JPWO2008143047A1 - 樹状細胞の製造方法 - Google Patents
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Abstract
Description
Steinman, R. M., 1991, Ann. Rev. Immunol. 9: 271-296 Banchereau, J.B. および R.M. Steinman, 1998, Nature 392: 245-252 Shibata, S. et al., J. Immunol, 2006 177: 3564-3576 Yoneyama, Y. et al., Biochem. Biophys. Res. Commun., 2007, 355:129-135
〔1〕樹状細胞を製造する方法であって、樹状細胞前駆細胞を複数のサイトカインの存在下で培養する工程を含む方法。
〔2〕複数のサイトカインが、顆粒球/マクロファージコロニー刺激因子(GM-CSF)および幹細胞因子(SCF)である、〔1〕に記載の方法。
〔3〕樹状細胞前駆細胞は、ヒト由来の細胞である、〔1〕または〔2〕に記載の方法。
〔4〕該工程が、樹状細胞前駆細胞をGM-CSF 1 ng/ml以上、およびSCF 0.5 ng/ml以上の存在下で培養する工程である、〔2〕または〔3〕に記載の方法。
〔5〕該工程が、樹状細胞前駆細胞をGM-CSF 10 ng/ml以上、およびSCF 5 ng/ml以上の存在下で培養する工程である、〔4〕に記載の方法。
〔6〕該工程が、GM-CSF 1 ng/mlから100 ng/ml 、およびSCF 0.5 ng/mlから50 ng/mlの存在下で培養する工程である、〔4〕に記載の方法。
〔7〕該工程が、樹状細胞前駆細胞をGM-CSF 10 ng/mlから100 ng/ml 、およびSCF 5 ng/mlから50 ng/mlの存在下で培養する工程である、〔5〕または〔6〕に記載の方法。
等に関する。
なお上記の各項において、同一の項を引用する各項に記載の発明の2つまたはそれ以上を任意に組み合わせた発明は、それらに引用される上位の項に記載の発明において、既に意図されている。また、本明細書に記載した任意の発明要素およびその任意の組み合わせは、本明細書において意図されている。また、それらの発明において、本明細書に記載の任意の要素またはその任意の組み合わせを除外した発明も、本明細書に意図されている。また本明細書は、明細書中に例えば好ましいとしてある特定の態様を記載した場合、それを開示するのみならず、その態様を含むより上位の本明細書に開示された発明から、その態様を除外した発明も開示するものである。
1.E+04、1e4、または1.00E+04:1.0×104(個)
1.E+05または1.00E+05:1.0×105(個)
1.E+06または1.00E+06:1.0×106(個)
1.E+07または1.00E+07:1.0×107(個)
1.E+08または1.00E+08:1.0×108(個)
1.E+09または1.00E+09:1.0×109(個)
1.E+10または1.00E+10:1.0×1010(個)
1.E+11または1.00E+11:1.0×1011(個)
1.E+12または1.00E+12:1.0×1012(個)
さらに好ましくは、FLT-3L、SCF、IL-3、およびIL-6のすべてを添加した培地の存在下で培養した工程の後で、(i) GM-CSFおよびIL-4、または (ii) GM-CSFおよびSCFの存在下で培養する工程をさらに含むことが好ましい。DC前駆細胞を効率よくDCへ分化する上で有効である。すなわち、患者から採取したDCが少なくても、治療効果を得るのに十分な細胞数のDCを効率よく調製することが可能となる。
CD80は約60 kDの膜貫通型糖蛋白であり Ig supergene familyの一員である。CD80はT細胞で発現するCD28およびCD152 (CTLA-4) のリガンドである(Schlossman, S. et al., eds., 1995, Leucocyte Typing V: White Cell Differentiation Antigens. Oxford University Press, New York; Schwarts, R.H., 1992, Cell 71: 1065; Azuma, M. et al., 1993, J. Exp. Med. 177: 845; Koulova, L. et al., 1991, J. Exp. Med. 173: 759; Freeman, G.J. et al., 1998, J. Immunol. 161: 2708; Behrens, L. et al., 1998, J. Immunol., 161(11):5943; Guesdon, J.-L. et al., 1979, J. Histochem. Cytochem. 27: 1131-1139)。
