JP2018531025A - 多能性幹細胞の免疫細胞への分化を誘導する方法 - Google Patents
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Abstract
Description
ある態様では、リプログラミングは、リプログラミング因子を体細胞集団に導入することを含む。一部の態様では、リプログラミングは、RNA、タンパク質、又は小分子を体細胞集団に導入することを含む。
本明細書で使用される場合、特定の成分に関する「本質的に含まない」は、本明細書では、特定の成分が組成物に意図的に全く配合されておらず、及び/又は単に汚染物質として若しくは微量で存在するという意味で用いられる。従って、あらゆる意図しない組成物の汚染に起因する特定の成分の総量は、0.05%を遥かに下回り、好ましくは0.01%未満である。最も好ましいのは、特定の成分の量を標準的な分析方法で検出することができない組成物である。
A.体細胞の開始集団
本開示の実施形態は、iPSCにリプログラミングされる体細胞(例えば、赤血球又は皮膚細胞)の開始集団に関する。血液細胞集団には、末梢血単核細胞(PBMC)、全血又はその画分を含む混合集団、脾細胞、骨髄細胞、腫瘍浸潤リンパ球、白血球搬出法によって得られる細胞、生検組織、及びリンパ節、例えば、腫瘍から排出されるリンパ節が含まれ得る。適切なドナーには、免疫化ドナー、非免疫化(ナイーブ)ドナー、処置又は未処置ドナーが含まれる。「処置」ドナーは、1つ以上の生物学的修飾因子に曝露されたドナーである。「未処置」ドナーは、1つ以上の生物学的修飾因子に曝されていない。
ある実施形態では、体細胞の開始集団は、リプログラミング因子の導入によってiPS細胞にリプログラミングされる。iPS細胞の作製では、導入に用いられるリプログラミング因子が重要である。以下の因子又はその組み合わせを、本開示で明らかにされる方法で使用することができる。ある態様では、Sox及びOct(特にOct3/4)をコードする核酸は、リプログラミングベクターに含まれる。例えば、1つ以上のリプログラミングベクターは、Sox2、Oct4、Nanog、及び任意選択によるLin28をコードする発現カセット、又はSox2、Oct4、Klf4、及び任意選択によるc−Mycをコードする発現カセット、又はSox2、Oct4、及び任意選択によるEsrrbをコードする発現カセット、又はSox2、Oct4、Nanog、Lin28、Klf4、c−Myc、及び任意によるSV40ラージT抗原をコードする発現カセットを含み得る。これらのリプログラミング因子をコードする核酸は、同じ発現カセット、異なる発現カセット、同じリプログラミングベクター、又は異なるリプログラミングベクターに含めることができる。
本開示のある態様では、リプログラミング因子は、1つ以上のベクター、例えば、組み込みベクター又はエピソームベクターに含まれる発現カセットから発現される。さらなる態様では、リプログラミングタンパク質は、タンパク質導入によって体細胞に直接導入することができる。
ウイルスベクターは、本開示のある態様で提供することができる。組換えウイルスベクターの作製では、非必須遺伝子は、典型的には、異種(又は非天然)タンパク質の遺伝子又はコード配列で置換される。ウイルスベクターは、ウイルス配列を利用して核酸及び場合によりタンパク質を細胞に導入するある種の発現構築物である。受容体媒介性エンドサイトーシスによって細胞に感染する又は細胞に侵入し、宿主細胞のゲノムに組み込まれてウイルス遺伝子を安定且つ効率的に発現させるあるウイルスの能力により、このようなあるウイルスは、外来核酸を細胞(例えば、哺乳動物細胞)に移入するための魅力的な候補となる。本開示のある態様の核酸を送達するために使用することができるウイルスベクターの非限定的な例を以下に記載する。
