JP6574179B2 - エフェクターtレグ細胞を同定するための方法及びキット - Google Patents
エフェクターtレグ細胞を同定するための方法及びキット Download PDFInfo
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Description
本出願は、2013年7月31日に出願された、欧州特許出願番号第EP13306106.9号の優先権を主張する。欧州特許出願は、その全体が参照により本明細書に組み入れられる。
本発明は、エフェクター制御性T細胞を同定するための方法及びキットに関する。
FoxP3転写因子を発現している制御性T(Tレグ)細胞は、自己寛容の維持に役立つ3。全てのマウスFoxP3発現CD4+T細胞が効果的なTレグ細胞であると考えられるが、そのヒト対応物は表現型及び機能において異質である4。あらゆるヒト通常型CD4+T細胞が、抑制能を有さないIL−2の存在下で活性化されるとFoxP3をアップレギュレートすることができることが広く受け入れられているが5〜9、本発明者らは、PBMC中の全てのFoxP3発現CD4+T細胞が制御機能を有するわけではないことを実証した。実際に、FoxP3+CD4+T細胞は、(1)CD127(low)CD25++CD45RA+FoxP3(low)表現型を有するナイーブ/休止Tレグ細胞(nTレグ)、及び(2)CD127(low)CD25+++CD45RA−FoxP3(high)表現型を有するエフェクター/活性化Tレグ(eTレグ)(どちらもインビトロにおいて非常に抑制性である)、及び(3)CD127(low)CD25++CD45RA−FoxP3(low)表現型を有する抑制性ではないCD4+T細胞に分類され得る。本発明者らはまた、胸腺遊出マーカーを有するナイーブTレグ細胞が、エフェクターTレグ細胞の前駆体であることを示すことができた10。
ここで本発明者らは、最もよく知られている表面マーカーの徹底的な研究に基づいて、CD15s(シアリルルイスx)の発現が、抑制性eTレグ細胞とFoxP3(low)非Tレグ細胞とを効果的に区別することができることを示す。本発明者らはまた、胸腺におけるFoxP3発現CD4+T細胞のCD15s発現が、末梢でeTレグによって生じる他の活性化マーカーと並行することを示す。最後に、本発明者らは、eTレグ細胞の特異的マーカーとしてのCD15sの使用は、FoxP3発現サブセットの異常を有する標準的な疾患において妥当であることを示す。
エフェクターTレグ細胞(eTレグ)を同定するための方法
本発明の目的は、i)液体サンプル中に含まれる細胞集団上のCD4、CD25、CD127及びCD15sマーカーの細胞表面発現を検出する工程、及びii)CD4、CD25、低いレベルのCD127、及びCD15sを発現している細胞がエフェクターTレグ細胞であると結論付ける工程を含む、液体サンプル中のエフェクターTレグ細胞(eTレグ)を同定するための方法に関する。
本発明のさらなる目的は、上記の方法の1つに従って得ることができる又は得られた単離されたeTレグに関する。
最後に、本発明者らは、CD15sが、疾患におけるeTレグ細胞の妥当なマーカーであることを確認した。本発明者らは、eTレグ細胞の追加のマーカーとしてCD15sを使用した場合、FoxP3、CD45RA及びKi−67の発現に基づいたTレグサブセットの定義を使用するeTレグ細胞の保有率は、健康なドナーにおいては変更されておらず、サルコイドーシスでは僅かに高く見積もられ、SLE(全身性エリテマトーデス)では僅かに低く見積もられたことを観察した。特に、FoxP3発現CD4+T細胞サブセットにおいて観察された異常は、このマーカーを使用すると依然として存在しかつ顕著であった。最後に、本発明者らは、本発明の方法を、軽度の未処置の菌状息肉腫を有する被験者のPBMCに適用し、明瞭に異なるCD15s+FoxP3(high)eTレグ細胞集団を観察することができた。図5に示されているように、活動性SLEにおけるCD15s+エフェクターTレグ細胞のレベルは、健康なドナーと比較して有意に減少している。
a)癌を患う患者から腫瘍組織サンプルの集合を提供する工程;
b)工程a)で提供された集合に含まれる各腫瘍組織サンプルについてeTレグ細胞のレベルを決定する工程;
c)該発現レベルに従って腫瘍組織サンプルを順位付けする工程;
d)eTレグ細胞のそのレベルに従って順位付けされたそれぞれ数の増加しているメンバーと数の減少しているメンバーのサブセット対に、該腫瘍組織サンプルを分類する工程;