CD86 (B70/B7-2) は約75 kDの細胞表面蛋白質でCD28およびCTLA-4の第2のリガンドであり初期免疫応答におけるT細胞の副刺激に重要な役割を持つ(Azuma M. et al., 1993, Nature 366: 76; Nozawa Y. et al., 1993, J. Pathology 169: 309; Engle, P. et al. 1994., Blood 84: 1402; Engel, P. et al., CD86 Workshop Report. In: Leukocyte Typing V. Schlossman, S.F. et al. eds., 1994, Oxford University Press; Yang, X.F. et al., 1994, Upregulation of CD86 antigen on TPAstimulated U937 cells, 1994, (abstract). American Society of Hematology, Nashville, TN; Guesdon, J.-L.et al., 1979, J. Histochem. Cytochem. 27: 1131-1139)。
例えば病原体由来の抗原としては、A型肝炎ウイルス、B型肝炎ウイルス、C型肝炎ウイルス、デルタ型肝炎ウイルス、乳頭腫ウイルス抗原、単純ヘルペスウイルス(HSV)、水痘−帯状疱疹ウイルス(VZV)、エプスタイン−バーウイルス、サイトメガロウイルス(CMV)、HIV、およびマラリアなどが有する蛋白質またはその部分ペプチドが挙げられる(G.L. Mandell et al. (Ed.) Hinman et al., Principles and Practice of Infectious Diseases,3rd Ed., Churchill Livingstone Inc., NY, pp. 2320-2333)。これらの抗原を提示するDCを、感染症に対して予防的および治療的に用いることができる。具体的には、例えばインフルエンザにおいては、強毒株H5N1型等のエンベロープ、日本脳炎においては、例えば日本脳炎ウイルスのエンベロープ蛋白質(Vaccine, vol. 17, No. 15-16, 1869-1882 (1999))、エイズにおいては、例えばHIV gagまたは SIV gag 蛋白質(J. Immunology (2000) vol. 164, 4968-4978)、HIVエンベロープ蛋白質、Nef蛋白質、その他のウイルス蛋白質などが挙げられる。コレラにおいては、例えばコレラ毒素のBサブユニット(CTB)(Arakawa T, et al., Nature Biotechnology (1998) 16(10): 934-8、Arakawa T, et al., Nature Biotechnology (1998) 16(3): 292-7)、狂犬病においては、例えば狂犬病ウイルスの糖タンパク(Lodmell DL et al., 1998, Nature Medicine 4(8):949-52)、子宮頚癌においては、ヒトパピローマウイルス6型のカプシドタンパクL1(J. Med. Virol, 60, 200-204 (2000))などが挙げられる。また、日本脳炎のJE-E抗原タンパク質(特開昭64-74982、特開平1-285498)、ヒト単純ヘルペスウイルスの gD2タンパク質(特開平5-252965)、C型肝炎ウイルス由来ポリペプチド(特開平5-192160)、仮性狂犬病ウイルス由来ポリペプチド(特表平7-502173)などを用いることもできる。例えば、これらの病原性微生物に感染した患者由来の細胞を解析して、抗原提示細胞(APC)において提示された抗原蛋白のエピトープを同定し、これを用いてもよい。HLA型を適宜選択することにより、所望のHLA型に対するエピトープを同定して用いることも好ましい。