プラスミド又はリポソームベースの染色体外(即ち、エピソーム)ベクターの使用も本開示のある態様で提供することができる。このようなエピソームベクターは、例えば、oriPベースのベクター、及び/又はEBNA−1の誘導体をコードするベクターを含み得る。これらのベクターにより、DNAの大きい断片を細胞に導入し、染色体外で維持し、細胞周期ごとに1回複製し、効率的に娘細胞に分裂させることができ、免疫応答を実質的に誘発しない。
ある態様では、プログラミング因子の送達は、トランスポゾン−トランスポザーゼ系を使用することができる。例えば、トランスポゾン−トランスポザーゼ系は、周知のSleeping Beauty、Frog Princeトランスポゾン−トランスポザーゼ系(後者の説明については、例えば、欧州特許第1507865号明細書を参照されたい)、又はTTAA特異的トランスポゾンPiggyBac系であり得る。
本開示に有用なリプログラミングベクターに含まれる発現カセットは、好ましくは、(5’から3’の方向に)タンパク質コード配列、介在配列を含むスプライスシグナル、及び転写終結/ポリアデニル化配列に機能的に連結された真核生物転写プロモーターを含む。
本明細書で提供される発現構築物は、プログラミング遺伝子の発現を駆動するためのプロモーターを含む。プロモーターは、一般に、RNA合成の開始部位の位置を定めるように作用する配列を含む。最もよく知られているこの例は、TATAボックスであるが、TATAボックスが欠損した一部のプロモーター、例えば、哺乳動物の末端デオキシヌクレオチジルトランスフェラーゼ遺伝子のプロモーター及びSV40後期遺伝子のプロモーターなどでは、開始部位自体を覆う別々の要素が開始部位を固定するのに役立つ。追加的なプロモーター要素は、転写開始の頻度を調節する。典型的には、これらは、開始部位の30〜110bp上流の領域に位置するが、多数のプロモーターが開始部位の下流にも機能要素を含むように示されている。コード配列をプロモーターの制御下に置くために、選択されたプロモーターの「下流」(即ち、3’側)の転写リーディングフレームの転写開始部位の5’末端を配置する。「上流」プロモーターは、DNAの転写を刺激し、コードされたRNAの発現を促進する。
特定の開始シグナルは、コード配列の効率的な翻訳のために本開示で提供される発現構築物で使用することもできる。これらのシグナルには、ATG開始コドン又は隣接配列が含まれる。ATG開始コドンを含む外因性の翻訳調節シグナルを提供する必要があり得る。当業者であれば、容易にこれを決定して必要なシグナルを提供することができるであろう。開始コドンは、インサート全体の翻訳を確実にするために、所望のコード配列のリーディングフレームを有する「インフレーム」でなければならないことは周知である。外因性の翻訳調節シグナル及び開始コドンは、天然又は合成のいずれかであり得る。発現の効率は、適切な転写エンハンサー要素を含めることによって高めることができる。
宿主細胞内でベクターを増殖させるために、ベクターは、1つ以上の複製部位の起点(多くの場合に「ori」と呼ばれる)、例えば、上述したEBVのoriPに対応する核酸配列、又は複製が開始される特定の核酸配列である、プログラミングにおいて類似若しくは高い機能を有する遺伝子操作されたoriPを含み得る。別法では、上記のような他の染色体外複製ウイルスの複製起点又は自律複製配列(ARS)を使用することができる。
ある実施形態では、核酸構築物を含む細胞は、発現ベクター中にマーカーを含めることによってin vitro又はin vivoで同定することができる。このようなマーカーは、識別可能な変化を細胞に与えて発現ベクターを含む細胞の容易な同定を可能にするはずである。一般に、選択マーカーは、選択を可能にする特性を与えるマーカーである。陽性選択マーカーは、マーカーの存在がその選択を可能にするマーカーであり、陰性選択マーカーは、その存在がその選択を妨げるマーカーである。陽性選択マーカーの例は、薬剤耐性マーカーである。
A.HPCの産生