e)工程a)で提供された各腫瘍組織サンプルについて、対応する癌患者の実際の臨床転帰に関連した情報(すなわち、無病生存期間(DFS)若しくは全生存期間(OS)又はその両方)を提供する工程;
f)腫瘍組織サンプルの各サブセット対について、カプランマイヤー生存率曲線を得る工程;
g)腫瘍組織サンプルの各サブセット対について、両方のサブセット間の統計学的有意性(p値)を計算する工程;
h)発現レベルの基準値として、p値が最小である発現レベルの数値を選択する工程
を含む方法を実施することによって予め決定され得る。
本発明のさらなる目的は、細胞集団上のCD4、CD25、CD127及びCD15sマーカーの細胞表面発現を検出するための手段を含むキットに関する。
材料及び方法
FoxP3、Ki−67及びHeliosを発現しているCD4+T細胞の表面マーカー分析及びフローサイトメトリー
血液サンプルを、若い健康な成人試験志願者から、及び活動的なサルコイドーシス又はSLEを有する被験者から入手した。SLE及びサルコイドーシスの診断は、先に記載された基準に従って行なわれた1、2。研究は、ヒトを対象とした地域倫理委員会からの承認とともにヘルシンキ宣言に従って実施された(Comite Consultatif de Protection des Personnes dans la Recherche Biomedicale of Pitie-Salpetriere Hospital, Paris)。胸腺細胞の分析のために、生物医学局による承認(PFS13−007番)を得た。
PBMCを、新たに採取した血液からフィコール勾配分離を通して単離した。CD4+T細胞をまず、CD4 T細胞分離キット(Miltenyi)を使用して磁気的に単離し、続いて、蛍光色素にコンジュゲートさせたmAbの以下の組合せを使用して表面染色した:BD bioscienceから入手した抗CD4抗体−PErCP5.5、抗CD25抗体−PE、抗CD127抗体−パシフィックブルー、抗CD45RA抗体−PECy7、及び抗CD15s抗体−AF647。CD127+CD25−CD45RA+CD4+、ナイーブFoxP3lowCD45RA+、エフェクターFoxP3highCD45RA−Tレグ細胞、CD127lowCD25+CD45RA−を、本発明者らが以前検証したゲーティング戦略に従って、FACSAria(BD bioscience)10を使用して、並びにCD15s−FoxP3lowCD4+T細胞及びCD127lowCD25+CD127lowCD15s+CD4+T細胞を該ゲーティング戦略に従って、フローサイトメトリーにより単離した後に、PBMCからフローサイトメトリーにより単離した。
nTレグ細胞の増大に関して、30×103個の単離されたnTレグを直ちに、培養のためにU底ウェルに分配した。細胞を、5%AB血清(Invitrogen Lifetech)を含みかつ2mM L−グルタミン、1mM ピルビン酸ナトリウム、1%非必須アミノ酸MEM、100U/ml ペニシリン、100μg/ml ストレプトマイシン及びアムホテリシンB(全てGibco製)、抗CD3抗体/抗CD28抗体でコーティングされたTレグ増大用ビーズ(Invitrogen Lifetech)を補充されたX-vivo 15培地(Lonza)中、培養培地単独中300 IU/ml IL−2(Miltenyi Biotec)の存在下で、又は培養培地中に希釈されたラパマイシン(Sigma-Aldrich)の存在下(1μg/mL)で培養した。300〜1000 IU/ml IL−2を3〜4日間毎に加えた。
eTレグとCD15s+FoxP3+細胞の%を比較するために、対応のあるt−検定を実施した。健康なドナー対SLE被験者におけるCD15s+%を比較するために、ノンパラメトリックU−マンホイットニー検定を実施した。
FoxP3、Helios及びKi−67を発現しているCD4+T細胞サブセットの細胞表面マーカー
FoxP3を発現しているCD4+T細胞内のサブセットを区別する具体的な表面マーカーを決定するために、本発明者らは、CD25、CD45RA、ICOS、HLA−DR、Ki−67、Helios、及びFoxP3発現を、細胞表面マーカーと一緒に分析することによって、ヒトCD4+T細胞のマルチパラメーター細胞蛍光測定分析を実施した。
