JPWO2015072544A1 - 自己免疫疾患の治療薬及び治療方法 - Google Patents
自己免疫疾患の治療薬及び治療方法 Download PDFInfo
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Abstract
Description
<1> CTRP3を含有する、自己免疫疾患治療薬。
<2> 前記自己免疫疾患が関節リウマチ又は多発性硬化症である、<1>に記載の自己免疫疾患治療薬。
<3> CTRP3を含有する自己免疫疾患治療薬を、自己免疫疾患の治療を必要とする対象に投与すること、を含む自己免疫疾患を治療する方法。
<4> 前記自己免疫疾患が関節リウマチ又は多発性硬化症である、<3>に記載の自己免疫疾患を治療する方法。
<5> <1>または<2>に記載の自己免疫疾患治療薬としてのCTRP3の使用。
<6> <1>または<2>に記載の自己免疫疾患治療薬の製造におけるCTRP3の使用。
<7> C1qtnf3遺伝子を欠損していることを特徴とする、関節リウマチ又は多発性硬化症のモデル動物。
また本明細書において「〜」を用いて示された数値範囲は、「〜」の前後に記載される数値をそれぞれ最小値および最大値として含む範囲を示す。
さらに本明細書において組成物中の各成分の量は、組成物中に各成分に該当する物質が複数存在する場合、特に断らない限り、組成物中に存在する当該複数の物質の合計量を意味する。
以下、本発明の態様について説明する。
MLWRQLIYWQLLALFFLPFCLCQDEYMESPQTGGLPPDCSKCCHGDYSFRGYQGPPGPPGPPGIPGNHGNNGNNGATGHEGAKGEKGDKGDLGPRGERGQHGPKGEKGYPGIPPELQIAFMASLATHFSNQNSGIIFSSVETNIGNFFDVMTGRFGAPVSGVYFFTFSMMKHEDVEEVYVYLMHNGNTVFSMYSYEMKGKSDTSSNHAVLKLAKGDEVWLRMGNGALHGDHQRFSTFAGFLLFETK
ATGCTTTGGAGGCAGCTCATCTATTGGCAACTGCTGGCTTTGTTTTTCCTCCCTTTTTGCCTGTGTCAAGATGAATACATGGAGTCTCCACAAACCGGAGGACTACCCCCAGACTGCAGTAAGTGTTGTCATGGAGACTACAGCTTTCGAGGCTACCAAGGCCCCCCTGGGCCACCGGGCCCTCCTGGCATTCCAGGAAACCATGGAAACAATGGCAACAATGGAGCCACTGGTCATGAAGGAGCCAAAGGTGAGAAGGGCGACAAAGGTGACCTGGGGCCTCGAGGGGAGCGGGGGCAGCATGGCCCCAAAGGAGAGAAGGGCTACCCGGGGATTCCACCAGAACTTCAGATTGCATTCATGGCTTCTCTGGCAACCCACTTCAGCAATCAGAACAGTGGGATTATCTTCAGCAGTGTTGAGACCAACATTGGAAACTTCTTTGATGTCATGACTGGTAGATTTGGGGCCCCAGTATCAGGTGTGTATTTCTTCACCTTCAGCATGATGAAGCATGAGGATGTTGAGGAAGTGTATGTGTACCTTATGCACAATGGCAACACAGTCTTCAGCATGTACAGCTATGAAATGAAGGGCAAATCAGATACATCCAGCAATCATGCTGTGCTGAAGCTAGCCAAAGGGGATGAGGTTTGGCTGCGAATGGGCAATGGCGCTCTCCATGGGGACCACCAACGCTTCTCCACCTTTGCAGGATTCCTGCTCTTTGAAACTAAGTAA
経口投与に適した剤型としては、例えば、錠剤、カプセル剤、粉剤、顆粒剤、液剤、エリキシル剤等が挙げられる。
なお、特に記載がない場合には、統計解析はスチューデントの両側t検定により行われた。
発明者らは以前に、2つのRAモデルであるHTLV−I TgマウスとIL−1Ra KOマウスのDNAマイクロアレイを用いる網羅的遺伝子発現解析に基づいて、C1qtnf3を自己免疫関連遺伝子の候補として特定した。qPCR技術を用いてRAモデルマウス(HTLV−I Tgマウス及びIL−1Ra KOマウス)の関節局所におけるC1qtnf3の発現の亢進を確認した(図1A)。C1qtnf3の発現は、HTLV−I TgマウスIl及びIL−1Ra−/−マウスの他に、K/BxNマウスの関節において非常に亢進されることが報告されている(参考文献22)。C1qtnf3−/−マウスを作製し、CIAの発症におけるCTRP3の影響を調べた。
1.コラーゲン誘導性関節炎(CIA)の誘導
自己免疫性関節炎の発生におけるCTRP3の役割を評価するために、C1qtnf3−/−マウスを用いてCIAを実施した。
