JP2011509676A - ヒトTh17細胞の選択的分化、同定および調節 - Google Patents
ヒトTh17細胞の選択的分化、同定および調節 Download PDFInfo
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Abstract
Description
本発明は、部分的に、National Institutes of Healthによって与えられた助成金第P01 NS038037号、第NS045937号および第30843号の下での政府の支援によってなされた。米国政府は、本発明に一定の権利を有する。
この出願は、2008年1月18日に出願された米国特許出願第61/006,541号および2008年2月27日に出願された米国特許出願第61/031,824号に関連し、これらからの優先権の利益を主張する。
自己免疫疾患(このうちの80個より多くは、既に同定されている)は、顕著な病的状態および障害(disability)を引き起こし、よく知られているように、診断するのが困難である。2400万人程度の米国人が、自己免疫疾患に罹患しており、処置費用は、年間1000億ドルを超えている。
本発明の実施形態は、ヒトTH17細胞の分化を提供する。より具体的には、本発明は、ヒトCD4+ T細胞からのIL−17A分泌の調節の理解をさらに正確にしかつ拡げ、ヒトTH17細胞分化に必要とされる条件を定義する。
本発明が本明細書に記載される特定の方法論、プロトコル、および試薬などに限定されず、よって、変動し得ることは、理解されるべきである。本明細書で使用される用語は、特定の実施形態を記載する目的に過ぎず、本発明の範囲を限定することは意図されない。本発明の範囲は、特許請求の範囲によってのみ定義される。
細胞ソーティング:PBMCを、健康な被験体の末梢血から、もしくは施設のIRBプロトコルに従って、臍帯血(全細胞(AllCells))から得た。CD4+ T細胞を、磁性ビーズ(Miltenyi Biotech Inc.,Auburn,CA)を使用して、ネガティブ選択によってその後に単離した。ナイーブ(CD25− CD62L+ CD45RAhi)CD4+ T細胞および中心的記憶(CD25− CD62L+ CD45RA−)CD4+ T細胞を、以下の抗体:CD62L−FITC、CD4−PerCP、CD45RA−PE−Cy7、CD25−APC−Cy7(BD Pharmingen,San Diego,CA)で染色することによって得、FACS Aria(BD Biosciences,Palo Alto,CA)でソートした。
ロイコトリエンB4(LTB4)(アラキドン酸の分解生成物であり、炎症の部位において急激に生成される強力な脂質炎症性メディエーターである)は、サイトゾルホスホリパーゼA2(PLA2)、5−リポキシゲナーゼ(5−LO)、およびLTA4ヒドロラーゼの一連の作用によって、膜リン脂質から得られる。Jala & Haribabu,25 Trends Immunol.315−22(2004)。LTB4は、内皮への白血球の接着および凝集を引き起こし、炎症部位へと顆粒球およびマクロファージを補充する、強力な化学誘引物質である。近年の研究は、LTB4が、T細胞についての化学誘引物質としても機能し得ることを示した。Goodarziら,4 Nat.Immunol.965−73(2003);Tagerら,4 Nature Immunol.982−90(2003);Tager & Luster,69 Prostaglandins,Luekot.Essential Fatty Acids 123−34(2003);Medoffら,202 J.Exp.Med.97−110(2005);Miyaharaら,174 J.Immunol.4979−85(2005);Miyaharaら,172 Am.J.Critical Care Med.161−70(2005)。
ポドプラニン(PDP)は、Th17細胞上で特異的に同定される別の表面分子である。ポドプラニンは、膜貫通ムチン含有分子であり、これは、病的条件下でリンパ内皮および腫瘍細胞上で発現される。22,23.Kanekoら,378 Gene,52−7(2006);Wicki & Christofori,96 Br.J.Cancer 96,1−5(2007)。これまで、PDPの発現は、造血細胞に関して記載されてこなかった。23. Wicki & Christofori, 2007。これは、PDPが、いくつかのT細胞上で発現され、より特異的に、分化している最中のTH17細胞上で発現されることを示す最初の研究である(図10)。
