JP5904953B2 - Alsの早期診断およびals進行のための細胞性血液マーカー - Google Patents
Alsの早期診断およびals進行のための細胞性血液マーカー Download PDFInfo
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Description
1の態様において、本発明は、試験した個人におけるALSの可能性を診断する方法に関し、該方法は:
(i)該個人から採取した末梢血液試料中の調節性T−細胞、ガンマ−デルタT−細胞、炎症誘発性単球、骨髄派生サプレッサー細胞またはナチュラルキラー細胞から選択される少なくとも1の細胞型のレベルを測定し;
(ii)該少なくとも1の細胞型の各1について測定したレベルを、年齢が一致する対照の血液試料中の該細胞型の各1の範囲レベルを表す参照レベルと各々比較し、したがって年齢が一致する対照の血液試料中の該少なくとも1の細胞型の各1のレベルに対する該個人の血液試料中の該少なくとも1の細胞型の各1のレベルを表す試験プロフィールを得;ついで
(iii)該試験プロフィールを、ALS患者における少なくとも1の細胞型の各1の代表的な相対レベルを表す参照プロフィールと比較することを含み、
ここに、該試験プロフィールと該参照プロフィールとの間の顕著な類似性が、該個人が該年齢が一致する対照よりもALSを有する高い可能性を有することを示すことを特徴とする。
(i)2の連続した時点(該時点の先方は該治療の前または間であり、該時点の後方は該治療の間)で該患者から採取した末梢血液試料中の調節性T−細胞、ガンマ−デルタT−細胞、骨髄派生サプレッサー細胞またはナチュラルキラー細胞から選択される少なくとも1の細胞型のレベルを測定し;ついで
(ii)該2の時点における該少なくとも1の細胞型の各1について測定したレベルを比較することを含み、
ここに、健全な対照の血液試料中の該細胞型の範囲レベルを表す所定のレベルに向かう、該先方の時点に該細胞型について測定したレベルと比較した該後方の時点に該少なくとも1の細胞型の1またはそれを超えるものについて測定したレベルの変化を、該治療の効力と関連付けることを特徴とする。
(i)調節性T−細胞、ガンマ−デルタ(γδ)T−細胞、炎症誘発性単球、骨髄派生サプレッサー細胞(MDSC)またはナチュラルキラー細胞から選択される細胞型のリスト;
(ii)該細胞型の各1に対する抗体;
(iii)該抗体を検出する試薬;
(iv)年齢が一致する対照の血液試料中の該細胞型の範囲レベルを表す参照レベルのリスト;
(v)所望により、ALS患者の血液試料中の該細胞型の各1の代表的な相対レベルを表す参照プロフィール;および
(vi)使用指示書
を含む。
本発明は、疾患の病理とそれを撃退するための免疫系の試行との間の長いステージの努力の後にCNSの病理が現れた概念に基づく。詳細には、この概念は、実際に、身体がガンを防ぐプロセス、すなわち、3の連続的な相「除去」、「平衡」および「回避」(「3のE」、広範なレビューについては、Dunnら,2002およびSmythら,2006を参照されたい)によって特徴付けられる「腫瘍イムノエディティング(tumor immunoediting)」といわれるプロセスに非常に類似する多段階のプロセスを記載する。
かかる状況は、ALSのような慢性の神経変性障害において起こり得る。動物の研究はすべてのこれらの症状において、臨床的症状が発現したら、免疫活性が疾患の過程に影響することを示しているが(Butovskyら,2006;Beersら,2006;Laurieら,2007)、本発明者らは、免疫系がこれらの疾病が症候性になるずっと前にこれらの疾病の早期兆候と争っていることを示す。このようにして、免疫活性はガンにおけるのと非常に似た様式で神経病理的障害を休止状態に数年間維持することができる。臨床的症状が現れる時点が、「回避」相に平行すると考え得るものの開始を表し、それは死滅ニューロンによって課せられる免疫応答、または局所的な先天的炎症応答のいずれかの抑制の結果となり得る。
(i)該個人から採取した末梢血液試料中の調節性T−細胞、ガンマ−デルタT−細胞、炎症誘発性単球、骨髄派生サプレッサー細胞またはナチュラルキラー細胞から選択される少なくとも1の細胞型のレベルを測定し;
