JP2016515571A - 調節性t細胞への分化を誘導し、及び増殖を促進することにより免疫反応を抑制するための医薬組成物 - Google Patents
調節性t細胞への分化を誘導し、及び増殖を促進することにより免疫反応を抑制するための医薬組成物 Download PDFInfo
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Abstract
Description
(1,1−ジオキソ−チオモルホリン−4−イル)メチル−1H−インドール−7−イル]アミンを含む免疫抑制のための医薬組成物は、他の公知の免疫抑制剤と組み合わせて用いられてもよい。併用可能な他の免疫抑制剤の例には、以下に限定されないが、シクロスポリンA、ラパマイシン、タクロリムス、サクロリムス(sacrolimus)、メトトレキサート、アザチオプリン、ミコフェノール酸モフェチル、又は各種ステロイド製剤などが挙げられる。
互いに異なるMHCクラスを有する6〜8週齢のC57BL/6(H−2kb)およびBALB/c(H−2kd)マウスをオリエントバイオ社から購入した。カトリック大学校の実験動物研究室管理委員会の規定を通過し、前記マウスを同委員会の管理下で使用した。レシピエントマウスのBALB/c(H−2kd)は、800cGyで放射線を全身に照射した(放射線供給源:X−ray Mevatron MXE−2)。24時間以内に、ドナーマウスのC57BL/6(H−2kb)から単離した骨髄の5×106細胞および脾臓の5×106細胞を、同種レシピエントマウスに静脈内から移植して、移植片対宿主拒絶反応モデルを作製した。前記骨髄移植マウスを観察し、下記の点について評価した:各2点ずつ合計10点の評価基準で体重、姿勢、活動性、毛状態、皮膚密度(1週間に2回ずつ)(表1)。
マウスを、試験群として(テトラヒドロピラン−4−イル)−[2−フェニル−5−(1,1−ジオキソ−チオモルホリン−4−イル)メチル−1H−インドール−7−イル]アミン(韓国のLG生命科学社、以下、「化合物A」という)で処理したGVHD群、および対照群として化合物Aで処理していないGVHD群に分けた。各群の脾臓を単離し、次いで単一細胞を単離した。CD4+CD25+Foxp3+(調節性T細胞の表現型)の発現、ならびにCD4+IFN−γ細胞及びCD4+IL−4細胞を、蛍光モノクローナル抗体およびフローサイトメーターを用いて分析した。
各群のマウスを屠殺し、これらの脾臓を単離した。単一細胞を単離し、得られた細胞をリン酸緩衝液で2回洗浄した。3μMのカルボキシ−H2DCFDA試薬を用いて37℃で10分間反応させた。PBSで洗浄し、フローサイトメーターを用いて540nmで分析した。
総RNAは、TRIzol試薬を用いて前記細胞から抽出した。1μgのRNAをAMV逆転写酵素およびランダムヘキサマーと45℃で1時間反応させて、cDNAを合成した。リアルタイムPCRを、鋳型として1μgのcDNA、プライマーS、プライマーAS、および蒸留水を混合した混合物、ならびにSYBR Greenを用いて行った。前記PCRは、HMGB1(5'−GATGGGCAAAGGAGATCCTAAG−3'と5'−TCACTTTTTTGTCTCCCCTTTGGG−3')を用いて、95℃で15秒、60℃で10秒、72℃で30秒の35サイクルの条件で行った。蛍光データは、Rad CFX96 Real−Time System(Bio−Rad Laboratories)を用いて測定した。
4μmの連続切片をパラフィンに包埋した組織から得て、キシレンで3回処理してパラフィンを除去し、次いで95%、90%、70%のエタノールで段階的に含水した。内在性ペルオキシダーゼを0.5%過酸化水素中で除去し、前記試料を通常のヤギ血清で30分間処理し、続いて製造業者の指示に従ってPBS中の3%BSA(ウシ血清アルブミン)で希釈した一次抗体と1時間反応させた。前記実験で発現の差を示す遺伝子に対する発現タンパク質への一次抗体を反応させた後、前記試料をトリス緩衝食塩水(TBS)で3回洗浄し、3%のBSAで希釈した5μg/mLのビオチン化抗マウス/抗ウサギIgGと30分間反応させ、TBSで3回洗浄した。該試料を3μg/mLのセイヨウワサビのペルオキシダーゼストレプトアビジン中で30分間保ち、DABおよび過酸化水素で発色させ、マイヤーのヘマトキシリンまたは1%のメチルグリーンで対照染色させた。
1.本発明の化合物(テトラヒドロピラン−4−イル)−[2−フェニル−5−(1,1−ジオキソ−チオモルホリン−4−イル)メチル−1H−インドール−7−イル]アミンによるモデルマウスでの免疫移植拒絶の抑制
本発明では、GVHDモデルマウスにおける本発明の化合物(テトラヒドロピラン−4−イル)−[2−フェニル−5−(1,1−ジオキソ−チオモルホリン−4−イル)メチル−1H−インドール−7−イル]アミンによる免疫拒絶反応の抑制効果を調べた。実験結果として、本発明の化合物で処理した群の生存率が、未処理の群のものと比較して大きく増加し、体重および移植片対宿主反応の評価で顕著な結果が観察できた(図1及び2)。組織学的所見において、大腸のH&E染色の結果として、本発明の化合物で処理していないGVHD群では、大腸の絨毛及び粘膜が破壊されていることが観察されたが、本発明の化合物で処理した群では、正常な大腸組織と同様であることが観察された(図3)。
