JP2014226079A - Nk細胞の調製方法 - Google Patents
Nk細胞の調製方法 Download PDFInfo
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- JP2014226079A JP2014226079A JP2013107568A JP2013107568A JP2014226079A JP 2014226079 A JP2014226079 A JP 2014226079A JP 2013107568 A JP2013107568 A JP 2013107568A JP 2013107568 A JP2013107568 A JP 2013107568A JP 2014226079 A JP2014226079 A JP 2014226079A
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Abstract
Description
ヒト臍帯血由来造血前駆細胞
ヒト臍帯血由来造血前駆細胞試料は、PromoCell社(タカラバイオ株式会社、C−12921)又はZenBio社(株式会社B−Bridge、SER−CD34−F)より入手された。前記試料は、免疫磁気ビーズCD34を用いて単核球細胞からCD34陽性前駆細胞が精製(CD34陽性率:90%以上)され、凍結されたものである。なお前記試料の採取に当っては、母親から書面による同意を得ている。また、HIVウイルス及びB型肝炎ウイルス検査の結果が陰性であると確認されている。
培地としてSTEMLINE II(シグマ アルドリッチ ジャパン合同会社、カタログ番号:S0192、ロット番号:SLBB3210)及び/又はKBM501培地(コージンバイオ株式会社、カタログ番号:16025015、ロット番号:K1M120924、1750JRU/mL、すなわち、2813IU/mLのIL−2と、2000mg/mL以下のヒト血清アルブミンとを含む)が使用され、最終濃度10%のヒトAB型血清(コージンバイオ株式会社、カタログ番号:12181301、ロット番号:12020165)が添加された。以下の実験で添加されるサイトカイン等のタンパク質は特記されない場合はすべてヒト組換えタンパク質である。
前記臍帯血由来のCD34陽性細胞は、製造者の仕様書にしたがって解凍された後、増幅培養用培地1で5×105個/mLになるように希釈され、6ウェルの培養プレート(140675、nunc、サーモフィッシャーサイエンティフィック株式会社)に播種された。培地交換は培養5日目に行われた。増幅培養用培地1は、25ng/mLのTPO、25ng/mLのSCF、25ng/mLのFlt3L、250pg/mLのG−CSF、10pg/mLのGM−CSF、50pg/mLのIL−6及び10%ヒトAB型血清が添加されたSTEMLINE II培地であった。
前記臍帯血由来のCD34陽性細胞は、増幅培養用培地1で1週間培養された後、PBSで3回洗浄され、増幅培養用培地2で5×105個/mLになるように希釈され、6ウェルの培養プレート(140675、nunc、サーモフィッシャーサイエンティフィック株式会社)に播種され、さらに4週間培養された。培地交換は培養3日目から4日ごとに行われた。培地交換に際しては細胞懸濁液が回収され、室温にて500g、5分間遠心操作で培地が除去された後、新鮮な増幅培養用培地2で5x105個/mLになるように細胞が希釈され、6ウェルの培養プレートに播種された。増幅培養用培地2は、25ng/mLのIL−15、25ng/mLのSCF、25ng/mLのIL−7、25ng/mLのFlt3L及び10%ヒトAB型血清が添加されたSTEMLINE II培地であった。
前記臍帯血由来のCD34陽性細胞は、増幅培養用培地2だけで5週間培養された。培地交換は培養3日目から4日ごとに行われた。
前記臍帯血由来のCD34陽性細胞は、増幅培養用培地3だけで5週間培養された。培地交換は培養3日目から4日ごとに行われた。増幅培養用培地3は、25ng/mLのIL−15、25ng/mLのSCF、25ng/mLのIL−7、25ng/mLのFlt3L、25ng/mLのTPO及び10%ヒトAB型血清が添加されたSTEMLINE II培地であった。
前記臍帯血由来のCD34陽性細胞は、増幅培養用培地1ないし3を用いて合計35日間増幅された後、培地が分化誘導用培地1に切り替えられて、7日間NK細胞への分化が誘導された。分化誘導用培地1は、10%ヒトAB型血清が添加されたKBM501培地であった。
前記臍帯血由来のCD34陽性細胞は、増幅培養用培地3を用いて合計35日間増幅された後、培地が分化誘導用培地2に切り替えられて、7日間NK細胞への分化が誘導された。分化誘導用培地2は、1750JRU/mL、すなわち、2813IU/mLのIL−2及び10%ヒトAB型血清が添加されたが添加されたSTEMLINE II培地であった。
前記造血前駆細胞の細胞数は血球計算盤を用いて生細胞数を計測することにより決定された。前記細胞の細胞表面マーカーは、抗CD3抗体(BioLegend Japan株式会社、カタログ番号:317308)、抗CD56抗体(318321、BioLegend Japan株式会社、カタログ番号:304607)、抗CD69抗体(BioLegend Japan株式会社、カタログ番号:310905)、抗CD335(NKp46)抗体(BioLegend Japan株式会社、カタログ番号:331907)、抗CD337(NKp30)抗体(BioLegend Japan 株式会社、カタログ番号:325207)、抗CD314(NKG2D)抗体(BioLegend Japan株式会社、カタログ番号:320805)、抗グランザイムB抗体(BD Pharmingen、カタログ番号:560211、日本ベクトン・ディッキンソン株式会社)及び抗パーフォリン抗体(BioLegend Japan株式会社、カタログ番号:308111)を用いて、フロー・サイトメトリー法で解析された。