本発明者らは、CD15sはeTレグ細胞上に高度に発現されているが、シアリル化されていないCD15は発現されていないことに気付いた(図2A)。CD15sは、フコシルトランスフェラーゼ7(α(1,3)フコシルトランスフェラーゼ)を通したCD15のシアリル化の結果である。FoxP3を発現しているCD4+T細胞の本発明者らの以前のトランスクリプトーム10分析により、この酵素が、他のCD4+T細胞サブセットと比較してeTレグ細胞サブセット上に特異的に発現されていることが示され、このことは、CD15のシアリル化が、CD4+T細胞中のeTレグ細胞に特異的であることを示す(マイクロアレイデータは、国立生物工学情報センターの遺伝子発現情報データベース(GEO)アクセッションナンバー15659で入手可能である)。
胸腺に由来するnTレグ細胞は、eTレグ細胞上に存在する大半のマーカーを発現しないが(すなわち低いレベルのCD25、及びICOSは存在せず)、いくつかの発達中の胸腺Tレグ細胞はこれらのマーカーを発現すると報告されているので、本発明者らは、CD15sがこれらの前記の活性化マーカーと一緒にどのように胸腺において発達中の天然型Tレグ細胞によって発現されるのかを決定しようと考えた。
最後に、本発明者らは、健康なドナー(n=8)及びFoxP3発現サブセットにおける異常の保有が知られている疾患、すなわちサルコイドーシス(n=8)及び全身性エリテマトーデス(n=8)を有する被験者のPBMC中のCD15sの発現を研究した。
ヒトFoxP3発現CD4+T細胞は機能において異質であるので4、FoxP3を発現する、抑制性Tレグ細胞とエフェクターT細胞へのその分離を可能とするマーカーが、特に、免疫媒介性疾患、例えば自己免疫疾患及び/又は炎症性疾患、移植、並びに癌等において必要とされる。本発明者らは以前に、FoxP3発現CD4+T細胞は、細胞内FoxP3のそのレベル及びCD45RAの発現に基づいて3つのサブセットに分離され得ることを示した10。現在、ナイーブ表現型を有し低い発現のFoxP3を有するCD4+T細胞は、マウス天然胸腺由来Tレグ細胞に相当する胸腺由来のTレグ細胞の個別のサブセットであることが十分に受け入れられている。これらの細胞は単純にCD45RA+CD25+CD4+T細胞としてフローサイトメトリーで単離され得る10。
本出願全体を通して、様々な参考文献が、本発明が属する技術分野の状況を記載する。これらの参考文献の開示は、本開示への参照により本明細書に組み入れられる。
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Claims (27)
- i)液体サンプル中に含まれる細胞集団上のCD4、CD25、CD127及びCD15sマーカーの細胞表面発現を検出する工程、及びii)CD4、CD25、低いレベルのCD127、及びCD15sを発現している細胞がエフェクターTレグ細胞であると結論付ける工程を含む、液体サンプル中のエフェクターTレグ細胞(eTレグ)を同定するための方法。
- 液体サンプルが、血液サンプル、PBMCサンプル、又は懸濁液中のTレグ細胞のサンプルからなる群より選択される、請求項1記載の方法。
- 液体サンプル中に含まれる細胞集団上のCD4、CD25、CD127及びCD15sマーカーの細胞表面発現の検出が、マーカーに特異的な一連の抗体を用いて実施される、請求項1又は2の方法。
- 液体サンプル中に含まれる細胞集団上のCD4、CD25、CD127及びCD15sマーカーの細胞表面発現の検出が、フローサイトメトリーによって実施される、請求項1〜3のいずれか一項に記載の方法。
- i)CD4、CD25、Foxp3、及びCD15sマーカーの細胞発現を検出する工程、及びii)CD4、CD25、Foxp3、及びCD15sを発現している細胞がエフェクターTレグ細胞であると結論付ける工程を含む、組織サンプル中のエフェクターTレグ細胞(eTレグ)を同定するための方法。
- 組織サンプルを、CD4、CD25、Foxp3、及びCD15sに特異的な一連の抗体を用いて染色することからなる工程を含む、請求項5の方法。
- 組織サンプル中のCD4、CD25、Foxp3、及びCD15sマーカーの細胞発現の検出が免疫化学法によって実施される、請求項5又は6の方法。
- 組織サンプルが、脳、副腎、結腸、小腸、胃、心臓、肝臓、皮膚、腎臓、肺、膵臓、精巣、卵巣、前立腺、子宮、甲状腺、及び脾臓の組織切片からなる群より選択される、請求項5〜7のいずれか一項に記載の方法。
- CD45RAの表面発現を検出することからなる工程をさらに含む、請求項1〜8のいずれか一項に記載の方法。
- サンプル中に存在するeTレグ細胞のレベルを決定することからなる工程をさらに含む、請求項1〜9のいずれか一項に記載の方法。
- サンプルからeTレグ細胞を単離することからなる工程をさらに含む、請求項1〜9のいずれか一項に記載の方法。