FS36投与群:Flt-3リガンド(20ng/ml)、幹細胞因子(Stem cell factor;SCF)(10ng/ml)、IL-3(10ng/ml)、IL-6(10ng/ml) (FS36と略記) を含む10%FBS添加RPMI1640
GMIL-4投与群:GM-CSF(20ng/ml)、IL-4(20ng/ml)を含む10%FBS添加RPMI1640
GMSCF投与群:GM-CSF(20ng/ml)、SCF(10ng/ml)を含む10%FBS添加RPMI1640
GMIL-4投与群(1):組換えヒトGM-CSF(25 ng/ml)(Wako, Japan)、組換えヒトIL-4(50 ng/ml)(Wako,Japan)を含む10%FBS添加IMDM
GMIL-4投与群(2):組換えヒトGM-CSF(100 ng/ml)(Wako, Japan)、組換えヒトIL-4(50 ng/ml)(Wako,Japan)を含む10%FBS添加IMDM
GMSCF投与群:組換えヒトGM-CSF(100 ng/ml)(Wako, Japan)、組換えヒトSCF(50 ng/ml)(Wako, Japan)を含む10%FBS添加IMDM
0.1 GMSCF投与群:組換えヒトGM-CSF(10 ng/ml)(Wako, Japan)、組換えヒトSCF(5 ng/ml)(Wako, Japan)を含む10%FBS添加IMDM
0.01 GMSCF投与群:組換えヒトGM-CSF(1 ng/ml)(Wako, Japan)、組換えヒトSCF(0.5 ng/ml)(Wako, Japan)を含む10%FBS添加IMDM
(1)iDC処理:下記濃度の培地で2日間インキュベーションすることである。
10%FBS添加IMDM
(2)SeV/dF処理:下記濃度の培地で2日間インキュベーションすることである。
F遺伝子が欠失しているセンダイウイルス (moi=50) を含む10%FBS添加IMDM
(3)LPS処理:下記濃度の培地で2日間インキュベーションすることである。
LPS(1μg/ml) を含む10%FBS添加IMDM
尚本実験では以下のLPSを用いた。
SIGMA カタログNo. L7895-1MG(由来生物=Salmonella typhosa)
(4)Poly(I:C)処理:下記濃度の培地で2日間インキュベーションすることである。
Poly(I:C) (100μg/ml) を含む10%FBS添加IMDM
(5)CpG処理:下記濃度の培地で2日間インキュベーションすることである。
CpG (10μg/ml) を含む10%FBS添加IMDM
(6)R-848処理:下記濃度の培地で2日間インキュベーションすることである。
R-848 (1μg/ml) を含む10%FBS添加IMDM
(7)OK432処理:下記濃度の培地で2日間インキュベーションすることである。
OK432(0.5KE/ml)(中外製薬 日本標準商品分類番号874299)を含む10%FBS添加IMDM
先ず、マウス (C3H) の大腿骨・脛骨の骨髄からネガティブセレクションによって、造血前駆細胞を採取した (SpinSep mouse hematopoietic progenitor enrichment kit, StemCell technologies, Canada)。この前駆細胞を、FS36投与群、GMIL-4投与群、GMSCF投与群と3グループに分けて、培養した。培養は2.4×105 cellsから始め、3〜4日ごとに200万cells/ml 以下の濃度となるように継代を続け、6週間まで培養した。尚、その過程において、樹状細胞(DC)前駆細胞が調製される(図1)。その間、細胞数をカウントし、増殖速度を確認するとともに、抗CD11b-FITC、抗CD11c-PE、抗c-kit-PE、抗CD131-PEにて染色後、FACS解析を行い、上記前駆細胞の分化能を確認した(図3)。
