JP2016510013A - ヒトcd34陰性前駆細胞による免疫に媒介される細胞傷害性反応からの血管内皮の保護 - Google Patents
ヒトcd34陰性前駆細胞による免疫に媒介される細胞傷害性反応からの血管内皮の保護 Download PDFInfo
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Abstract
Description
a)前記CD34陰性前駆細胞を単離する工程と、
b)前記CD34陰性前駆細胞を少なくとも12日間、細胞増殖培地中で増殖する(expanding)工程と、
c)前記CD34陰性前駆細胞を収集する工程と、
を含む、方法も提供する。
本出願において、すべてが以下に示す意味を有するいくつかの用語が使用される。
血管内皮は、種々の血管炎症性障害における一次標的である。本発明の発明者らは、リスクに適合した、個別化された予防及び/又は治療介入の点から、内皮の特異的保護が、大きな臨床及び健康経済的価値があるであろうということに気付いた。
直径が0.22 μmより大きい固形物を含まないヒト血小板溶解産物であって、前記細胞増殖培地の総容積の2 %〜15 %を構成する、ヒト血小板溶解産物と、
直径が0.22 μmより大きい固形物を含まないヒト新鮮凍結血漿(FFP)濾液であって、前記細胞増殖培地の総容積の1 %〜10 %を構成する、ヒト新鮮凍結血漿(FFP)濾液と、
前記細胞増殖培地の0 U/ml〜10 U/mlの濃度のヘパリンと、
0.5 mM〜10 mMの濃度のL-グルタミンと、
哺乳類細胞増殖に適した無血清、低グルコース培地であって、前記細胞増殖培地の総容積の75 %〜97 %を構成する、無血清、低グルコース培地と、
を含む培地を含む。
以下の実施例において、本発明のいくつかの実施形態を図面及び実験データを参照して更に詳細に説明する。実施例及び図面は具体的詳細に関して限定する意図のものではない。
以下の実施例は、免疫に媒介される細胞傷害性反応から血管内皮を保護することに関してCD34陰性前駆細胞の能力を評価するために、本発明者らによって計画された実験設定を記載する。
実施例1に記載した細胞傷害性アッセイを使用して、第3者由来CD34陰性前駆細胞有り及び無しで、同種細胞傷害性Tリンパ球による内皮標的細胞(HMEC)の溶解を評価した。この場合では、骨髄から単離したCD34陰性間葉系幹細胞/間質細胞を使用した。BM-MSCをBio-1培地中で増殖させた結果、幹細胞の特徴、細胞の生存能及び免疫に媒介される細胞傷害性反応から血管内皮を保護する能力を維持することについて、治療的使用に有利な細胞集団が得られた。
対照として、CD34陰性BM-MSCを内皮細胞に添加しないが、エフェクター細胞とともにプレインキュベートし、その後除去した点で実施例2とは異なる実験を実施例2に記載のようにして行った。この場合、BM-MSCとともにプレインキュベートしなかったエフェクター細胞と比較して、エフェクター細胞をBM-MSCとともにプレインキュベートした場合に、内皮標的細胞の特異的溶解の低下は観察されなかった。それゆえBM-MSCの免疫調節性活性はBM-MSCと内皮標的細胞との特異的相互作用に関連していると結論づけることができる。
更なる対照として、同種CD8+細胞傷害性Tリンパ球エフェクター細胞の溶解活性がアロ抗原のMHCクラスI提示に拘束されることによって抗原特異的であるか否かを調べた。この目的のため、内皮標的細胞を実施例2と同様にして、ただし中和MHCクラスI抗体(W6/32)の存在下で、CD8+エフェクター細胞に供した。さらに、エフェクター細胞はナチュラルキラー細胞又は非特異的リンホカイン活性化キラー細胞の活性と対応する活性を有さないことを示すべきであった。この対照は、実施例2と同様にして、ただし、内皮標的細胞を、ナチュラルキラー細胞についての対照標的細胞株(K562)に置換して実験を行うことによって達成した。