ロイコトリエンB4(LTB4)(これは、アラキドン酸の分解生成物であり、炎症の部位において急激に生成される強力な脂質炎症性メディエーターである)は、サイトゾルホスホリパーゼA2(PLA2)、5−リポキシゲナーゼ(5−LO)、およびLTA4ヒドロラーゼの一連の作用によって、膜リン脂質から得られる。Jala & Haribabu,25 Trends Immunol 315−22(2004)。LTB4は、内皮への白血球の接着および凝集を引き起こし、炎症部位へと顆粒球およびマクロファージを補充する、強力な化学誘引物質である。近年の研究は、LTB4が、T細胞についての化学誘引物質としても機能し得ることを示した。Goodarziら,4 Nat.Immunol.965−73(2003);Tagerら,4 Nature Immunol.982−90(2003);Tager & Luster,69 Prostaglandins,Luekot.Essential Fatty Acids 123−34(2003);Medoffら,202 J.Exp.Med.97−110(2005);Miyaharaら,174 J.Immunol.4979−85(2005);Miyaharaら,172 Am.J.Critical Care Med.161−70(2005)。
ポドプラニンは、TH17細胞のマーカーとして同定され、多発性硬化症の動物モデル(EAE)の進行におけるその役割を、本明細書で探査した。抗ポドプラニン特異的抗体(Farrら,176 J.Exp.Med.1477−82(1992))を、EAEに耐えているマウスにインビボで注射した。コントロール抗体を受容したマウスは、重篤な疾患を発症し、麻痺したが、上記抗ポドプラニン特異的抗体を受容したマウスは、それほど重篤な疾患を発症させなかった。このことは、上記抗ポドプラニン抗体が、自己免疫疾患の進行を阻害したことを示す。従って、これらデータは、抗ポドプラニン抗体の注射が、TH17細胞、およびおそらくIL−17生成マクロファージの病原性活性をブロックし、従って、多発性硬化症の動物モデル(EAE)を使用して本明細書で例示されるように、自己免疫疾患の進行を制限するために使用され得ることを示す。図5を参照のこと。
Claims (40)
- ヒトナイーブCD4+ T細胞の集団からヒトTH17細胞の分化を増大させる方法であって、該方法は、該細胞と、TGF−βおよびIL−21とを、TH17細胞分化を増大させるために十分な量において接触させる工程を包含する、方法。
- ヒトナイーブCD4+ T細胞からのIL−17の発現のレベルを調節する方法であって、該方法は、該細胞と、TGF−βおよびIL−21とを、IL−17発現を増大させるために十分な量において接触させる工程を包含する、方法。
- TH17細胞活性および/もしくはTH17細胞数を増大させるための方法であって、該方法は、細胞もしくは細胞集団と、TGF−βアゴニストおよびIL−21アゴニストとを、該細胞もしくは細胞集団の、TH17細胞への分化を増大させ、それによって、TH17細胞活性および/もしくは細胞数を増大させるために十分な量において接触させる工程を包含する、方法。
- 前記接触させる工程の前に、TH17分化が所望される細胞もしくは細胞集団を同定する工程をさらに包含する、請求項3に記載の方法。
- 前記細胞もしくは細胞集団は、T細胞もしくはT細胞集団である、請求項4に記載の方法。
- TH17細胞もしくはTH17細胞集団への、前駆T細胞もしくは前駆T細胞集団の分化を阻害するための方法であって、該方法は、該T細胞もしくはT細胞集団と、TGF−βのアンタゴニストおよびIL−21のアンタゴニストとを、もしくはTGF−βRおよびIL−21Rとを、TH17細胞分化を阻害するために十分な量において接触させる工程を包含する、方法。
- T細胞もしくはTH17細胞、またはこれらの細胞集団におけるIL−17の活性、発現、分泌もしくはプロセシングのうちの1つ以上を調節するための方法であって、該方法は、IL−17の活性もしくはレベルの調節が所望される細胞を同定する工程、および該細胞もしくは細胞集団と、該細胞もしくは細胞集団におけるIL−17の活性もしくはレベルを調節するのに十分な量のTGF−β/IL−21モジュレーターとを接触させる工程を包含する、方法。
- 前記調節は、IL−17の活性、発現、分泌もしくはプロセシングにおける増大を含み、前記モジュレーターは、TGF−βのアゴニストおよびIL−21のアゴニストを含む、請求項7に記載の方法。