FS36投与群においては、他の投与群に比べ、マウス造血前駆細胞は顕著に増幅され、FS36を用いた培養により21日間で約10,000 倍に増幅された(図1、図2)。尚、図2において(1)で示している写真は、グラフ中に(1)で示した時点に対応しており、マウス造血前駆細胞をGMIL-4投与群の条件で7日間培養して得られたDCの細胞形態を表した写真(顕微鏡で観察)であるが、実施例1、2、4、5、及びそれら実施例に係る図面で示す通常DC(normal DC)とは、この細胞、すなわちマウス造血前駆細胞をGMIL-4投与群の条件で7日間培養して得られたDCとする。尚通常DC(normal DC)においても、樹状突起が確認できる。更に、図2(3)は、図8で示しているFS36投与群の条件で四週間培養し、その後培地をGMIL-4投与群の条件にし、一週間培養して得られたDCの細胞形態を表した写真(顕微鏡で観察)を示しているが、樹状突起が確認できた。尚、図2においては、(3)で示している写真は、曲線(ii)に該当する過程を経て得られたものである。
マウス造血前駆細胞から得られたDCにF遺伝子欠失型センダイウイルス(SeV/dF)をmoi50で感染、あるいはLPS (1μg/ml) 添加後、さらに2日間培養を行い、CD80-PerCP、CD86-PerCP、MHC classII-PerCP、CD40-PerCPを用いてDCの表面マーカーの発現をFlow cytometer により分析した(図11、図12)。その結果、センダイウイルスの感染またはLPSによって、通常DC(normal DC)と同様に(図11(B))、FS36投与群の条件で三週間培養し、その後培地をGMIL-4投与群の条件にし、一週間培養したことにより製造したDCにおいては、co-stimuratory molecule であるCD80、CD86 の発現、MHC ClassIIの発現、接着分子(CD40)を発現していることが確認できた(図11(A))。
ヒト臍帯血CD34+ 細胞 (Cambrex社より購入) をGMSCF投与群又はGMIL-4投与群(1)の条件で35日間培養し、増幅と分化を行った。培養期間中、培養3日〜7日ごとにc-kit、CD11c、CD86の発現をFlow cytometer により分析した。1×105個のヒト臍帯血CD34+細胞をGM-CSFおよびSCFを添加した培地中で培養することにより、CD11c+細胞が徐々に増殖し、35日後には3.8×109個得ることが出来た。また32日目にLPSを加え、その3日後にCD11c-PE、CD86-PEでFACSを行った。その結果、上記実施例2の結果と同様に、LPSによってCD86の発現が増強されることが確認された(図16)。このように、マウス、ヒト共に、CD11c+ 細胞をサイトカインカクテルにより増幅させることができる(図13、14、および 15)。
FS36投与群の条件により培養し、その後培地をGMIL-4投与群の条件にし、更に1週間培養して得られたDCについて、サイトカイン産生量(図17)及び抗原取り込み能(図18)及びT細胞への増殖・活性化能の検討(図19)を行った。
マウス骨髄由来造血前駆細胞をFS36投与群の条件で三週間培養し、その後培地をGMIL-4投与群の条件にし、一週間培養したことにより得られたDCは、通常DC(normal DC)(マウス造血前駆細胞をGMIL-4投与群の条件で7日間培養して得たもの)と同様に、IL-12 及びIFN-βの産生が確認され(図17)、抗原取り込み能(図18)及び T細胞の増殖・活性化能(図19)を有していることが示された。
<サンプルの調製>
マウス造血前駆細胞由来のDC(1×105個)に腫瘍溶解液(3×105個腫瘍細胞が入っている)を加え、8時間インキュベーションした。その後、そのDCにF遺伝子欠失型センダイウイルス(SeV/dF)(moi50)を導入し、さらに2日間培養を行った。その培養後のDCをマウス(C3H、7週齢雌マウス)の尾静脈に投与した。投与2日後、LM8マウス骨肉腫細胞をマウスの尾静脈に投与した。LM8マウス骨肉腫細胞投与17日後、マウスを開胸し、肺への転移結節数を肉眼でカウントした(図20)。
FS36投与群の条件により培養し、その後更にGMIL-4投与群またはGMSCF投与群の条件にして1週間培養して得られたDC(図20の (3) 及び (4) 参照)の投与において、通常DC(normal DC)(マウス造血前駆細胞をGMIL-4投与群の条件で7日間培養して得たもの)と同様に、肺への癌転移が抑制されたのが確認できた。FS36投与群の条件により培養し、その後培地をGMIL-4投与群またはGMSCF投与群の条件にし、更に1週間培養して得られたDCが、癌治療に有用であることが示唆された。
<実験1>
ヒト臍帯血由来CD34+ 細胞 (Lonza社より購入)及び ヒトG-CSF処置末梢血由来CD34+ 細胞 (Lonza社より購入)を、GM-CSFおよびSCFを含む培地で、35日間培養し、増幅と分化を行った。