ROSは、体内の細胞機能の調節において非常に重要な役割を果たしており、免疫系における免疫細胞の防御作用に関連している。ネクローシス細胞では、ROSはミトコンドリアにより生成され、これによりHMGB1が酸化される。そして、免疫寛容が酸化されたHMGB1によって生じる。
HMGB1の放出は、炎症及び免疫を調節する機能を有しうることが広く知られてきた。それゆえ、本研究では、GVHDモデルマウスにおいて本発明の化合物で処理した実験群と対照群で動物を屠殺し、脾臓細胞からRNAを抽出し、cDNAを合成し、HMGB1の発現をリアルタイムPCRで比較実験を行った。その結果、本発明の化合物で処理した群におけるHMGB1の放出が、対照群と比較して時間依存的に顕著に抑制されることが確認された(図5)。
本発明者らは、GVHDモデルマウスにおいて、本発明の化合物により、免疫移植拒絶反応が減少され、ROS及びHMGB1の生成抑制、組織内の細胞ネクローシスが抑制されることを見出し、免疫疾患動物モデルにおける免疫反応を調節する可能性を見ようとした。よって、本発明の化合物で処理した実験群および対照群のマウスを屠殺し、それらの脾臓を単離し、単一細胞を単離し、次いで免疫調節機能をフローサイトメトリー分析により調べた。その結果、本発明の化合物で処理した群は、対照群と比較して、CD4+CD25+Foxp3+免疫調節細胞(調節T)が6倍またはそれ以上に増加された。さらに、CD4+IL−4細胞が増加し、CD4+IFN−γ細胞が半分以上減少した(図6)。GVHDモデルマウスにおいて、高用量の放射線で照射し、ドナーの移植されたT細胞が、宿主の抗原提示細胞により活性化され、増殖し、代表的なGVHD誘発サイトカインとして知らされたIFN−γを分泌する。前記実験結果により、本発明の化合物が、調節性T細胞およびIL−4の上方調節によってIFN−γを抑制したことが示された。従って、本発明の化合物は、移植されたT細胞の活性化を抑制することによって免疫反応を抑制できることが分かった。
リンパ球Th細胞分化における本発明の化合物の効果を調べるために実験した。マウス脾臓細胞から単離した5×105個のCD4+T細胞を、1μg/mLの抗CD3(aCD3)でコーティング処理した24ウェルプレートに分注し、次いで1μg/mLの抗CD28(aCD28)および5ng/mLのTGF−βで処理して、調節性T細胞への分化を3日間誘導した。調節性T細胞への分化前に、本発明の化合物(テトラヒドロピラン−4−イル)−[2−フェニル−5−(1,1−ジオキソ−チオモルホリン−4−イル)メチル−1H−インドール−7−イル]アミン(以下、「化合物A」という)(LG生命科学社、韓国)で40μMおよび80μMの濃度にて処理した。フローサイトメトリー分析のために、これらに抗マウスCD4 PerCP、CD25 APCおよびFoxP3PE蛍光で標識した抗体を加え、4℃で30分間反応させた。PBSで洗浄し、フローサイトメーター(FACs Calibur(登録商標))で測定した。
RAは、TGF−βの存在下でFoxp3+Tregへの分化を増加させることが知られている。実施例6の実験結果から、化合物Aは、特にFoxp3+の発現を強力に亢進させることが確認されたので、化合物Aを一般的に公知のRAの効果と比較する実験を行った。
化合物Aによって誘導された調節性T細胞(以下、「iTreg」という)の機能を確認するために、iTreg細胞が、T細胞の増殖(aCD3+aCD28+刺激)及び同種免疫反応細胞の活性(B6 CD4+および2000cGy B/c APCの同種反応)を抑制できるかどうかを評価した。このために、(1)aCD3及びaCD28の添加によって誘導されたTreg細胞、(2)aCD3、aCD28及びTGF−βの添加によって誘導されたTreg細胞(以下、「TGF−β Treg」という)、(3)aCD3、aCD28、TGF−β及びRAの添加によって誘導されたTreg細胞(以下、「RA Treg」という)、(4)aCD3、aCD28、TGF−β及び40μMの化合物Aの添加によって誘導されたTreg細胞(以下、「化合物A Treg」という)、並びに(5)aCD3、aCD28、TGF−β及び80μMの化合物Aの添加によって誘導されたTreg細胞(以下、「化合物A Treg」という)を準備し、比較分析を白血球混合培養法により行った。
C57BL/6の脾臓細胞から単離した1×106個のCD4+T細胞および20Gyで照射したBALBc抗原提示細胞(APC)を、48ウェルプレートに加え、37℃で5日間インキュベートした。脾臓細胞に対して抗原提示細胞による同種免疫反応が誘導される条件下でインキュベートし、比較分析のためにインキュベーション前に化合物Aを様々な濃度で処理した。細胞を5日のインキュベーション後に回収し、フローサイトメトリー分析のために、そこに、抗マウスCD4 PerCP、CD25 APCとFoxP3 PE蛍光標識抗体を加え、4℃で30分間反応させた。PBSで洗浄し、フローサイトメーター(FACs Calibur(登録商標))で測定した。