(ii)該少なくとも1の細胞型の各1について測定したレベルを、年齢が一致する対照の血液試料中の該細胞型の各1の範囲レベルを表す参照レベルと各々比較し、年齢が一致する対照の血液試料中の該少なくとも1の細胞型の各1のレベルに対する該個人の血液試料中の該少なくとも1の細胞型の各1のレベルを表す試験プロフィールを得;ついで
(iii)該試験プロフィールと、ALS患者における少なくとも1の細胞型の各1の代表的な相対レベルを表す参照プロフィールとを比較することを含み、
ここに、該試験プロフィールと該参照プロフィールの間の有意な類似性が、該個人が該年齢が一致する対照よりもALSを有するより高い可能性を有することを示すことを特徴とする。
特定の実施形態において、ALS患者において測定した細胞型の各1の代表的な相対レベルを表す予め決定した参照プロフィールは、γδ T-細胞のレベルの増大;CD11b+/CD14-、CD11b+/CD14-/CD15+、CD11b+/CD14+/CD15+、Lin-/DR-、Lin-/DR-/CD33+、CD34+/CD33+/CD13+、ARG+/CD14+、CD34+/Lin-/DR-/CD11b+/CD15+、CD14+/HLA-DR-/lowまたはLin-/HLA-DR-/low/CD11b+/CD33+から選択されるMDSCの少なくとも1の型のレベルの増大;およびCD14+/CD16+細胞のレベルにおける変化なしを含む。
(i)該個人から得た末梢血液試料中の細胞型、ガンマ-デルタT-細胞、CD11b+/CD14-細胞、Lin-/DR-/CD33+細胞およびCD14+/CD16+細胞のレベルを測定し;ついで
(ii)該細胞型の各1について測定したレベルを、各々、年齢が一致する対照の血液試料における該細胞型の各1の範囲レベルを表す参照レベルと比較することを含み、
ここに、ガンマ−デルタT−細胞のレベルの増大、CD11b+/CD14-細胞のレベルの増大、Lin-/DR-/CD33+細胞のレベルの増大およびCD14+/CD16+細胞のレベルにおける変化なしが、該個人が該年齢が一致する対照よりもALSを患っている高い可能性を有することを示すことを特徴とする。
(i)2の連続する時点(該時点の先方は該治療の前または間であり、該時点の後方は該治療の間)において、該患者から得た末梢血液試料中の調節性T−細胞、ガンマ−デルタ T−細胞、骨髄派生サプレッサー細胞またはナチュラルキラー細胞から選択される少なくとも1の細胞型のレベルを測定し;ついで
(ii)該2の時点における該少なくとも1の細胞型の各1について測定したレベルを比較することを含み、
ここに、年齢が一致する対照の血液試料中の該細胞型の範囲レベルを表す参照レベルに向かう、該先方の時点において該細胞型について測定したレベルと比較した該後方の時点において該少なくとも1の細胞型の1またはそれを超えるものについて測定したレベルの変化を、該治療の効力と関連付けることを特徴とする。
本明細書中で用いる「年齢が一致する対照の血液試料中の該細胞型の範囲レベルを表す参照レベルに向かう、該先方の時点において該細胞型について測定したレベルと比較した該後方の時点において該少なくとも1の細胞型の1またはそれを超えるものについて測定したレベルの変化」なる句は、試験した細胞型またはサブセットの少なくとも1について先方の時点において測定したレベルと該細胞型またはサブセットの正常な範囲レベルとの間の差が、該細胞型またはサブセットの正常な範囲レベルと比較した場合に、後方の時点において該細胞型またはサブセットについて得られたものよりも顕著に大きい場合をいう。該細胞型またはサブセットの正常な範囲レベルに向かう、該先方の時点においてある種の細胞型またはサブセットについて測定したレベルと比較した該後方の時点において該細胞型またはサブセットについて測定したレベルの変化は、各々前記に定義したように、先方の時点における該細胞型またはサブセットの相対レベルが「増大」によって表される場合は著しく小さい宣告した増大(a significantly less pronounced increase)と定義し得、あるいは先方の時点における該細胞型またはサブセットの相対レベルが「低下」によって表される場合は著しく小さい宣告した低下(a significantly less pronounced decrease)となり得る。