骨髄由来CD34陰性間葉系幹細胞/間質細胞等のCD34陰性前駆細胞は比較的大きな細胞である。それゆえ、内皮標的細胞のBM-MSCによる保護は、BM-MSCの免疫調節性能力に基づくものであるか否かではなく、CD8+Tリンパ球エフェクター細胞の内皮細胞への接近からのBM-MSCによる立体阻害に基づくものであるか否かを評価すべきであった。実験計画は実施例2と類似のものとしたが、ただし、ヒト心臓組織からの線維芽細胞様細胞をBM-MSCの代わりに内皮標的細胞に添加した。線維芽細胞様細胞はBM-MSCとサイズを一致させた。
CD34陰性前駆細胞自体は免疫原性ではないことは重要である。この理由のために、骨髄CD34陰性間葉系幹細胞/間質細胞の免疫原性を調べた。実験は実施例2に記載のようにして、ただし内皮細胞ではなく、骨髄間葉系幹細胞/間質細胞を標的細胞として使用して内皮細胞の非存在下で行った。同種CD8+細胞傷害性Tリンパ球エフェクター細胞の溶解活性は、BM-MSCが標的として提示された場合には観察されなかった。この知見は、CD34陰性前駆細胞、特に間葉系幹細胞/間質細胞の免疫無感作性(immunologic naivety)と一致している。
CD8+CTL媒介性溶解からの内皮標的細胞の保護における、様々な組織源由来のCD34陰性前駆細胞の有効性を比較した。実験は、実施例2に記載のようにして、ただし、CD34-前駆細胞(21)を骨髄由来MSC(BM-MSC、9の個別サンプル)、臍帯由来MSC(UC-MSC、4の個別サンプル)、又は羊膜由来MSC(AMC-MSC、3の個別サンプル)のいずれかとして行った。これら実験の結果を図5に要約する。各カラム対は、MSC保護無し(中実のカラム)及びMSC保護有り(斜線カラム)でのMSC源に応じたパーセントでの特異的内皮標的細胞溶解の算術平均及び標準偏差を示す。すべての試験したMSCは内皮標的細胞をCD8+CTL媒介性溶解から保護することができた。最も強力な保護はBM-MSCによって観察され、BM-MSCでは、内皮細胞溶解はMSC保護の無い対照と比較して平均すると72.3 %低下していた。AMC-MSCは内皮細胞溶解を平均するとおよそ53.2 %低下させ、UC-MSCもまた内皮細胞溶解を平均するとおよそ39.5 %低下させた。本実施例はまた、様々な源からの細胞の保護能を評価し、かつCD34陰性前駆細胞のin vivoでの効果を積極的に予測するために、血管内皮を免疫に媒介される細胞傷害性反応から保護するCD34陰性前駆細胞の能力を決定する本発明の方法の重要性を強調する。
Claims (22)
- 血管炎症性疾患のリスクがある又は血管炎症性疾患に罹患している対象の免疫に媒介される細胞傷害性反応から血管内皮を保護することにおける使用のためのヒトCD34陰性前駆細胞。
- 前記血管炎症性疾患が、CD8+細胞傷害性Tリンパ球によって引き起こされる血管内皮特異的細胞溶解を含む、請求項1に記載の使用のためのヒトCD34陰性前駆細胞。
- 前記CD8+細胞傷害性Tリンパ球が、CD27陰性及びCD28陰性である内皮特異的細胞傷害性Tリンパ球を含む、請求項1又は2に記載の使用のためのヒトCD34陰性前駆細胞。
- 前記血管炎症性疾患が、前記対象に関して同種である移植固形臓器の血管内皮に対するアロ反応を含む、請求項1〜3のいずれか一項に記載の使用のためのヒトCD34陰性前駆細胞。
- 前記血管炎症性疾患が、同種造血幹細胞移植後の移植関連合併症を含む、請求項1〜3のいずれか一項に記載の使用のためのヒトCD34陰性前駆細胞。
- 前記移植関連合併症が、移植片対宿主病(GvHD)を含む、請求項5に記載の使用のためのヒトCD34陰性前駆細胞。
- 前記移植関連合併症が、微小血管障害性疾患を含む、請求項5に記載の使用のためのヒトCD34陰性前駆細胞。
- 前記血管炎症性疾患が、自己免疫応答の結果としての、急性、炎症性又はアレルギー性血管炎を含む、請求項1〜3のいずれか一項に記載の使用のためのヒトCD34陰性前駆細胞。
- 前記急性、炎症性又はアレルギー性血管炎が、アレルギー性肉芽腫症、巨細胞性動脈炎、ウェゲナー肉芽腫症、高安動脈炎、川崎病、閉塞性血栓血管炎(バージャー病)、結節性多発動脈炎、チャーグストラウス症候群、顕微鏡的多発血管炎、クリオグロブリン血症性血管炎、蕁麻疹様血管炎、ベーチェット病、グッドパスチャー症候群、感染後血管炎又は薬剤誘発血管炎を含む、請求項8に記載の使用のためのヒトCD34陰性前駆細胞。
