JP5406019B2 - 自動化組織分析のための方法 - Google Patents
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Description
本出願は、2006年5月17日に出願された米国特許仮出願第60/801,035号の恩典を主張する。
病理における適用のための多色蛍光での能力(capability)の開発は、10年以上前に導入された[3,6-8]が、市場ではまだ広く容認されていない。特に、Dow et al. [7]には、多色蛍光を用いて、ヒューマンインタラクティブ画像解析プロセスにより黒色腫組織切片におけるリンパ球表現型および活性化状態を測定した研究が記載されている。つい最近では、多色蛍光が病理において適用され[9]、HistoRx,Inc.(New Haven、CT)により、これらのアプローチのいくつかが商品化された。これらの刊行物および適用には、組織細胞分析において蛍光に基づく画像化技術を使用することが示されているが、その適用に限定されており、組織の系統的または細胞システム生物学の理解の必要性は示されていない。
細胞は、最も単純な生体系である。組織は、相互作用する細胞群を形成している特定の細胞型の集合体である。細胞および組織は、完全な生物体よりは複雑ではないが、相当な機能の複雑性を有し、生物体全体に影響を及ぼす多くの側面、例えば、疾患の細胞的根拠、治療有効性および治療の潜在的毒性の詳細な理解を可能にする。検索可能なデータベースを多重化バイオマーカーの多色蛍光と連結させると、細胞システム生物学(本明細書において、システム細胞生物学ともいう)プロファイリングおよび分析の基礎が提供される。
「細胞システム生物学」は、機能および生命をもたらす遺伝子、タンパク質および代謝反応の統合された相互作用性のネットワークの研究と定義される。組織内の細胞は、複雑な系として、細胞状態を特徴付けするために多くの要素の分析を必要とする創発性(emergent properties)として知られる、個々の成分の分析から予測されない特性を示す。TaylorおよびGiuliano[10]には、薬物発見へのインビトロ細胞系分析の適用が記載されている。この分析では、薬物治療に対する細胞応答を同定および解釈するのに、個々の細胞の測定間の相関が必要であった。
1. 鱗状上皮細胞および線維芽細胞-支質の一部を形成
2. 神経線維-実質を神経支配するための血管を伴う細胞プロセス
3. 毛細管上皮-血管の壁を形成する細胞
4. クッパー細胞-特殊マクロファージ
5. 脂肪細胞-トリグリセリドを貯蔵する
6. 血液細胞-赤血球、免疫細胞および血小板を含む細胞
7. 肝細胞-肝臓における最も主要な細胞型を含む数種類の細胞からなる。肝細胞は上述の肝臓の機能のほとんどを実行する。
1. 代謝バイオマーカー:
・シトクロムP450アイソタイプ-肝細胞中の発現レベルおよびアイソタイプの比。
・P糖タンパク質活性-細胞、特に肝細胞外の複数の化合物基質を排出する膜結合タンパク質。
2. DNA損傷バイオマーカー:
・細胞周期調節-組織切片中に含まれる細胞の核内の全DNA含量の分布は、ヘキスト33342、Draq-5、またはヨウ化プロピジウムなどの核標識を使用して測定することができる。
・核形態およびクロマチン凝集-核の損傷はしばしば核の形態の変化またはクロマチンの凝集状態と相関可能である。組織切片に含まれる核のクロマチンの形態(例えば、形状および大きさ)または構造(単位面積当たりの明るさ)は、ヘキスト33342、Draq-5、またはヨウ化プロピジウムなどの核標識を使用して測定可能である。
・8-オキソグアニン - DNAに対する酸化的損傷はしばしばグアニンの酸化アナログを生じる。細胞中のDNAが損傷されたという8-オキソグアニンシグナルの上昇。
・DNA修復タンパク質(APE/ref-1)の活性化-肝細胞またはDNAを含む肝臓中の他の任意の細胞中のDNAは疾患または化合物処理により損傷し易い。細胞中のDNA損傷応答機構が活性化されたというAPE/ref-1シグナルの発現レベルの変化。