NK細胞は、本実施例で説明された方法にしたがって増幅及び分化誘導され、エフェクター細胞として用いられた。慢性骨髄性白血病細胞のK562細胞は、当業者に周知の方法で培養され、標的細胞として用いられた。増幅されたNK細胞と、増幅されていないNK細胞(以下、「非増幅NK細胞」という。)との細胞傷害活性が、当業者に周知の方法で定量された。簡潔には、前記標的細胞は、終濃度:0.01mMの3−3’−ジオクタデシロキサカルボシアニン(シグマ アルドリッチ ジャパン合同会社、カタログ番号D4292)が添加されたRPMI−1640培地で10分間培養することによって標識された。前記標的細胞は、標識後、PBS(−)及びRPMI培地を用いて3回洗浄された。前記エフェクター細胞と、前記標的細胞とは、丸底の96ウェルの培養プレートに播種され、RPMI培地で4時間共培養された。エフェクター細胞と標的細胞との比(E:T比)は、2対1に調整された。細胞傷害活性(%)は、7−アミノ−アクチノマイシンD(シグマ アルドリッチ ジャパン合同会社、A9400)を用いてフロー・サイトメトリー法によって定量された。
臍帯血由来造血前駆細胞の増幅
図1は、増幅培養用培地1を用いる1週間の増幅と、増幅培養用培地2を用いる4週間の増幅との後、分化誘導用培地1に切り替えて1週間培養される第1のプロトコール(白塗り菱形(◇)でプロットされたグラフ、I)と、増幅培養用培地2だけを用いる5週間の増幅の後、分化誘導用培地1に切り替えて1週間培養される第2のプロトコール(白塗り四角(□)でプロットされたグラフ、II)と、増幅培養用培地3だけを用いる5週間の増幅の後、分化誘導用培地1に切り替えて1週間培養される第3のプロトコール(黒塗り三角(▲)でプロットされたグラフ、III)とにおける臍帯血由来造血前駆細胞の増幅倍率の経時変化が比較される折れ線グラフである。横軸は、臍帯血から調製された造血前駆細胞の培養開始からの日数を表す。縦軸は、培養開始時の細胞数を1倍とする増幅倍率を表す。図1に示されるとおり、臍帯血由来造血前駆細胞は、培養30日頃から増殖速度が非常に低下した。第1及び3のプロトコールにより得られる細胞はともに増幅倍率が約10,000倍であったが、第2のプロトコールにより得られる細胞は増幅倍率が約1,000倍で、第1及び3のプロトコールに比べて10分の1しか増えなかった。なお、42日まで増幅培養用培地で培養しても、35日目と細胞数はほとんど変わらなかった(図示されない)。
Claims (8)
- 造血前駆細胞を単一の培養条件で増幅するステップと、前記増幅するステップで得られた細胞をNK細胞に分化誘導させるステップとを含む、NK細胞の調製方法。
- 前記造血前駆細胞を単一の培養条件で増幅するステップに用いる培地は、IL−15、SCF、IL−7及びFlt3Lを含む、請求項1に記載のNK細胞の調製方法。
- 前記造血前駆細胞を単一の培養条件で増幅するステップに用いる培地は、TPOをさらに含む、請求項2に記載のNK細胞の調製方法。
- 前記NK細胞を分化誘導させるステップは、増幅された前記造血前駆細胞をIL−2を含む培養条件下で培養することを含む、請求項1ないし3のいずれか1つに記載のNK細胞の調製方法。
- 前記各ステップに用いる培地は、ヒトAB型血清、及び/又は、ヒト血清アルブミンを含む、請求項1ないし4のいずれか1つに記載のNK細胞の調製方法。
- 前記造血前駆細胞は、臍帯血及び/又は成体血球系組織に含まれる造血前駆細胞と、人工多能性幹細胞、胚性幹細胞及び/又は成体幹細胞から分化誘導される造血前駆細胞と、分化した細胞から直接変換される造血前駆細胞とからなるグループから選択される少なくとも1種類の造血前駆細胞である、請求項1ないし5のいずれか1つに記載のNK細胞の調製方法
- 請求項1ないし5のいずれか1つに記載の調製方法によって調製されるNK細胞を含む、細胞療法のための医薬品組成物。
- 感染症及び/又は癌を治療するために用いられる、請求項6に記載の医薬品組成物。
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KR20220138330A (ko) | 2019-01-21 | 2022-10-12 | 가부시키가이샤 가이아바이오메디신 | Nk 세포를 포함하는 세포 집단의 제조 방법 |
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WO2020152661A1 (ja) | 2019-01-21 | 2020-07-30 | 株式会社ガイアバイオメディシン | Nk細胞を含む細胞集団の製造方法 |
KR20220138330A (ko) | 2019-01-21 | 2022-10-12 | 가부시키가이샤 가이아바이오메디신 | Nk 세포를 포함하는 세포 집단의 제조 방법 |
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EP3000876A4 (en) | 2016-10-26 |
EP3000876B1 (en) | 2019-04-24 |
AU2014269813A1 (en) | 2015-11-26 |
WO2014188680A1 (ja) | 2014-11-27 |
JP5511039B1 (ja) | 2014-06-04 |
EP3000876A1 (en) | 2016-03-30 |
TW201512399A (zh) | 2015-04-01 |
US20160097035A1 (en) | 2016-04-07 |
AU2014269813B2 (en) | 2019-11-14 |
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