- 前記調節は、IL−17の活性、発現、分泌もしくはプロセシングにおける減少を含み、前記モジュレーターは、TGF−βのアンタゴニストおよびIL−21のアンタゴニストを含む、請求項7に記載の方法。
- TH17細胞もしくはTH17細胞集団の活性を調節するための方法であって、該方法は、該細胞または集団と、Th17細胞もしくはTh17細胞集団の活性を調節するのに十分な量のTh17活性モジュレーターとを接触させる工程を包含する、方法。
- 前記モジュレーターは、ポドプラニンアンタゴニストもしくはBLT1アンタゴニストを含む、請求項10に記載の方法。
- 生物学的サンプル中のTh17細胞の存在を検出するための診断試験キットであって、該キットは、ポドプラニンを検出するための手段および/もしくはBLT1を検出するための手段を含み、ここで該ポドプラニンおよびBLT1の検出は、該生物学的サンプル中のTh17細胞の存在を示す、診断試験キット。
- TH17関連自己免疫疾患を診断するための診断試験キットであって、該診断キットは、ポドプラニンのためのプローブおよびBLT1のためのプローブを含み、ここで該ポドプラニンおよび/もしくはBLT1の存在は、Th17細胞の存在を同定する、診断試験キット。
- 前記プローブは、固体基材に結合されている、請求項12または13に記載のキット。
- 前記固体基材は、イムノブロットを行うための膜である、請求項14に記載の診断試験キット。
- Th17関連自己免疫疾患を診断するための診断試験キットであって、該診断試験キットは、生物学的サンプルと、ポドプラニンに結合する抗体とを、該抗体と該生物学的サンプル中に存在するポドプラニン保有Th17細胞との間で抗体−抗原複合体の形成を可能にする条件下で接触させるための手段、および該抗体を含む抗体−ポドプラニン複合体を検出するための手段を含み、ここで該抗体−ポドプラニン複合体の形成は、被験体のTh17関連自己免疫疾患を示す、診断試験キット。
- TH17関連自己免疫疾患を診断するための診断試験キットであって、該診断試験キットは、生物学的サンプルと、BLT1に結合する抗体とを、該抗体と該生物学的サンプル中に存在するBLT1保有Th17細胞との間で抗体−抗原複合体の形成を可能にする条件下で接触させるための手段、および該抗体を含む抗体−BLT1複合体を検出するための手段を含み、ここで該抗体−BLT1複合体の形成は、被験体のTH17関連自己免疫疾患を示す、診断試験キット。
- 生物学的サンプル中のTh17細胞を検出する方法であって、該方法は、該生物学的サンプルと、2つの異なるTh17特異的表面分子に対して指向される少なくとも2つの異なるプローブとを、該TH17特異的表面分子への該プローブの結合に適した条件下で接触させる工程であって、ここで各プローブは、該Th17細胞上の別個の部位と反応性である、工程;および該プローブが、該生物学的サンプル中の該TH17特異的表面分子に結合するか否かを、フローサイトメトリーによって検出する工程であって、ここで該プローブが該TH17特異的表面分子に結合する場合、Th17細胞の存在が示される、工程、を包含する、方法。
- 前記生物学的サンプルは、血液サンプル、血清サンプル、細胞サンプル、組織サンプル、骨髄および生検物からなる群より選択される、請求項18に記載の方法。
- 前記プローブは、アレイ上に配置されている、請求項18に記載の方法。
- 診断試験キットであって、該キットは、少なくとも第1のプローブおよび第2のプローブ;ならびにTh17特異的表面分子を検出するための手段を含み、ここで該プローブは、該TH17特異的表面分子に指向され、各プローブは、Th17細胞上の別個の部位と反応性である、診断試験キット。
- 前記プローブのうちの少なくとも一方は、蛍光色素で標識されている、請求項21に記載の診断試験キット。
- 前記TH17特異的表面分子は、セファロース−ウェスタンブロッティングを介して検出される、請求項21に記載の診断試験キット。
- Th17特異的表面マーカーが、ディップ−スティックアッセイを介して検出される、請求項21に記載の診断試験キット。
- TH17細胞特異的表面マーカーを免疫学的に検出するための成分をさらに含む、請求項21に記載の診断試験キット。
- フローサイトメトリー検出のための診断試験キットであって、該キットは、少なくとも第1のプローブおよび第2のプローブ、ならびにTH17特異的表面分子を検出するための手段を含み、ここで該プローブは、第1および第2の該TH17特異的表面分子に対して指向され、ここで該TH17特異的表面分子は、Th17細胞上で特異的にアップレギュレートされている、診断試験キット。
- 前記プローブのうちの少なくとも一方は、ビーズで標識されている、請求項26に記載の診断試験キット。