・ヒストンH2A.Xリン酸化-肝細胞またはDNAを含む肝臓中の他の任意の細胞中のDNAは、疾患または化合物処理により損傷し易い。細胞中のDNA損傷応答機構が活性化されたというヒストンH2A.Xシグナルのリン酸化。
・p53タンパク質活性化。
・Rbタンパク質リン酸化
3. 細胞形態および分化バイオマーカー:
・細胞拡散および肥大
・細胞-細胞または細胞支質の接着
・新規血管の脈管形成
・神経支配神経線維のリモデリング
4. ストレス誘導型転写因子活性化または抑制バイオマーカー:
・NF-κB
・ATF-2
・CREB
・AP-1
・MSK
・NFAT
・Stat1、2、3
・Oct-1
5. ストレスキナーゼバイオマーカーのリン酸化状態の変化:
・ERK
・JNK
・p38
・RSK90
・MEK
6. アポトーシスまたはネクローシスバイオマーカーの誘導:
・DNA含量および分解
・核形態
・カスパーゼ活性化(複数のサブタイプ)
・ミトコンドリア機能(質量-電位)
・Baxのミトコンドリアへの移行
・ミトコンドリアのシトクロムcの放出
・PARP活性化
7. 細胞骨格バイオマーカーのリモデリング:
・アクチン細胞骨格の安定性
・微小管細胞骨格の安定性
8. オルガネラ形態バイオマーカー:
・ミトコンドリアの大きさ、数、および形状
・ゴルジ体の大きさおよび局在
・ペルオキシソームの大きさおよび数
・グリコーゲン粒子の大きさおよび数
・リソソームの大きさおよび数
・脂肪滴の大きさおよび数
・内質小網の形状および局在
・タイトジャンクションの数および局在
9. 免疫細胞の存在および活性のバイオマーカー:
・肝細胞、リンパ系、および血液供給中の特定の移動性免疫細胞の割合および比率。
・抗腫瘍および腫瘍支持機能のいずれかを反映する肝臓癌組織の重要な免疫細胞の表現型。
・免疫細胞のアポトーシス
・TRAILなどのデスレセプターリガンドの発現
・リンパ球中のPD1などの免疫細胞機能不全に関連するバイオマーカーの発現
・抗腫瘍サーベイランスを特徴付けるためのNKおよびLAK細胞活性
a. 遺伝子発現プロファイリングは、「正常」肝臓組織と疾患または化合物処理動物由来の組織を比較するように実施する。
b. 遺伝子発現インフォマティクス-遺伝子発現プロフィールは、疾患または化合物処理の機能としての遺伝子発現を特徴付けるためおよび遺伝子産物を同定するためのインフォマティクスツールにより解析される。
c. 遺伝子産物は公知の参照ポイントに基づいて正常肝臓組織よりも優先され、その後抗体を取得するか作製して試験パネルを作製する。
2. 組織学的染色および重要なバイオマーカーの組み合わせを「機能的」バイオマーカーの蛍光ベース免疫細胞化学について多重化する:
a. 複数の5μm切片を肝臓組織から調製する。第一の切片をH&Eまたは従来の病理解析についての他の組織学的染色で標識する。多重化蛍光ベース細胞学について、連続切片を処理する。
b. 遺伝子発現プロファイリングに基づく潜在的バイオマーカーのパネルに加えて、重要な移動性免疫細胞(リンパ球(例えば、CD3およびCD8)を含む)についての抗体の多重化したパネルによりいくつかの切片を標識する。免疫細胞活性化のレベル、濃度および器官形成はプロフィールの重要な要素である。
連続切片#1
1. 核を標識して核形態、細胞周期調節、クロマチン凝集の測定を提供するためのヘキスト33342。
2. 酸化DNA損傷のバイオマーカーとしての抗ホスホヒストンH2A.X
3. DNA損傷応答のバイオマーカーとしての抗p53。
4. ストレスキナーゼ誘導のバイオマーカーとしての抗ホスホc-jun。
連続切片#2
1. ヘキスト33342
2. ミトコンドリア数、大きさ、形状のバイオマーカーとしての抗シトクロムc
3. 微小管細胞骨格リモデリングのバイオマーカーとしての抗αチューブリン。
4. アクチン細胞骨格リモデリングのバイオマーカーとしての蛍光標識ファロイジン。
連続切片#3
1. ヘキスト33342
2. 細胞周期チェックポイント活性のバイオマーカーとしての抗ホスホレチノブラストーマタンパク質。
3. 炎症関連細胞シグナリングのバイオマーカーとしての抗NF-κB。
4. 組織へのリンパ球浸潤のバイオマーカーとしての抗CD3。
連続切片#4
1. ヘキスト33342
2. アポトーシスのバイオマーカーとしての抗活性化カスパーゼ3。