互いに異なるMHCクラスを有する6〜8週齢のC57BL/6(H−2kb)マウスおよびBALB/c(H−2kd)マウスを使用した。レシピエントマウスBALB/c(H−2kd)は、8Gyで全身放射線を照射した。24時間以内に、ドナーマウスC57BL/6(H−2kb)から単離した5×106個の骨髄細胞および5×106個の脾臓細胞をレシピエントマウスに静脈内から移植して、移植片対宿主拒絶反応モデル(GVHDモデル)を作製した。化合物Aは、このようなGVHDモデルに2週間にわたり1週間に4回ずつ静脈内から注入した。マウスを屠殺し、単一細胞を単離し、脾臓における免疫調節機能をフローサイトメトリー分析により調べた。その結果、化合物Aを投与した群では、CD4+CD25+Foxp3+調節性T細胞が増加することが確認された(図14)。
Claims (11)
- (テトラヒドロピラン−4−イル)−[2−フェニル−5−(1,1−ジオキソ−チオモルホリン−4−イル)メチル−1H−インドール−7−イル]アミン、その薬学的に許容しうる塩又は異性体を含む、免疫反応を抑制するための医薬組成物。
- 皮膚、血液、角膜、肝臓、肺、腸、膵臓、心臓、腎臓、骨髄、幹細胞又は前駆細胞の移植に対する免疫拒絶反応を抑制するためのものである、請求項1に記載の免疫反応を抑制するための医薬組成物。
- 移植片対宿主疾患、アレルギー性疾患、自己免疫疾患又は炎症疾患の治療及び予防に使用されるものである、請求項1に記載の免疫反応を抑制するための医薬組成物。
- (テトラヒドロピラン−4−イル)−[2−フェニル−5−(1,1−ジオキソ−チオモルホリン−4−イル)メチル−1H−インドール−7−イル]アミン、その薬学的に許容しうる塩又は異性体を含む、未熟T細胞から調節性T細胞への分化を誘導し、及び/又は調節性T細胞の増殖を促進するための組成物。
- 抗CD3抗体、抗CD28抗体及びTGF−βを更に含む、請求項4に記載の組成物。
- レチノイン酸(RA)又はレチナールを更に含む、請求項4に記載の組成物。
- 前記調節性T細胞が、CD4+、CD25+及びFoxp3+の表現型を有するものである、請求項4に記載の組成物。
- 未熟T細胞を、生体外において請求項4〜7のいずれか1項に記載の組成物で処理する工程を含む、調節性T細胞への分化を誘導する方法。
- 未熟T細胞を、生体外において請求項4〜7のいずれか1項に記載の組成物で処理する工程を含む、調節性T細胞の増殖を促進する方法。
- 未熟T細胞を、生体外において請求項4〜7のいずれか1項に記載の組成物で処理する工程を含む、調節性T細胞への分化を誘導し、及び調節性T細胞の増殖を促進することにより調節性T細胞を取得する方法。
- 請求項10に記載の方法により取得された調節性T細胞を含む、移植拒絶反応、移植片対宿主疾患、アレルギー性疾患、自己免疫疾患及び炎症疾患のような免疫疾患の治療用組成物。
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EP4201407A1 (en) | 2020-08-19 | 2023-06-28 | MitoImmune Therapeutics Inc. | Mitochondria-targeted antioxidant as agent for treating pathologic inflammation caused by mabc-r infection |
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US9867832B2 (en) | 2018-01-16 |
CA2907574A1 (en) | 2014-10-02 |
CA2907574C (en) | 2017-09-05 |
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AU2014244744B2 (en) | 2016-09-01 |
ES2738658T3 (es) | 2020-01-24 |
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CN105073110A (zh) | 2015-11-18 |
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US20160051558A1 (en) | 2016-02-25 |
EP2992881B1 (en) | 2019-05-22 |
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JP6072347B2 (ja) | 2017-02-01 |
WO2014157918A1 (ko) | 2014-10-02 |
AU2014244744A1 (en) | 2015-10-08 |
MX2015013480A (es) | 2016-07-21 |
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