(i)調節性T−細胞、ガンマ−デルタ(γδ)T−細胞、炎症誘発性単球、骨髄派生サプレッサー細胞(MDSC)またはナチュラルキラー細胞から選択される細胞型のリスト;
(ii)該細胞型の各1に対する抗体;
(iii)該抗体を検出する試薬;
(iv)年齢が一致する対照の血液試料中の該細胞型の範囲レベルを示す参照レベルのリスト;
(v)所望により、ALS患者の血液試料中の該細胞型の各1の代表的な相対レベルを表す参照プロフィール;および
(vi)使用指示書
を含む。
ここで、本発明を以下の非−限定的な実施例によって説明する。
材料および方法
患者:患者のグループには、筋萎縮性側索硬化症(ALS)に苦しむと臨床的に診断され、インフォームド・コンセントに同意して署名した男性および女性の両方の個人を含ませた。対照グループには、ALSの臨床的症状を有さず、インフォームド・コンセントに同意して署名した男性および女性の志願者を含ませた。
骨髄サプレッサー細胞は、潜在的な免疫抑制機能を有する未成熟骨髄細胞の集団を構成する。この細胞は実験動物およびヒトのガン患者において腫瘍に浸潤し、ガン細胞に対する適応免疫応答を調整することが示されている。それは、正常、炎症または外科手術/外傷性ストレス障害下で免疫抑制を誘導し得る。骨髄サプレッサー細胞の蓄積は、腫瘍エスケープの主な機構の1である(Frey,2006;Serafiniら,2006a;Buntら,2006;Makarenkovaら,2006)。骨髄サプレッサー細胞は、それが種々の機構によってT−細胞免疫応答を抑制する能力を有するため関心がある(SicaおよびBronte,2007;Serafiniら,2006a;Talmadge,2007;NagarajおよびGabrilovich,2007)。この細胞は、マクロファージ、顆粒球、未成熟樹状細胞および早期骨髄前駆体を含む不均一な細胞集団である。
骨髄細胞集団は多くの異なる細胞型を含み、骨髄細胞分化はプロセスの連続であるため、MDSCは未成熟から成熟までの骨髄細胞のスペクトルを反映する多様な表現型マーカーを示し得る。
ガンマ−デルタ(γδ)T細胞は、その表面に異なるT細胞受容体(TCR)を有する小さいサブセットのT細胞を表す。この細胞は微生物および腫瘍に対する宿主防御に関与するが、その機能の様式はほとんど解明されていないままである。
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Claims (2)
- ALSの可能性を評価する方法であって、
(i)末梢血液試料中の細胞型ガンマ−デルタ(γδ)T−細胞、CD11b+/CD14-細胞、Lin-/DR-/CD33+細胞およびCD14+/CD16+細胞のレベルを測定し;ついで
(ii)該細胞型の各1について測定したレベルを、対照の血液試料中の該細胞型の各1の範囲レベルを表す参照レベルと各々比較する
ことを含み、
ここに、γδ T-細胞のレベルの増大;CD11b+/CD14-細胞のレベルの増大、Lin-/DR-/CD33+細胞のレベルの増大、およびCD14+/CD16+細胞のレベルに変化がないことが、対照よりもALSの高い可能性を示すことを特徴とする該方法。 - 試験した個人におけるALSの可能性を診断するキットであって、
(i)ガンマ−デルタ(γδ)T−細胞、炎症誘発性CD14+/CD16+単球、およびCD11b+/CD14-およびLin-/DR-/CD33+からなる細胞型のリスト;
(ii)該細胞型の各1に対する抗体;
(iii)該抗体を検出する試薬;
(iv)年齢が一致する対照の血液試料中の該細胞型の範囲レベルを表す参照レベルのリスト;および
(v)使用指示書
を含む該キット。
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PCT/IL2011/000227 WO2011111043A1 (en) | 2010-03-10 | 2011-03-10 | Cellular blood markers for early diagnosis of als and for als progression |
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