3. ペルオキシソームの大きさおよび数のバイオマーカーとしての抗PMP70。
4. 肝細胞代謝活性のバイオマーカーとしての抗シトクロムP450。
・Her2/Neuタンパク質(現在単一のバイオマーカーとして使用されている)
・エストロゲンレセプタータンパク質(ER)
・Ki-67
・Cox-2
・P16
・主要なタンパク質または癌プロセスに相関するタンパク質の翻訳後修飾の増加数
・特定の癌に関連するマイクロRNAの増加数
・腫瘍、腫瘍排出リンパ節、非センチネルリンパ節および末梢血中の特異的な移動性免疫細胞の割合および比率
・抗腫瘍機能または腫瘍支持機能を反映する、乳癌患者における主要な免疫細胞型の表現型
・免疫細胞のアポトーシス
・TRAILなどのデスレセプターリガンドの発現
・腫瘍侵入性リンパ球中のPD1などの免疫細胞機能不全に関連するバイオマーカーの発現。
・抗腫瘍サーベイランスを特徴付けるためのNKおよびLAK細胞活性
1.患者腫瘍試料-従来の方法で、遺伝子発現プロファイリングにより「正常」組織と病期決定患者腫瘍を比較する。
2. 遺伝子発現インフォマティクス-乳癌の病期の関数として遺伝子発現を特徴付けるためおよび遺伝子産物を同定するためのインフォマティクスツールにより遺伝子発現プロフィールを解析する(参照としてHer2/Neuを使用する)。
3. 遺伝子産物はHer2/Neuを含む公知の参照点に基づいて優先され、その後試験パネルを作製するために抗体が取得または作製される。
4. 選択される癌細胞バイオマーカーの組み合わせが蛍光ベース免疫組織化学について多重化される。
5. 複数の5ミクロン組織切片を腫瘍試料から調製する。第一の切片は病理学者による従来の病期決定のためにH&Eについて染色される。多重化蛍光ベースサイトメトリーのために連続切片を処理する。
6. 遺伝子発現プロファイリングに基づいた潜在的癌細胞バイオマーカーのパネルに加えて、いくつかの切片を、リンパ球(例えば、CD3および/またはCD8)を含む主要な移動性免疫細胞に対する抗体の多重化パネルで標識する。免疫細胞活性化のレベル、濃度および形成はプロフィールの重要な要因である。
リンパ球:1%〜90%(この割合中の明確なサブタイプ)
好中球:1%〜90%
好酸球:0.01%〜50%
単球:0.01%〜50%(この割合中の明確なサブタイプ)
細胞システム生物プロフィールについての組織中の免疫細胞の比率の例示的範囲:
T細胞リンパ球サブタイプI/T細胞リンパ球サブタイプII:0.01〜1000
T細胞リンパ球/B細胞リンパ球:0.1〜1000
樹状細胞/リンパ球:0.01〜1000
マクロファージ/リンパ球:0.01〜1000
リンパ球サブセット/リンパ球サブセット:0.01〜1000
この態様において、ヒト脳組織を得て、固定および切片化する。一組の切片を1つ以上の染色剤で標識して、アルツハイマー病の病理に関連する組織中の形態学的構造を可視化する。一例において、銀染色を使用して、神経突起プラークおよび神経原線維変化を有する神経などのアルツハイマー病の特徴(hallmark)を可視化する[41]。薬物による治療前、最中またはその後の複数の患者からの銀染色した組織の解析により、その後プロフィールに組み込まれるデータが提供される。
Claims (8)
a) 1つ以上の組織試料から少なくとも2つの切片を得る工程;
b) 少なくとも1つの切片を組織学的染色で標識して、組織学的に染色された切片を作製する工程;
c) 少なくとも1つの切片を蛍光標識試薬のパネルで標識して、蛍光標識された切片を作製する工程、ここでそれぞれの蛍光標識試薬はバイオマーカーに特異的であり、蛍光標識試薬のパネルが
i) 少なくとも3種類の癌細胞バイオマーカーに特異的な一組の蛍光標識試薬;および
ii) 少なくとも3種類の移動性免疫細胞バイオマーカーに特異的な一組の蛍光標識試薬
の組み合わせを含み、蛍光標識試薬のパネルが少なくとも4つの異なるバイオマーカーを検出し、バイオマーカーの検出が細胞システム生物プロフィールの1つ以上の特徴の読み出しである;
d) 組織学的に染色された切片を少なくとも第1の光学様式で画像化する工程、ここで画像化により第1の組のデータが作成される;