- 診断試験キットであって、該キットは、セファロース−ウェスタンブロッティング手順を行って、TH17特異的表面分子を免疫学的に検出するための手段を含み、該手段は、異なるTH17特異的表面分子に対して指向される少なくとも1つの異なるプローブを含み、該プローブは、Th17細胞上の別個の部位と反応性である、診断試験キット。
- 診断キットであって、該キットは、ディップ−スティックアッセイを行って、TH17特異的表面分子を免疫学的に検出するための手段を含み、該手段は、異なるTH17特異的表面分子に対して指向される少なくとも2つの異なるプローブを含み、各プローブは、Th17細胞上の別個の部位と反応性である、診断キット。
- 生物学的サンプル中のTh17細胞の存在を検出するための方法であって、該方法は、ポドプラニンもしくはBLT1のいずれかをコードする核酸の存在を検出する工程を包含する、方法。
- (a)ポドプラニンコード標的ポリヌクレオチドもしくはBLT1コード標的ポリヌクレオチドまたはこれらのフラグメントのいずれかを含むと推測される生物学的サンプルから、核酸を得る工程;(b)該(a)の核酸と、該標的ポドプラニンコードポリヌクレオチドもしくはBLT1コードコードポリヌクレオチドにおける少なくとも1つの核酸配列を識別し得るオリゴヌクレオチドとを接触させる工程であって、該接触させる工程は、識別的なシグナルを発生させる、工程;(c)該(b)において得られた識別的なシグナルから、ポドプラニンコードポリヌクレオチドもしくはBLT1コードポリヌクレオチドまたはそのフラグメントの存在を推測し、従って、該生物学的サンプル中のTh17細胞の存在を検出する工程、を包含する、請求項30に記載の方法。
- 被験体における自己免疫疾患を診断する方法であって、該方法は、(a)該被験体に由来するサンプル中においてポドプラニンを検出する工程;(b)該被験体に由来するサンプル中においてBLT1を検出する工程;および(c)ポドプラニンおよびBLT1の存在もしくはレベルに基づいて、該被験体における自己免疫疾患の存在もしくは重篤度を診断する工程、を包含する、方法。
- 被験体における抗自己免疫疾患治療の効力をモニターする方法であって、該方法は、(a)抗自己免疫疾患治療を施された被験体に由来するサンプル中において、ポドプラニンを検出する工程;(b)該被験体に由来するサンプル中においてBLT1を検出する工程;および(c)ポドプラニンもしくはBLT1の存在もしくはレベルに基づいて、該被験体における自己免疫疾患の存在もしくは重篤度を検出し、それによって、抗自己免疫疾患治療の効力をモニターする工程、を包含する、方法。
- 被験体における自己免疫疾患もしくは慢性炎症性疾患を診断するかもしくはモニターする方法であって、該方法は、該被験体におけるTH17細胞の存在を検出して、該被験体における該自己免疫疾患もしくは慢性炎症性疾患を診断もしくはモニターする工程を包含し、ここで該Th17細胞は、ポドプラニンおよびBLT1を特異的にアップレギュレートする、方法。
- ナイーブCD4+ T細胞の集団から、ヒトTH17細胞の分化を増大させるための、TGF−βおよびIL−21の使用。
- ナイーブCD4+ T細胞の集団から、ヒトTH17細胞の分化を増大させるための、TGB−βのアゴニストおよびIL−21のアゴニストの使用。
- TH17細胞もしくはTH17細胞集団への、T細胞もしくはT細胞集団の分化を阻害するための、TGF−βのアンタゴニストおよびIL−21のアンタゴニストの使用。
- T細胞もしくはT細胞集団におけるIL−17の発現、活性、分泌もしくはプロセシングを増大させるための、TGF−βおよびIL−21もしくはこれらのアゴニストの使用。
- T細胞もしくはT細胞集団におけるIL−17の発現、活性、分泌もしくはプロセシングを低下させるための、TGF−βのアンタゴニストおよびIL−21のアンタゴニストの使用。
- TH17細胞活性によって影響を与えるもしくは媒介される障害の処置のための医薬の調製における、TGF−βのアンタゴニストおよびIL−21のアンタゴニストの使用。
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US20110245107A1 (en) | 2011-10-06 |
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WO2009092087A2 (en) | 2009-07-23 |
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