JP2022513590A - 新規な化合物およびカルシニューリン阻害剤を含む、移植拒絶反応または移植拒絶疾患を予防および治療するための組成物 - Google Patents
新規な化合物およびカルシニューリン阻害剤を含む、移植拒絶反応または移植拒絶疾患を予防および治療するための組成物 Download PDFInfo
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Abstract
Description
<化学式2>
1-1:試験管内のシンジェニック移植モデルまたはアロジェニック移植モデル
In vitro実験として、正常なレシピエント(Balb/c、レスポンダー)由来のCD4+T細胞(2×105個)を、96ウェル丸底プレートの各ウェルに注入した。その後、シンジェニック移植のために、放射線を照射した正常なレシピエント由来のT細胞除去の脾細胞(2×105個)を各ウェルに加え、混合培養した。アロジェニック移植のために、ドナー(C57BL/6、スティミュレーター)由来のT細胞除去の脾細胞を各ウェルに加え、混合培養した。
aGVHDモデルを作製するために、レシピエントマウスBalb/c(H-2k/d)に800cGyで全身照射(TBI)を行った。ドナーマウスC57BL/6(H-2k/b)の大腿骨と脛骨から造血幹細胞と脾細胞を採取した。造血幹細胞(5×106)と脾細胞(1×107)をレシピエントマウスBalb/c(H-2k/d)に移植した。aGVHDの発症後、各薬物を経口投与して、疾患に対する調節効果を分析した。
皮膚移植動物モデルを作製するために、レシピエントマウスBalb/c(H-2k/d)に、皮膚移植の3日前から、薬物を注射した。ドナーマウスC57BL/6(H-2k/b)の皮膚から1cm以下の皮膚片を切り取り、皮膚片の端が丸まらないように真っ直ぐにして、BALB/Cマウスに移植した。移植後の経過を観察して、拒絶反応の有無を確認した。各薬物の注射濃度は、SD282は50mg/kg、FK506は10mg/kgであった。
SD282単独、FK506単独またはこれらの組み合わせの処理によるT細胞増殖を評価するために、実施例1-1の未処理のシンジェニック群および未処理のアロジェニック群を対照として使用した。アロジェニックモデルを、50μM、250μM、および500μMのSD282単独、または1nMおよび5nMのFK506単独で処理した。また、FK506(1nMおよび5nM)とSD282(250μM)をそれぞれ組み合わせて処理した。処理後、各群を4日間培養した後、3H-チミジン取り込み法、CFSEアッセイ法、またはフローサイトメトリー法に従って、培養細胞中のT細胞増殖を観察することによってアロ反応を評価した。
[式1]
CI=(D併用)1/(D単独)1 +(D併用)2/(D単独)2
3-1:病原性Th17細胞に対する抑制効果の評価
T細胞反応はTh17(Tヘルパー17細胞)/IL-17(インターロイキン17)の活性を調節し、IL-17は炎症性サイトカインとして分類される。実施例2では、T細胞は、SD282とFK506の単独または組み合わせの処理によって効果的に阻害されることが確認された。ここでは、SD282とFK506の単独処理または併用処理による、炎症性サイトカインに対する阻害活性を評価した。実施例1-1の未処理のシンジェニック群および未処理のアロジェニック群を対照として使用した。アロジェニックモデルを、50μM、250μM、および500μMのSD282単独、または1nMおよび5nMのFK506単独で処理した。また、FK506(1nMおよび5nM)とSD282(250μM)をそれぞれ組み合わせて処理した。処理後、各群を4日間培養した後、抗CD3(0.1μg/ml)で刺激した。IL-17+CD4+T細胞およびIL-17に対する阻害効果は、ELISA法に従って培養Th17細胞を分析することにより評価した。Fox3+Treg細胞の増殖は、Treg細胞の分析により評価した。