本開示の実施形態は、体細胞由来PSCのHPCへの分化に関する。体細胞由来PSCは、参照により本明細書に組み入れられる米国特許第8,372,642号明細書に記載されているような当技術分野で公知の方法によってHPCに分化させることができる。例えば、BMP4、VEGF、Flt3リガンド、IL−3、及びGM−CSFの組み合わせを使用して造血分化を促進することができる。ある実施形態では、分化のためのPSCを調製するための第1の培地、並びにBMP4、VEGF、及びFGFを含む第2の培地への細胞培養物の連続的な曝露、続くFlt3リガンド、SCF、TPO、IL−3、及びIL−6を含む第3の培地中での培養により、多能性細胞を造血前駆細胞及び造血細胞に分化させることができる。第2の規定された培地は、ヘパリンも含み得る。さらに、BMP4及びVEGFを含有する培地にFGF−2(50ng/ml)を含めることにより、多能性細胞から造血前駆細胞を発生させる効率を高めることができる。加えて、第1の規定された培地にグリコーゲンシンターゼキナーゼ3(GSK3)阻害剤(例えば、CHIR99021、BIO、及びSB−216763)を含めることにより、HPCの発生をさらに促進することができる。
次いで、体細胞由来PSCから分化したHPCを、T細胞、NK細胞、及びT/NK細胞を含むリンパ系統細胞にさらに分化させることができる。一部の態様では、分化中のHPCは、リンパ細胞への分化のために7日目〜12日目、例えば、8日目〜11日目に単離される。この段階でのHPCは、CD34及びCD43の発現によって同定することができる。加えて、リンパ系分化能を有するHPCは、低レベルでCD144、DLL4、CD7及びCD235を発現することができ、この発現は11日目に減少し、これらのマーカーのある閾値レベルの発現がDLL4の存在下での細胞をリンパ系分化に向かわせるために必要であることを意味する。
体細胞由来PSCから産生されるHPCは、例えば、骨髄系分化培地を用いて骨髄細胞に分化させることができる。骨髄系分化培地は、無血清培地又は規定された培地であり得、この培地は、SCF、EPO、TPO、インスリン、デキサメタゾン、又はヒドロコルチゾン、及び/又はトランスフェリンを含み得る。骨髄細胞は、樹状細胞、マクロファージ、好中球、単球、好塩基球、好中球、肥満細胞、及び/又は好酸球であり得る。特定の態様では、骨髄細胞は樹状細胞である。例示的な骨髄系分化培地及び増殖培地は、例えば、表4〜6に記載されている。
ある実施形態では、実質的な低酸素条件を使用してHPCの骨髄又はリンパ系統への分化を促進することができる。ある実施形態では、約20%未満、約19%未満、約18%未満、約17%未満、約16%未満、約15%未満、約14%未満、約13%未満、約12%未満、約11%未満、約10%%未満、約9%未満、約8%未満、約7%未満、約6%未満、約5%未満、約5%、約4%、約3%、約2%、又は約1%の大気酸素含有量を使用して造血前駆細胞への分化を促進することができる。ある実施形態では、低酸素雰囲気は約5%の酸素ガスを含む。
ある態様の方法及び組成物によって提供される免疫細胞は、様々な適用で使用することができる。これらには、限定されるものではないが、少数の例を挙げると、in vivoでの細胞の移植又は注入;in vitroでの細胞毒性化合物、発癌物質、変異誘発物質成長/調節因子、医薬化合物などのスクリーニング;血液疾患及び傷害の機構の解明;薬物及び/又は成長因子が作用する機構の研究;患者の癌の診断及び監視;遺伝子治療;及び生物学的に活性な製品の生産が含まれる。
本開示の免疫細胞を使用して、本明細書で提供されるリンパ細胞の特性に影響を及ぼす因子(例えば、溶媒、小分子薬物、ペプチド、及びポリヌクレオチド)又は環境条件(例えば、培養条件又は操作)をスクリーニングすることができる。