e) 蛍光標識された切片を少なくとも第2の光学様式で画像化する工程、ここで画像化により第2の組のデータが作成される;
f) 第1の組のデータおよび第2の組のデータを解析して5つ以上の特徴を同定する工程、ここで第1の組のデータおよび第2の組のデータのそれぞれにおいて、少なくとも1つの特徴が同定され、前記5つ以上の特徴が1つ以上の組織試料の創発性を特徴付けるものである、ならびに
g) 前記5つ以上の特徴の相互関係を計算する工程、ここで5つ以上の特徴の相互関係が1つ以上の組織試料の細胞システム生物プロフィールである、
を含み、
それにより、1つ以上の組織試料の創発性の細胞システム生物プロフィールを作成するための方法が提供され、ここで、該組織試料が、癌の存在、癌の病期、癌の診断、癌の予後またはそれらの組み合わせの創発性についてプロファイルされる、方法。
i) 少なくとも1つの末梢血試料から少なくとも1つの血液試料スメアを得ること;
ii) 少なくとも1つの血液試料スメアを蛍光標識試薬のパネルで標識して、蛍光標識された血液試料スメアを作製すること、ここでそれぞれの蛍光標識試薬がバイオマーカーに特異的であり、蛍光標識試薬のパネルが少なくとも4つの異なるバイオマーカーを検出し、バイオマーカーの検出が細胞システム生物プロフィールの1つ以上の特徴の読み出しである;
iii) 蛍光標識された血液試料スメアを少なくとも第3の光学様式で画像化すること、ここで画像化により第3の組のデータが作成される;
iv) 第3の組のデータを解析して5つ以上の特徴を同定すること、ここで前記5つ以上の特徴が少なくとも1つの血液試料の創発性を特徴付けるものである、ならびに
v) 前記5つ以上の特徴の相互関係を計算すること、ここで5つ以上の特徴の相互関係が少なくとも1つの血液試料スメアの細胞システム生物プロフィールである、
を含み、それにより、該1つ以上の組織試料と同じ供給源から得られた少なくとも1つの末梢血試料の創発性の細胞システム生物プロフィールが作成される、方法。
i) 1つ以上の末梢血試料から少なくとも2つの血液試料スメアを得ること;
ii) 少なくとも1つの血液試料スメアを組織学的染色で標識して、組織学的に染色された血液試料スメアを作製すること;
iii) 少なくとも1つの血液試料スメアを蛍光標識試薬のパネルで標識して、蛍光標識された血液試料スメアを作製すること、ここでそれぞれの蛍光標識試薬がバイオマーカーに特異的であり、蛍光標識試薬のパネルが少なくとも4つの異なるバイオマーカーを検出し、バイオマーカーの検出が細胞システム生物プロフィールの1つ以上の特徴の読み出しである;
iv) 組織学的に染色された血液試料スメアを少なくとも第3の光学様式で画像化すること、ここで画像化により第3の組のデータが作成される;
v) 蛍光標識された血液試料スメアを少なくとも第4の光学様式で画像化すること、ここで画像化により第4の組のデータが作成される;
vi) 第3の組のデータおよび第4の組のデータを解析して、5つ以上の特徴を同定すること、ここで第3の組のデータおよび第4の組のデータのそれぞれにおいて、少なくとも1つの特徴が同定され、前記5つ以上の特徴が1つ以上の血液試料の創発性を特徴付けるものである、ならびに
vii) 前記5つ以上の特徴の相互関係を計算すること、ここで5つ以上の特徴の相互関係が1つ以上の末梢血試料の細胞システム生物プロフィールである、
を含み、それにより、該1つ以上の組織試料と同じ供給源から得られた1つ以上の末梢血試料の創発性の細胞システム生物プロフィールが作成される、方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US80103506P | 2006-05-17 | 2006-05-17 | |
US60/801,035 | 2006-05-17 | ||
PCT/US2007/011865 WO2007136724A2 (en) | 2006-05-17 | 2007-05-17 | Method for automated tissue analysis |
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