図21(A)、 (B)に示した結果より臍帯血由来CD34+ 細胞の培養及び ヒトG-CSF処置後末梢血由来CD34+ 細胞の培養によっても、GM-CSFおよびSCFを添加した培地中で培養することにより、大量に細胞を得ることができた(図21、図22)。またその細胞は、CD11c陽性(+)細胞の割合が高い(図21(C)、(D)、図22(B))。
また図記載のGMSCF投与群において、培養35日時点での細胞に上記LPS処理をしたものについては、樹状突起が確認できた(図23)。
実験1で示しているヒト臍帯血由来CD34+ 細胞の培養期間中、培養14日と培養35日の時点の細胞のうちCD11c陽性(+)細胞についてのCD11b、CD33、HLA-ABCの発現をFlow cytometer により分析した(図24)。成熟した樹状細胞であれば、CD11c陽性(+)でかつCD11b陽性(+)、CD11c陽性(+)でかつCD33陽性(+)、及びCD11c陽性(+)でかつHLA-ABC陽性(+)という傾向が示される。
また、ヒト臍帯血由来CD34+ 細胞の培養期間中、培養35日の時点の細胞について、LPS処理又はSeV/dF処理した場合における、ICAM-1、CD86、HLA-DR、CD40、CD80、及びCCR7の発現をFlow cytometer により分析した(図25)。成熟した樹状細胞であれば、LPS処理又はSeV/dF処理した場合において、処理していない場合(iDC処理)と比べ、ICAM-1、CD86、HLA-DR、CD40、CD80、及びCCR7の発現が亢進する傾向が示される(Nauta AJ., et al. Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells. J Immunol 177(4), 2080-2087 (2006))(Yoneyama, Y., et al. Development of immunostimulatory virotherapy using non-transmissible Sendai virus-activated dendritic cells. Biochem Biophys Res Commun 355, 129-135 (2007))。
図24で示している結果から(図面中の矢印を参照)、CD11c陽性(+)でかつCD11b陽性(+)、CD11c陽性(+)でかつCD33陽性(+)、及びCD11c陽性(+)でかつHLA-ABC陽性(+)という傾向が示された。
また、図25で示している結果から、LPS処理又はSeV/dF処理した場合において、処理していない場合(iDC処理)と比べ、ICAM-1、CD86、HLA-DR、CD40、CD80、及びCCR7の発現が亢進する傾向が示された。
よって、図24及び図25に示された結果から、GM-CSF及びSCFを含む培地で培養し増幅された細胞は、表面マーカの発現の傾向から、樹状細胞である可能性が示唆される。
ヒト臍帯血由来CD34+ 細胞の培養期間中、培養35日の時点の細胞について、ファゴサイトーシス(食作用)の能力を調べた(図26)。
細胞の食作用の能力が極めて低い4℃の条件と比べ、37℃の条件においては、細胞の食作用の能力が亢進していることが判明した(図26)。
そして、37℃の条件において、iDC処理と比べ、LPS処理をしたものにおいては、細胞の食作用の能力が低下していることが判明した。樹状細胞は成熟に伴い貪食能力が低下する事が知られていることから踏まえると(Yoneyama, Y., et al. Development of immunostimulatory virotherapy using non-transmissible Sendai virus-activated dendritic cells. Biochem Biophys Res Commun 355, 129-135 (2007))、本実験で用いている細胞(GM-CSFおよびSCFを含む培地で培養し増幅させた細胞)は、樹状細胞である可能性が示唆される。
ヒト臍帯血由来CD34+ 細胞の培養期間中、培養35日の時点の細胞について、サイトカイン産生能を調べた。実験においては、ベクトン・ディッキンソン アンド カンパニー(BD)社のHuman Inflammation Kit(カタログ番号:551811)を用いた(図27)。