本開示は、恐らく血液疾患又は障害又は傷害によりそのような治療を必要とする対象の機能をある程度回復させるための、本明細書で提供される免疫細胞の使用も提供する。例えば、本明細書に開示される方法によって誘導される免疫細胞を使用して、血液疾患及び障害、例えば、異常ヘモグロビン症、貧血などを処置することができる。このような細胞は、細胞抑制療法、例えば、化学療法によって引き起こされる造血細胞欠乏の処置に有用であり得る。
製造目的、分配目的、及び使用の目的で、本開示の免疫細胞が、典型的には、等張性賦形剤又は培地中の細胞培養物又は懸濁物の形態で供給され、任意選択により輸送又は貯蔵を容易にするために凍結される。
iPS細胞の産生のために、血液試料からT細胞を単離してiPSCへのレトロウイルスリプログラミング前に活性化させた。最初に末梢血単核細胞(PBMC)を、新しく調製したAIM−V培地+pen/strep/グルタミン(AIV−V/ps/s/g培地)(Invitrogen)+300IU/ml rhIL2(Peprotech)及び10ng/ml可溶性抗CD3抗体(OKT3クローン、eBiosciences)及び抗CD28抗体で増殖させた。活性化の数日後、CEDEX細胞カウントを用いて指数増殖を確認した。培養の3日後、細胞をT細胞表現型についてアッセイし、次いでリプログラミング因子で形質導入した。
実施例1のTiPSCを含む様々なエピソーム及びウイルスによりリプログラミングされたiPSC(表1)にHPCの産生のために3D分化プロトコルを行った(図1)。最初に、iPSCを、Essential 8(E8)培地中のMatrigel(商標)又はビトロネクチン被覆超低付着(ULA)プレート上において、フィーダーフリー条件下で5〜10回継代するために低酸素条件に馴化させた。凝集体は、5uMブレビスタチンが添加された無血清の規定された(SFD)培地の存在下において、25万〜50万細胞/mlの密度でサブコンフルエントなiPSCから作製した。このプロセスは、75% IMDM(Invitrogen 12200−069)(グルタミン及び25mM HEPES+P/Sを含む)、25% Hams F12(Mediatech 10−080−CV)、0.5% N2添加剤(Invitrogen 17502−048)、レチノイン酸を含まない1% B27添加剤(Invitrogen 12587−010)、0.05% BSA、50μg/mlアスコルビン酸、及び4.5×10-4Mモノチオグリセロールを含むSFD基礎培地中の超低付着(ULA)プレート又はスピーナ−フラスコで行った。
1C T細胞由来iPSC(TiPSC、レトロウイルスリプログラミングによって誘導)を凝集体懸濁(3D)培養によってCD34+造血前駆細胞に分化させた。1C細胞をEssential 8(E8)培地のMatrigel(商標)又はビトロネクチン被覆6ウェルプレート上においてフィーダーフリー条件下で維持した。凝集体は、50ng/ml FGF2、50ng/ml VEGF、2μM CHIR99021(GSK−3阻害剤)、及び10μMブレビスタチン(ミオシン−II阻害剤)が添加されたEssential 3(E3)培地(E8培地の8成分のうちの3成分のみ:DMEM/F12基礎培地、アスコルビン酸2−リン酸マグネシウム、及び亜セレン酸ナトリウムを含む)において、50万〜100万細胞/mlの密度でサブコンフルエント(80%未満のコンフルエンス)な1C細胞から形成した。凝集体形成は、ロッカープラットフォーム上での15rpmでの連続撹拌下、超低付着(ULA)フラスコ内での24時間の培養中に生じた(その後の培養工程を全て含む)。
実施例2及び実施例3のHPCのリンパ系分化のためのパラメーターを決定するために、細胞株をT細胞分化及びNK細胞分化の培養条件に曝露した。最初に、いくつかの変数を間質依存プロトコルでT細胞分化について試験した。12日目、異なる細胞株由来のHPCを、OP9骨髄間質細胞及びMS5マウス骨髄間質細胞を含む間質系でのT細胞分化能について試験した。細胞を、20% FBS、10ng/mL SCF、5ng/mL Flt−3、及び5ng/mL IL−7を含むαMEM培地で培養した。細胞を週に3回、培地を半分交換して新鮮にした。T細胞の存在についての細胞の分析により、骨髄細胞が発生する傾向にあり、CD3+細胞の存在は検出できなかった。加えて、間質共培養は、低酸素条件下ではそれほど機能しなかった。