実施例1-1のアロジェニックモデルを、20μMおよび500μMのSD282単独、または1nMおよび5nMのFK506単独で処理した。また、FK506(1nMおよび5nM)とSD282(250μM)をそれぞれ組み合わせて処理した。Th17細胞への分化を誘導するために、単離したT細胞を、Th17細胞分化の条件下で4日間培養した。その後、Th17細胞分化の条件下でも、各処理群においてTreg細胞活性が誘導されるかどうかを評価するために、Foxp3 Treg細胞をフローサイトメトリーによって分析し、そのアロジェニック反応を評価した。
4-1:SD282とFK506の併用処理によるGVHDマウスモデルの変化
図5に示すような実験を、実施例1-2のGVHD動物モデルで実施した。GVHDの発症後、50mg/kgもしくは100mg/kgのSD282を単独で、または10mg/kgのFK506を単独で投与した。また、10mg/kgのFK506と50mg/kgまたは100mg/kgのSD282をそれぞれ経口で併用投与した。その後、GVHDマウスモデルにおいて、体重(g)、体重の変化率(%)、および体重の変化率のスコア(%)を評価した。
図5に示すような実験を、実施例1-2のGVHD動物モデルで実施した。GVHDの発症後、50mg/kgのSD282単独、または10mg/kgのFK506単独で処理した。また、10mg/kgのFK506と50mg/kgのSD282をそれぞれ経口で併用投与した。その後、GVHDの治療効果を、皮膚、肺、肝臓、大腸、小腸、盲腸において疾患の重症度を示す組織学的スコアにより評価した。
サイトカインIFN-γ(インターフェロン-γ)を分泌するTh1細胞(Tヘルパー1細胞)、サイトカインIL-4(インターロイキン4)を分泌するTh2細胞(Tヘルパー2細胞)、サイトカインIL-17(インターロイキン17)を分泌するTh17細胞(Tヘルパー17細胞)、およびFoxp3転写因子を発現するTreg細胞の活性を評価した。具体的には、図5に示すように、実施例1-2のGVHD動物を、GVHDの発症後に、50mg/kgのSD282単独または10mg/kgのFK506単独で処理した。また、10mg/kgのFK506と50mg/kgのSD282をそれぞれ経口で併用投与した。その後、それぞれの細胞およびサイトカインの活性を評価した。
5-1:SD282単独、FK506単独、またはこれらの組み合わせの処理による皮膚移植拒絶反応の抑制に関する評価
皮膚移植後の拒絶反応を評価するために、実施例1-3の皮膚移植動物モデルを使用して、図10aおよび図10bに示す手順に従って、実験を実施した。皮膚移植後、50mg/kgのSD282を単独で、または10mg/kgのFK506を単独で投与した。また、10mg/kgのFK506と50mg/kgのSD282をそれぞれ経口で併用投与した。その後、表皮の厚さを測定して、移植された皮膚組織の生着レベルを評価し、続いてH&E(ヘマトキシリンおよびエオシン)染色で分析した。
Th17細胞のサイトカインIL-17分泌、Foxp3転写因子を発現するTreg細胞の活性、およびSTAT3を調節する能力を評価するために、上記実施例と同じ条件で、皮膚動物モデルでの皮膚移植後21日目に移植部位を摘出して、組織中のSTAT3、リン酸化STAT3(pSTAT3(Tyr705)およびpSTAT3(Ser727))、IL-17およびFoxp3の活性レベルを評価した。
正常なヒトPBMC(末梢血単核細胞、PBMC)において、SD282単独処理、FK506単独処理、またはこれらの併用処理によるT細胞増殖を評価するために、混合白血球反応(MLR)およびCFSE(カルボキシフルオレセインスクシンイミジルエステル)染色を行った。未処理のシンジェニック群および未処理のアロジェニック群を対照として使用した。アロジェニックモデルを、50μM、250μM、および500μMのSD282単独、または1nMおよび5nMのFK506単独で処理した。また、FK506(1nMおよび5nM)とSD282(250μM)をそれぞれ組み合わせて処理した。処理後、各群を4日間培養した後、3H-チミジン取り込み法またはフローサイトメトリー法に従って、培養細胞中のT細胞増殖を観察することによってアロ反応を評価した。