- 請求項11の方法によって得られた単離されたeTレグ。
- 請求項12に記載の単離されたeTレグ細胞集団を含む医薬組成物。
- 自己免疫疾患、炎症性疾患、アレルギー性疾患、及び移植片拒絶からなる群より選択される疾患の処置のための請求項13の医薬組成物。
- eTレグ細胞のためのバイオマーカーとしてのCD15sの使用。
- i)被験者から得られたサンプル中において、請求項10の方法を実施することによってeTレグ細胞集団のレベルを決定する工程、ii)工程i)で決定されたレベルを基準値と比較する工程、及びiii)工程i)で決定されたレベルが基準値よりも低い場合に、被験者は疾患を患っていることを示す工程を含む、被験者における自己免疫疾患、炎症性疾患、及びアレルギー性疾患からなる群より選択された疾患をインビトロで診断するための方法。
- 請求項1〜9のいずれか一項に記載の方法を実施することによってeTレグ細胞集団を検出する工程を含む、被験者において自己免疫疾患、炎症性疾患、及びアレルギー性疾患からなる群より選択された疾患を有するリスクがあるかどうかをインビトロで決定するための方法であって、該集団の存在は被験者が疾患を有するリスクがあることを示す、前記方法。
- 請求項1〜9のいずれか一項に記載の方法を実施することによってeTレグ細胞集団の有無を検出する工程を含む、移植片拒絶のリスクがあるかどうかをインビトロで決定するための方法であって、該集団の不在は被験者が移植片拒絶のリスクがあることを示す、前記方法。
- i)被験者から得られたサンプル中において、請求項10の方法を実施することによってeTレグ細胞集団のレベルを決定する工程、ii)工程i)で決定されたレベルを基準値と比較する工程、及びiii)工程i)で決定されたレベルが基準値よりも低い場合に、被験者が移植片拒絶のリスクがあることを示す工程を含む、移植片拒絶のリスクがあるかどうかをインビトロで決定するための方法。
- i)請求項10の方法を実施することによって疾患の1回目の特定の時期に、被験者から得られたサンプル中のeTレグ細胞集団のレベルを決定する工程、ii)請求項10の方法を実施することによって疾患の2回目の特定の時期に、被験者から得られたサンプル中のeTレグ細胞集団のレベルを決定する工程、iii)工程i)で決定されたレベルを工程ii)で決定されたレベルと比較する工程、及びiv)工程ii)で決定されたレベルが工程i)で決定されたレベルよりも低い場合に、疾患は悪い方向に進展したことを示す工程を含む、自己免疫疾患、炎症性疾患、及びアレルギー性疾患からなる群より選択された疾患をインビトロでモニタリングするための方法。
- i)請求項10の方法を実施することによって処置前に被験者から得られたサンプル中のeTレグ細胞集団のレベルを決定する工程、ii)請求項10の方法を実施することによって処置後に被験者から得られたサンプル中のeTレグ細胞集団のレベルを決定する工程、iii)工程i)で決定されたレベルを工程ii)で決定されたレベルと比較する工程、及びiv)工程ii)で決定されたレベルが工程i)で決定されたレベルよりも高い場合に、処置は効果的であることを示す工程を含む、自己免疫疾患、炎症性疾患、及びアレルギー性疾患からなる群より選択された疾患の処置をインビトロでモニタリングするための方法。
- i)請求項10の方法を実施することによって被験者から得られたサンプル中のeTレグ細胞集団のレベルを決定する工程、ii)工程i)で決定されたレベルを基準値と比較する工程、及びiii)工程i)で決定されたレベルが基準値より高い場合に、患者は悪い予後を有することを示す工程を含む、癌を患っている患者の生存期間をインビトロで予測するための方法。
- i)請求項10の方法を実施することによって被験者から得られたサンプル中のeTレグ細胞集団のレベルを決定する工程、ii)工程i)で決定されたレベルを基準値と比較する工程、及びiii)工程i)で決定されたレベルが基準値より低い場合に、患者は処置に有意に応答するであろうことを示す工程を含む、癌を患っている患者が処置に応答するかどうかをインビトロで決定するための方法。
- 処置が、免疫療法剤を用いて行なわれる、請求項23の方法。
- 細胞集団上のCD4、CD25、CD127及びCD15sマーカーの細胞表面発現を検出するための手段を含むキット。
- 細胞集団上のCD4、CD25、Foxp3及びCD15sマーカーの細胞発現を検出するための手段を含むキット。
- 該手段が抗体である、請求項25又は26のキット。
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