実施例2及び3のCD34+ HPCをヒト樹状細胞(DC)の比較的純粋な集団の形成のために骨髄系分化させた。細胞を全プロセスにわたって低付着組織培養プレート又はフラスコ上で培養した。細胞を50ng/mL Flt−3リガンド(Flt−3L)、50ng/mL幹細胞因子(SCF)、50ng/mLトロンボポエチン(TPO)、50ng/mLインターロイキン−3(IL−3)、及び50ng/mLインターロイキン−6(IL−6)を含む無血清培地において、0.5〜1×106細胞/mLの密度で再懸濁した。
CD34+リンパ造血前駆細胞へのPSCの分化:1C T細胞由来iPSC(TiPSC、レトロウイルスリプログラミングにより誘導)を凝集体懸濁(3D)培養によってCD34+造血前駆細胞に分化させた。1C細胞をEssential 8(E8)培地において、Matrigel(商標)又はビトロネクチンで被覆された6ウェルプレート上においてフィーダーフリー条件下で維持した。凝集体は、50ng/ml FGF2、50ng/ml VEGF、2μM CHIR99021(GSK−3阻害薬)、及び10μMブレビスタチン(ミオシン−II阻害薬)が添加されたEssential 3(E3)培地(E8培地の8つの成分のうちの3つの成分:DMEM/F12基礎培地、アスコルビン酸2−リン酸マグネシウム、及び亜セレン酸ナトリウムのみを含む)において、50万〜100万細胞/mlの密度でサブコンフルエントな1C細胞(80%未満のコンフルエンス)で形成した。凝集体の形成は、15rpmでのロッカープラットフォーム上での連続撹拌下の、超低付着(ULA)フラスコ内での24時間の培養中で行った(その後の培養工程を全て含む)。
01279.107.3902 MeCP2ノックアウト細胞及びTiPSCs1E細胞にHPCの産生のための2D分化プロトコルを行った(図16)。最初に、iPSCを、Essential 8(E8)培地でMatrigel(商標)又はビトロネクチンが被覆された、フィーダーフリー条件下で5〜10回継代して低酸素条件に馴化させた。iPSCを個別化し、5μMブレビスタチンが添加された無血清の規定された(SFD)培地の存在下において、25000/cm2の密度でPureCoat Amineで被覆された6ウェルプレート(Corning Inc.)にプレーティングした。SFD基礎培地は、75% IMDM(Invitrogen 12200−069)(グルタミン及び25mM HEPES+P/Sを含む)、25% Hams F12(Mediatech 10−080−CV)、0.5% N2添加剤(Invitrogen 17502−048)、レチノイン酸を含まない1% B27添加剤(Invitrogen 12587−010)、0.05% BSA、50μg/mlアスコルビン酸、並びに50ng/mlのBMP−4、VEGF、及びbFGFが添加された4.5×10−4Mモノチオグリセロールを含んでいた。
造血分化プロセスにおけるMeCP2の役割を決定するために、MeCP2ノックアウトiPSC細胞株を作製した。雄野生型(WT)01279 iPSC細胞株をエンジニアリングしてMeCP2をノックアウトし、MyCell(登録商標)01279.107.3902細胞株を作製した。TALヌクレアーゼを用いて、MeCP2 TALENのトランスフェクションにより、一連の停止コドンをMeCP2のメチルCpG結合ドメイン(図17B)の前に挿入し、及び停止コドンを含むドナープラスミドの挿入後、LoxPに隣接させてPGKp−Puromycin−SV40pAを逆向きに挿入した。0.1279 iPSCを、MeCP2 TALENS及び野生型EBNA1を発現するドナープラスミドp1553でトランスフェクトした。