正常なヒト末梢血細胞(PBMC)において、SD282単独、FK506単独、またはこれらの組み合わせによる処理による、炎症性サイトカインの活性に対する阻害を評価するために、未処理のシンジェニック群および未処理のアロジェニック群を対照として使用した。アロジェニックモデルを、50μM、250μM、および500μMのSD282単独、または1nMおよび5nMのFK506単独で処理した。また、FK506(1および5nM)とSD282(250μM)をそれぞれ組み合わせて処理した。処理後、各群を4日間培養した後、ELISA法に従って、培養細胞中のIL-17、IFN-γおよびTNF-αに対する阻害効果を評価してアロ反応を評価した。
8-1:併用投与による免疫細胞マーカーの変化の評価
肝臓移植患者の血液からフィコールを用いて、末梢血細胞(PBMC)を分離した。PBMCを、TCR刺激の条件下で(CD3刺激下で)、250μMのSD282単独、5nMのFK506単独、およびこれらを組み合わせて処理した。4日間培養した後、免疫細胞のサブタイプをフローサイトメトリーで分析して、Treg細胞の活性がそれぞれの薬物処理によって誘導されたかどうかを評価した。
肝臓移植患者の末梢血細胞(PBMC)において、薬物処理による免疫細胞調節に関連するシグナル因子の変化を調査するために、PBMCを、TCR刺激の条件下(CD3刺激下)で、250μMのSD282単独、5nMのFK506単独、およびこれらを組み合わせて処理した。48時間培養した後、Macrogen、Inc.でマイクロアレイ解析を行った。
マウスおよび肝臓移植患者の免疫細胞を各薬剤で48時間処理した後、細胞を回収して移動アッセイを行った。2×105個の細胞を上部トランスウエルにロードし、下部チャンバーでsDF-1で処理または処理せずに、2時間インキュベートした。2時間後、移動した細胞の数を数えた。
9-1:肝障害を有するヒト化マウスモデルの作製
肝障害を有するヒト免疫系を備えたヒト化マウスモデル(アバターモデル)を構築するために、ヒト由来のPBMC(末梢血単核細胞)をNSGマウスに静脈内注射した後、肝星細胞株を静脈内注射した。CCl4を注入して、肝障害(肝線維症)を誘発した。具体的には、正常な被験者に由来するPBMCまたは肝疾患を有する患者(HBV誘発性肝硬変患者またはアルコール性肝硬変患者)に由来するPBMCをNSGマウスに静脈内注射した。1日後、肝星細胞株およびCCl4を静脈内注射した。20日後にヒト細胞の生着を確認し、39日後にマウスを犠牲にして組織分析を行った。
正常な被験者または肝臓移植患者に由来する血液の注射と共にCCl4注射によって肝障害を誘発させたモデル(9-1で作製)では、正常な被験者に比べて、移植患者に由来する血液によって炎症および線維症がより誘発される。単独の処理または組み合わせの処理における炎症および線維症のレベルを評価した。
Claims (11)
- 前記カルシニューリン阻害剤が、FK506(タクロリムス)またはシクロスポリンである、請求項1に記載の医薬組成物。
- 前記移植拒絶反応が、細胞、血液、組織および器官からなる群から選択される1種以上の移植拒絶反応である、請求項1に記載の医薬組成物。
- 前記移植拒絶反応が、骨髄移植拒絶反応、心臓移植拒絶反応、角膜移植拒絶反応、腸移植拒絶反応、肝臓移植拒絶反応、肺移植拒絶反応、膵臓移植反応、腎臓移植拒絶反応、および皮膚移植拒絶反応からなる群から選択される1種以上である、請求項3に記載の医薬組成物。
- 前記移植拒絶疾患が、移植片対宿主病(GVHD)である、請求項1に記載の医薬組成物。
- 前記組成物が、T細胞の増殖を阻害する、請求項1に記載の医薬組成物。
- 前記組成物が、未分化T細胞のTh1細胞もしくはTh17細胞への分化またはTh1細胞もしくはTh17細胞の活性を減少させる、請求項1に記載の医薬組成物。
- 前記組成物が、未分化T細胞のTreg細胞への分化およびTreg細胞の活性を増加させる、請求項1に記載の医薬組成物。
- 移植拒絶反応または移植拒絶疾患を予防または治療するための方法であって、移植拒絶反応または移植拒絶疾患の予防または治療を必要とする対象に、薬学的に有効な量の請求項1に記載の組成物を投与することを含む方法。
- 移植後の免疫抑制のための方法であって、移植後の免疫抑制を必要とする対象に、薬学的に有効な量の請求項9に記載の組成物を投与することを含む方法。
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