完全フロイントアジュバント(CFA)で乳化した100μlの2mg/mlのII型コラーゲン(IIC)(シグマ社、米国)を用いてメスの野生型マウス又はC1qtnf3−/−マウスに免疫した。CFAは不完全フロイントアジュバント(サーモ・サイエンティフィック社、米国)と1.65mg/mlの加熱殺菌した結核菌(Mycobacterium tuberculosis)(H37Ra;Difco社、米国)から成り、0日目に尾の基部近くの3か所に皮内注射された。21日目にマウスに同量のIIC/CFAを以前の注射部位の近くの皮内にブースター注射した。
肉眼による評価により関節炎の発生を判定した。それぞれの足における関節炎の発生を次のように等級付けした:0=変化無し;1=軽度の腫脹;2=明確な関節の腫脹;3=重度の関節の腫脹と強直性変化(個々のマウスについて最大で12ポイント)(参考文献19、20)。CIAの発症率をカイ二乗検定により評価した。
図2Aに示されているように、野生型マウスと比較してC1qtnf3−/−マウスにおける関節炎の発生率が上昇し、C1qtnf3−/−マウスの関節炎の臨床スコアが顕著に増加した(図2B)。臨床スコアはマン・ホイットニーのU検定により評価した。
エーテル麻酔下でマウスを殺処理し、病理組織診断のために後肢の足首の関節を取り出し、固定し、脱灰化し、パラフィン包埋した。距骨全体の2〜3μm厚の連続切片を矢状に作製し、光学顕微鏡法による検査のためにH&Eで染色した。踵骨と足首の関節の前方と後方の滑膜組織を含んで病変を病理組織学的に評価した。各関節を0〜3の尺度で等級付けした。その等級付けでは0=正常、1=わずかな炎症細胞浸潤を有する肥厚化と滑膜表層の増殖、2=第1等級の変化と滑膜下層組織における肉芽腫病変、および3=第2等級の変化とパンヌス形成と骨破壊である。足首の関節の関節炎インデックスを各マウスの距骨、および脛骨と踵骨を含む周りの骨の等級の平均から推定した(参考文献20)。
1.補体系における役割
CTRP3は補体C1qドメインを有するので、補体系がCTRP3機能に関与する可能性を調査した。最初のIIC/CFA免疫後7日目におけるマウスから血漿を採取し、ELISAにより補体活性産物C3aおよびC5aのレベルを測定した。血漿中のC3aとC5aレベルを、捕捉抗体被覆プレートとC3aまたはC5aに対する検出抗体(BDファーミンジェン社、米国)を使用するサンドイッチELISAにより、メスのマウス(8〜10週齢)に由来する10mMのEDTAでキレートした血漿を使用して測定した。その結果、C1qtnf3−/−マウスにおけるC3aとC5aのレベルはC1qtnf3+/+マウスにおけるものと同様であることを示した(図3Aおよび3B)。
プレート(Nunc社、デンマーク)を古典的経路(CP)、レクチン経路(LP)および副経路(AP)の補体活性化のアッセイのためにそれぞれOVA/抗OVA免疫複合体(OVA:シグマ社、米国、および抗OVA Ab:ミリポア社、ドイツ)、50μg/mlのマンナン類(シグマ社、米国)、または200μg/mlのLPS(シグマ社、米国)で被覆した(参考文献16、17、18)。オスのマウスから血清を得て、CP活性とLP活性のアッセイのためにはGVB++緩衝液で希釈し、AP活性のためにはGVB/Mg2+EGTA緩衝液で希釈した。希釈したマウス血清(10%)をプレート上に37℃で1時間保温し、冷20mM EDTA/PBSにより反応を停止させた。マウスC3に対するラットモノクローナル抗体(Abcam社、英国)によりC3bの沈着を検出した。その結果、CTRP3欠損はインビトロでは補体活性化に影響しないことを発見した(図3C)。
野生型マウス又はC1qtnf3−/−マウスへの最初のIIC/CFA免疫後42日目における関節局所でのサイトカインの発現を調査した。足首の関節におけるTNF−α、IL−1b、IL−6及びIL−10のメッセンジャーRNA発現を定法に従い半定量的PCRにより測定した。その結果、関節炎を生じた関節局所におけるTNF−α、IL−1b、IL−6及びIL−10の発現量は、野生型マウスよりもC1qtnf3−/−マウスにおいて増加することが示された(図3D)。
CTRP3がヒト単球における炎症性サイトカインの放出を抑制することが報告されている(参考文献12)。しかし、CTRP3は関節炎の関節の滑膜細胞のサイトカイン産生を抑制しなかった。
滑膜表層と関節周囲領域へのT細胞とB細胞の浸潤はRA患者ならびにRAモデルにおいて共通して観察される。そこで、最初のIIC/CFA免疫後42日目の野生型マウス又はC1qtnf3−/−マウスの所属リンパ節から採取したリンパ節細胞の細胞組成をフローサイトメトリー解析で調べた。定法に従い、細胞をパシフィックブルー複合体化モノクローナル抗体、FITC複合体化モノクローナル抗体、およびAPC複合体化モノクローナル抗体(mAb)で染色した(参考文献21)。マウスCD3とB220に対するハムスターmAb(145−2C11)またはラットmAb(RA3−6B2)をバイオレジェンド社(米国)から、CD11cに対するハムスターmAb(HL3)をBDファーミンジェン社(米国)から購入し、標準的な技術に従って細胞を染色し、FACS Canto IIサイトメーターとCellQuestソフトウェア(ベクトンディッキンソン社、米国)かFlowJoソフトウェア(ツリー・スター社、米国)により分析した。