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Claims (85)
- 免疫細胞を産生する方法であって、
(a)多能性幹細胞(PSC)を得ること(ここで、PSCは体細胞集団からリプログラミングされる);
(b)前記PSCを造血前駆細胞(HPC)に分化させること;及び
(c)免疫細胞分化を促進する条件下で前記HPCを培養し、それにより免疫細胞を産生すること
を含む、方法。 - 前記PSCが誘導多能性幹細胞(iPSC)である、請求項1に記載の方法。
- 前記PSCが胚性幹細胞(ECS)である、請求項1に記載の方法。
- 前記免疫細胞がリンパ細胞である、請求項1に記載の方法。
- 前記リンパ細胞がT細胞、B細胞、及び/又はNK細胞である、請求項4に記載の方法。
- 前記免疫細胞が骨髄細胞である、請求項1に記載の方法。
- 前記骨髄細胞が樹状細胞である、請求項6に記載の方法。
- 前記体細胞集団が血液細胞集団又は皮膚細胞集団である、請求項1に記載の方法。
- 前記血液細胞集団がT細胞、B細胞、及び/又はNK細胞を含む、請求項8に記載の方法。
- 前記血液細胞集団が前駆血液細胞、末梢血単核細胞、又はリンパ芽球様細胞としてさらに定義される、請求項8に記載の方法。
- 前記体細胞集団が哺乳動物である、請求項1に記載の方法。
- 前記体細胞集団がヒトである、請求項1に記載の方法。
- 前記血液細胞集団が末梢血、臍帯血、又はリンパ系組織から単離される、請求項8に記載の方法。
- 前記リンパ系組織が骨髄、リンパ節、又は胎児肝臓を含む、請求項13に記載の方法。
- 前記血液細胞集団がT細胞を含む、請求項8に記載の方法。
- 前記T細胞が抗CD3抗体及び/又は抗CD28抗体の存在下で培養される、請求項15に記載の方法。
- 前記T細胞がCD4+又はCD8+T細胞である、請求項15に記載の方法。
- 前記T細胞がTヘルパー1(TH1)細胞、Tヘルパー2(TH2)細胞、TH17細胞、細胞傷害性T細胞、調節性T細胞、ナチュラルキラーT細胞、ナイーブT細胞、記憶T細胞、又はγδT細胞である、請求項15に記載の方法。
- 前記リプログラミングが、リプログラミング因子を前記体細胞集団に導入することを含む、請求項1に記載の方法。
- 前記リプログラミングが、RNA、タンパク質、又は低分子を前記体細胞集団に導入することを含む、請求項1に記載の方法。
- 前記体細胞集団が血液細胞又は皮膚細胞である、請求項19に記載の方法。
- 前記リプログラミング因子が1つ以上の発現カセットによってコードされる、請求項19に記載の方法。
- 前記リプログラミング因子が、Sox2、Oct4、cMyc、Klf4、Nanog、SV40ラージT抗原、及びLin28からなる群から選択される2つ以上の遺伝子を含む、請求項19に記載の方法。
- 前記リプログラミング因子が、Sox2、Oct4、cMyc、Klf4、Nanog、SV40ラージT抗原、及びLin28からなる群から選択される遺伝子の3つ、4つ、5つ、又は6つを含む、請求項19に記載の方法。
- 前記1つ以上の発現カセットが、ウイルスベクター、エピソームベクター、及びトランスポゾンからなる群から選択されるリプログラミングベクターに含まれる、請求項22に記載の方法。
- 前記ウイルスベクターがレトロウイルスベクターとしてさらに定義される、請求項25に記載の方法。
- 前記エピソームベクターがエプスタイン−バーウイルス(EBV)ベースのエピソームベクターとしてさらに定義される、請求項25に記載の方法。
- 前記リプログラミングが、規定されたフィーダーフリー条件下で前記細胞を培養することを含む、請求項1に記載の方法。
- 前記PSCが、組み込まれた外因性ウイルス要素を本質的に含まない、請求項1に記載の方法。
