑制物質を投与することで前記TL1A関連疾患を治療することを更に含む、請求項28に記載の方法。
- 対象における線維症の治療方法であって、
TL1A抑制物質及びDR3抑制物質を含む組成物を提供すること;ならびに、
治療効果のある用量の前記組成物を前記対象へ投与することを含む、前記対象における線維症の治療方法。 - 前記TL1A抑制物質がTL1A Abである、請求項39に記載の方法。
- 前記DR3抑制物質がDR3の発現を除去する、請求項39に記載の方法。
- 前記線維症が減少する、請求項39に記載の方法。
- 前記組成物がTL1A−DR3シグナル伝達機能を抑制する、請求項39に記載の方法。
- 対象における線維症の回復方法であって、
TL1A抑制物質及びDR3抑制物質を含む組成物を提供すること;ならびに、
治療効果のある用量の前記組成物を前記対象へ投与することを含む、前記対象における線維症の回復方法。 - 前記組成物が、Ifngamma、IL17、Tgfbeta1、Ctgf、及び/またはIL31RAシグナル伝達機能の抑制物質を更に含む、請求項44に記載の方法。
- 前記組成物がTL1A−DR3シグナル伝達機能を抑制する、請求項44に記載の方法。
- 炎症の治療方法であって、以下:
TL1A抑制物質及び/またはDR3抑制物質を含む組成物を提供すること;ならびに、
治療効果のある用量の前記組成物を前記対象へ投与することを含む、前記炎症の治療方法。 - 前記組成物が、Ifngamma、IL17、Ctgf、及び/またはIL31RAシグナル伝達機能の抑制物質を更に含む、請求項47に記載の方法。
- 前記組成物がTL1A−DR3シグナル伝達機能を抑制する、請求項47に記載の方法。
- 対象における疾患の治療方法であって、
Ifnγ及びIl−17発現を抑制すること、Tgfβシグナル伝達を下方制御すること、及び/または線維芽細胞/筋線維芽細胞を減少させること;ならびに、
前記対象を治療することを含む、前記対象における疾患の治療方法。 - 前記疾患が炎症性腸疾患である、請求項50に記載の方法。
- 前記疾患が線維症である、請求項50に記載の方法。
- 前記疾患が腸炎症である、請求項50に記載の方法。
- 前記疾患が炎症性腸疾患と関連する合併症である、請求項50に記載の方法。
- 組成物であって、以下:
1つ以上のTL1A、DR3、及びIL31RAシグナル伝達機能の抑制物質;ならびに、
薬剤的に許容可能な担体を含む、前記組成物。 - 前記1つ以上のTL1A抑制物質がTL1A Abである、請求項55に記載の組成物。
- 前記1つ以上のDR3抑制物質がDR3抗体である、請求項55に記載の組成物。
- IBDと関連する合併症の治療方法であって、
TL1A、DR3、及びIL31RAシグナル伝達機能の抑制物質を含む組成物を提供すること;ならびに、
治療効果のある用量の前記組成物を前記対象へ投与することを含む、前記IBDと関連する合併症の治療方法。 - 前記組成物が前記対象へ静脈注射によって投与される、請求項58に記載の方法。
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US11236393B2 (en) | 2008-11-26 | 2022-02-01 | Cedars-Sinai Medical Center | Methods of determining responsiveness to anti-TNFα therapy in inflammatory bowel disease |
US10633449B2 (en) | 2013-03-27 | 2020-04-28 | Cedars-Sinai Medical Center | Treatment and reversal of fibrosis and inflammation by inhibition of the TL1A-DR3 signaling pathway |
US10316083B2 (en) | 2013-07-19 | 2019-06-11 | Cedars-Sinai Medical Center | Signature of TL1A (TNFSF15) signaling pathway |
US11312768B2 (en) | 2013-07-19 | 2022-04-26 | Cedars-Sinai Medical Center | Signature of TL1A (TNFSF15) signaling pathway |
US11186872B2 (en) | 2016-03-17 | 2021-11-30 | Cedars-Sinai Medical Center | Methods of diagnosing inflammatory bowel disease through RNASET2 |
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EP3639841B1 (en) | 2023-09-06 |
MX2015013703A (es) | 2016-08-11 |
BR112015024752A2 (pt) | 2017-07-18 |
CL2015002866A1 (es) | 2016-08-05 |
CA2908553A1 (en) | 2014-10-02 |
EP2978440A4 (en) | 2017-01-18 |
JP2020033379A (ja) | 2020-03-05 |
CN105246501B (zh) | 2021-01-12 |
KR20150134393A (ko) | 2015-12-01 |
EP3639841A1 (en) | 2020-04-22 |
CN105246501A (zh) | 2016-01-13 |
KR20230109779A (ko) | 2023-07-20 |
JP6671276B2 (ja) | 2020-03-25 |
CN112870368A (zh) | 2021-06-01 |
WO2014160883A1 (en) | 2014-10-02 |
JP2022132362A (ja) | 2022-09-08 |
US10633449B2 (en) | 2020-04-28 |
EP4285988A3 (en) | 2024-03-06 |
EP2978440B1 (en) | 2019-10-02 |
KR20210157418A (ko) | 2021-12-28 |
AU2014241162A1 (en) | 2015-10-22 |
US11434296B2 (en) | 2022-09-06 |
KR102343212B1 (ko) | 2021-12-23 |
US20230091596A1 (en) | 2023-03-23 |
EP4285988A2 (en) | 2023-12-06 |
EP2978440A1 (en) | 2016-02-03 |
US20160060335A1 (en) | 2016-03-03 |
US20200190203A1 (en) | 2020-06-18 |
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