IIC免疫後7日目の野生型マウス又はC1qtnf3−/−マウスの関節炎発症部位の所属リンパ節からLN細胞を回収した。100または200μg/mlの変性IICが存在しない、または存在する状態でLN細胞を72時間培養し、続いて[3H]チミジン(0.25μCi/ml)(アマーシャム社、英国)を6時間取り込ませた。次に、細胞をマイクロ96セル・ハーベスター(スカトロン社、ノルウェー)で回収し、放射活性をマイクロ・ベータ(ファルマシア・バイオテック社、米国)で測定した。72時間後の増殖アッセイの培養上清中のIFN‐γレベルをマウスIFN−ガンマ DuoSet(R&Dシステムズ社、米国)で測定した。
関節リウマチと同様に多発性硬化症も自己免疫疾患の1つであるため、多発性硬化症の誘導モデルである実験的自己免疫性脳脊髄炎(Experimental autoimmune encephalomyelitis;EAE)を誘導したマウスを用いて、多発性硬化症におけるCTRP3の影響を評価した。
完全フロイントアジュバント(CFA)で乳化した、ミエリンオリゴデンドロサイト糖蛋白質(MOG)の一部分であるMOG35−55 ペプチド (MEVGWYRSPFSRVVHLYRNGK) (配列番号12)(Scrun Japan社製)600μgを用いてメスの野生型マウス又はC1qtnf3−/−マウスに免疫した。CFAは不完全フロイントアジュバント(サーモ・サイエンティフィック社、米国)と5mg/mlの加熱殺菌した結核菌(Mycobacterium tuberculosis)(H37Ra;Difco社、米国)から成り、0日目に四肢近くの4か所に皮内注射された。21日目にマウスに同量のエマルジョンを以前の注射部位の近くの皮内にブースター注射した。
これらの結果から、EAE発症においてCTRP3は抑制的に機能していることが示された。
DBA/1Jマウス(メス、6〜8週齢、n=6)を、フロインド完全アジュバント(ディフコ社、USA)と共にエマルジョンとした、2mg/mLのニワトリII型コラーゲン(シグマ社、USA)(IIC/CFA)を100μl用いて、0日目に尾の基部近くの3か所に皮内注射して免疫した。21日目に、マウスに同量のIIC/CFAを以前の注射部位の近くの皮内にブースター注射した。28日目からそれぞれのマウスに、左膝関節の関節腔に30μLの組換えヒトCTRP3(300ng/日、Avisceraバイオサイエンス社、USA)(配列番号1)を、右膝関節の関節腔に対照としてPBS、を1日1回注射した。
・関節炎の評価基準(臨床スコア)
0:変化なし。
1:紅斑及び軽微な腫脹が足根関節に認められた。
2:紅斑及び軽微な腫脹が足根関節から足指に広がっていた。
3:紅斑及び中等度の腫脹が中足骨関節から広がっていた。
4:紅斑及び重度の腫脹が足首、足及び足指に広がっていたか、又は、四肢に強直があった。
CTRP3が自己免疫性関節炎の発生を軽減することが明確に示された。CTRP3がRAなどの自己免疫疾患の治療のための医薬として有用であることを示している。
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本明細書に記載された全ての文献、特許出願、および技術規格は、個々の文献、特許出願、および技術規格が参照により取り込まれることが具体的かつ個々に記された場合と同程度に、本明細書中に参照により取り込まれる。
本発明に係る例示的実施形態についての以上の記載は例示および説明の目的でされたものであり、網羅的であることあるいは発明を開示されている形態そのものに限定することを意図するものではない。明らかなことではあるが、多くの改変あるいは変更が当業者には自明である。上記実施形態は発明の原理及び実用的応用を最もうまく説明し、想定される特定の用途に適するような種々の実施形態や種々の改変と共に他の当業者が発明を理解できるようにするために選択され、記載された。本発明に係る範囲の範囲は以下の請求項およびその均等物によって規定されることが意図されている。
Claims (4)
- CTRP3を含有する、自己免疫疾患治療薬。
- 前記自己免疫疾患が関節リウマチ又は多発性硬化症である、請求項1に記載の自己免疫疾患治療薬。
- CTRP3を含有する自己免疫疾患治療薬を、自己免疫疾患の治療を必要とする対象に投与すること、を含む自己免疫疾患を治療する方法。
- 自己免疫疾患が関節リウマチ又は多発性硬化症である、請求項3に記載の自己免疫疾患を治療する方法。
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