- 前記血液細胞集団が、外部から適用されるG−CSFで動員されていない、請求項8に記載の方法。
- 前記HPCが1つのHPC当たり少なくとも20の免疫細胞に分化する、請求項1に記載の方法。
- 前記HPCが1つのHPC当たり少なくとも50の免疫細胞に分化する、請求項1に記載の方法。
- 前記HPCが1つのHSC当たり少なくとも100の免疫細胞に分化する、請求項1に記載の方法。
- 前記PSCが1つのPSC当たり少なくとも50の免疫細胞に分化する、請求項1に記載の方法。
- 前記PSCをHPCに分化させることが、
(a)複数の実質的に未分化の多能性細胞を、少なくとも1つの成長因子を含む第1の規定された培地で培養又は維持すること;
(b)IL−3、Flt3リガンド、及びGM−CSFを含まない又は本質的に含まない第2の規定された培地で前記細胞をインキュベートすること;
(c)複数の前記細胞における分化を増大又は促進するのに十分なBMP4、FGF2、及びVEGFを含む第3の規定された培地で前記細胞を培養すること;及び
(d)複数の前記細胞における分化を増大又は促進するのに十分なIL−3及びFlt3リガンドを含む第4の規定された培地で前記細胞を培養すること
の一連の工程を含み、複数の前記多能性細胞がHPCに分化される、請求項1に記載の方法。 - 前記第2の規定された培地がブレビスタチン及び/又はRock阻害剤を含む、請求項35に記載の方法。
- 前記第2の規定された培地がGSK3阻害剤をさらに含む、請求項36に記載の方法。
- 前記GSK3阻害剤がCHIR99021である、請求項37に記載の方法。
- 前記第2の規定された培地がBMP4、VEGF、及びFGF2をさらに含む、請求項35に記載の方法。
- 前記細胞が工程(b)の前に個別化される、請求項39に記載の方法。
- 工程(b)〜(d)がアミン培養プレートを用いて行われる、請求項40に記載の方法。
- 前記第2の規定された培地がVEGF及びFGF2をさらに含む、請求項36に記載の方法。
- 前記第4の規定された培地が、IL−3、IL−6、SCF、TPO、及びBMP4からなる群から選択されるサイトカインの1つ以上をさらに含む、請求項35に記載の方法。
- 前記第4の規定された培地がヘパリンを含む、請求項35に記載の方法。
- 酸素が25%未満の大気圧で前記細胞を培養する工程を含む、請求項35に記載の方法。
- 酸素が5%未満の大気圧で前記細胞を培養する工程を含む、請求項35に記載の方法。
- 複数の前記多能性細胞が胚様体(EB)を形成する、請求項35に記載の方法。
- 前記HPCがCD34を発現する、請求項35に記載の方法。
- 前記HPCが、CD43、CD34、CD31、CD41、CD235、及びCD45からなる群からの少なくとも2つのマーカーを発現する、請求項35に記載の方法。
- 免疫細胞分化を促進する条件が、リンパ系分化を促進する条件としてさらに定義される、請求項1に記載の方法。
- CD34及びCD43を発現するHPCが、リンパ系分化を促進する条件下で培養される、請求項50に記載の方法。
- リンパ系分化を促進するために前記細胞を培養することが、
(i)規定された培地において、マトリックス及びNotchリガンドで被覆された表面上でHPCを培養すること(ここで、前記HPCは、CD34、CD43、CD7、DLL4、CD144、及びCD235からなる群から選択される細胞表面マーカーの1つ以上を発現する);及び
(ii)1つ以上のサイトカインの存在下で培養物を維持し、それによりリンパ細胞を産生すること、
を含む、請求項1に記載の方法。 - 前記マトリックスが細胞外マトリックスタンパク質である、請求項52に記載の方法。
- 前記HPCがCD144、CD34、CD45、及び/又はCD7を発現する、請求項52に記載の方法。
- 工程(i)が、1つ以上の細胞表面マーカーを発現する前記HPCを単離することをさらに含む、請求項52に記載の方法。