- 前記血管炎症性疾患が、血管内皮の慢性炎症を含む、請求項1〜3のいずれか一項に記載の使用のためのヒトCD34陰性前駆細胞。
- 前記CD34陰性前駆細胞が、CD34陰性間葉系幹細胞/間質細胞を含む、請求項1〜10のいずれか一項に記載の使用のためのヒトCD34陰性前駆細胞。
- 前記CD34陰性前駆細胞が、骨髄、臍帯、胎盤及び脂肪組織のCD34陰性前駆細胞、又はそれらの組合せを含む群から選択される、請求項1〜11のいずれか一項に記載の使用のためのヒトCD34陰性前駆細胞。
- 前記CD34陰性前駆細胞が、CD105、CD73及びCD90の発現、並びにCD45、CD34、CD14又はCD11b、CD79a又はCD19の発現の欠如を特徴とする、請求項1〜12のいずれか一項に記載の使用のためのヒトCD34陰性前駆細胞。
- 前記CD34陰性前駆細胞が、骨髄CD34陰性間葉系幹細胞/間質細胞である、請求項1〜13のいずれか一項に記載の使用のためのヒトCD34陰性前駆細胞。
- 前記CD34陰性前駆細胞が、少なくとも1つの更なる薬理活性成分と組み合わせて使用される、請求項1〜14のいずれか一項に記載の使用のためのヒトCD34陰性前駆細胞。
- 前記少なくとも1つの更なる薬理活性成分が、抗炎症活性、抗虚血活性、抗血栓活性、及びそれらの組合せを含む群から選択される薬理活性を有する、請求項15に記載の使用のためのヒトCD34陰性前駆細胞。
- 請求項1〜16のいずれか一項に記載の使用のためのヒトCD34陰性前駆細胞を産生する方法であって、以下の方法工程:
a)前記CD34陰性前駆細胞を単離する工程と、
b)前記CD34陰性前駆細胞を少なくとも12日間、細胞増殖培地中で増殖する工程と、
c)前記CD34陰性前駆細胞を収集する工程と、
を含む、方法。 - 方法工程a)において、前記CD34陰性前駆細胞を、骨髄、臍帯、羊膜及び脂肪組織、又はそれらの組合せを含む群の組織から単離する、請求項17に記載の方法。
- 方法工程b)の前記細胞増殖培地が、
直径が0.22 μmより大きい固形物を含まないヒト血小板溶解産物であって、前記細胞増殖培地の総容積の2 %〜15 %を構成する、ヒト血小板溶解産物と、
直径が0.22 μmより大きい固形物を含まないヒト新鮮凍結血漿(FFP)濾液であって、前記細胞増殖培地の総容積の1 %〜10 %を構成する、ヒト新鮮凍結血漿(FFP)濾液と、
前記細胞増殖培地の0 U/ml〜10 U/mlの濃度のヘパリンと、
0.5 mM〜10 mMの濃度のL-グルタミンと、
哺乳類細胞増殖に適した無血清、低グルコース培地であって、前記細胞増殖培地の総容積の75 %〜97 %を構成する、無血清、低グルコース培地と、
を含む培地を含む、請求項17又は18に記載の方法。 - 内皮標的細胞、細胞傷害性CD8+Tリンパ球及びCD34陰性前駆細胞を含むサンプルと、内皮標的細胞及び細胞傷害性CD8+Tリンパ球を含み、CD34陰性前駆細胞を含まない参照サンプルとを調製することと、該サンプル及び該参照サンプルにおける内皮標的細胞の溶解を比較することとによる、免疫に媒介される細胞傷害性反応から血管内皮を保護するCD34陰性前駆細胞の能力を決定する方法。
- 内皮標的細胞及び前記CD8+Tリンパ球を含む、前記サンプルと前記参照サンプルとを調製する前に、インターロイキン-2の存在下で、前記CD8+Tリンパ球を同種内皮細胞と共存培養する、請求項20に記載の方法。
- 少なくとも1つの更なる薬理活性成分を、前記サンプル及び/又は前記参照サンプルに添加する、請求項20又は21に記載の方法。
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PCT/EP2014/053923 WO2014131877A1 (en) | 2013-03-01 | 2014-02-28 | Protection of the vascular endothelium from immunologically mediated cytotoxic reactions with human cd34-negative progenitor cells |
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