- 単離することが磁気活性化細胞選別(MACS)を含む、請求項55に記載の方法。
- 前記細胞が、酸素が5%未満の大気圧で培養される、請求項52に記載の方法。
- 前記細胞が、酸素が5%の大気圧で培養される、請求項52に記載の方法。
- 前記規定された培地がアスコルビン酸及び/又はニコチンアミドを含む、請求項52に記載の方法。
- 前記アスコルビン酸が50μM〜1mMの濃度で存在する、請求項59に記載の方法。
- 前記アスコルビン酸が90μM〜100μMの濃度で存在する、請求項59に記載の方法。
- 前記ニコチンアミドが0.1mM〜5mMの濃度で存在する、請求項59に記載の方法。
- 前記マトリックスがレトロネクチン、コラーゲン、ラミニン、又はフィブロネクチンである、請求項52に記載の方法。
- 前記マトリクスがレトロネクチンである、請求項52に記載の方法。
- 前記NotchリガンドがDLL4である、請求項52に記載の方法。
- 前記DLL4がDLL4:Fcキメラタンパク質である、請求項63に記載の方法。
- 前記1つ以上のサイトカインが、SCF、TPO、IL−7、及びFlt−3からなる群から選択される、請求項52に記載の方法。
- 工程(ii)が1〜6週間である、請求項52に記載の方法。
- 工程(ii)が2〜4週間である、請求項52に記載の方法。
- 前記リンパ細胞が、CD8、CD7、CD45、CD5、CD4、及びCD3からなる群から選択される前記マーカーの1つ以上を発現する、請求項52に記載の方法。
- 前記リンパ細胞の5%超が前記マーカーの少なくとも2つに対して陽性である、請求項70に記載の方法。
- 前記リンパ細胞の10%超が前記マーカーの少なくとも2つに対して陽性である、請求項70に記載の方法。
- 免疫細胞分化を促進する条件が、骨髄系分化を促進する条件としてさらに定義される、請求項1に記載の方法。
- 骨髄系分化を促進する条件下で前記HPCを培養することが、
(i)TPO、SCF、及びFlt3リガンドを含む第1の規定された培地で前記HPCを培養し、それにより骨髄細胞集団を産生すること;及び
(ii)TPO、SCF、及びFlt3リガンドを本質的に含まない第2の規定された培地で前記細胞をインキュベートし、それにより骨髄細胞の濃縮集団を産生すること、
を含む、請求項73に記載の方法。 - 前記第1の規定された培地がIL−6及びIL−3をさらに含む、請求項74に記載の方法。
- 前記第2の規定された培地がGM−CSFを含む、請求項74に記載の方法。
- 工程(i)で産生された前記骨髄細胞集団の少なくとも50%がCD45、CD43、及びCD31に対して陽性である、請求項74に記載の方法。
- CD45、CD43、及びCD31に対して陽性の骨髄細胞集団がCD34の発現を本質的に有していない、請求項77に記載の方法。
- 前記骨髄細胞の濃縮集団の少なくとも80%がCD43+、CD45+、CD31+、及びCD34-である、請求項74に記載の方法。
- 工程(ii)が5〜10日間である、請求項74に記載の方法。
- 前記骨髄細胞の濃縮集団を樹状細胞に分化させることをさらに含む、請求項74に記載の方法。
- 前記骨髄細胞の濃縮集団を樹状細胞に分化させることが、GM−CSF、IL−4、及びTNFαを含む規定された培地で前記骨髄細胞の濃縮集団を培養し、それにより樹状細胞を産生することを含む、請求項81に記載の方法。
- 前記規定された培地がリポタンパク質をさらに含む、請求項82に記載の方法。
- 前記樹状細胞が、CD209、CD1a、HLA−DR、CD11c、CD14、CD83、及びCD86からなる群から選択されるマーカーの1つ以上を発現する、請求項82に記載の方法。
- 前記樹状細胞がCD12の発現を本質的に有していない、請求項82に記載の方法。
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