LPSなどの刺激により、IL-6、TNF-α、IL-1βの産生能が高まった。GM-CSFおよびSCFを含む培地で培養し増幅させた細胞は、サイトカインを産生する能力があると考えられる(図27)。
リンパ球の増殖刺激能の検討を行った(図28)。ヒト臍帯血由来CD34+ 細胞からGMSCF培地での培養を通して得たDCをマイトマイシンC(MMC)で処理し、CD3+ T細胞と以下の割合で混合した。
混合群1について
MMC処理したDC数:CD3+ T細胞数=1:100
混合群2について
MMC処理したDC数:CD3+ T細胞数=1:10
上記混合した細胞を5日間培養した。なお、混合群2については、T細胞の増殖を測定した。
混合群2において、混合群1に比べて、LPS等の刺激による効果が高いことが示された(図28)。また上記DCが、T細胞の増殖・活性化能(図28)を有していることが示された。
図29及び図30に示しているデータより、効率よくDCを増幅させるためには、GM-CSF を1 ng/mlより高い濃度で、およびSCFを 0.5 ng/ml より高い濃度で用いることが好ましい。また、0.01GMSCF投与群の条件で培養しても、DCを増幅できることから、少ないサイトカイン量で効率よくDCを増幅することができることが示唆され、本発明の方法が、製造コストが抑えられるDC製造方法となることが期待できる。
Claims (6)
- 樹状細胞を製造する方法であって、樹状細胞前駆細胞を複数のサイトカインの存在下で培養する工程を含む方法。
- 複数のサイトカインが、顆粒球/マクロファージコロニー刺激因子(GM-CSF)および幹細胞因子(SCF)である、請求項1に記載の方法。
- 樹状細胞前駆細胞は、ヒト由来の細胞である、請求項1または2に記載の方法。
- 該工程が、樹状細胞前駆細胞を顆粒球/マクロファージコロニー刺激因子(GM-CSF)1 ng/ml以上、および幹細胞因子(SCF)0.5 ng/ml以上の存在下で培養する工程である、請求項2または3に記載の方法。
- 該工程が、樹状細胞前駆細胞を顆粒球/マクロファージコロニー刺激因子(GM-CSF)10 ng/ml以上、および幹細胞因子(SCF)5 ng/ml以上の存在下で培養する工程である、請求項4に記載の方法。
- 該工程が、樹状細胞前駆細胞を顆粒球/マクロファージコロニー刺激因子(GM-CSF)1 ng/mlから100 ng/ml 、および幹細胞因子(SCF)0.5 から50 ng/mlの存在下で培養する工程である、請求項4に記載の方法。
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JP (1) | JP5227317B2 (ja) |
KR (1) | KR101506751B1 (ja) |
CN (1) | CN101755045B (ja) |
CA (1) | CA2687534A1 (ja) |
WO (1) | WO2008143047A1 (ja) |
Families Citing this family (13)
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US20070269414A1 (en) * | 2003-11-04 | 2007-11-22 | Shinji Okano | Method for Producing Gene Transferred Denritic Cells |
AU2005257105A1 (en) * | 2004-06-24 | 2006-01-05 | Dnavec Research Inc. | Anticancer agent containing minus-strand RNA virus |
CN102307989B (zh) | 2008-11-14 | 2015-04-22 | 生物载体株式会社 | 用于产生树突细胞的方法 |
EP2456458B1 (en) * | 2009-07-24 | 2018-12-26 | Rhode Island Hospital | Dendritic cell vaccines for asparaginyl - beta - hydroxylase expressing tumors |
JP2011239701A (ja) * | 2010-05-14 | 2011-12-01 | Tella Inc | 樹状細胞の培養方法 |
CN102154199B (zh) * | 2011-01-29 | 2013-05-15 | 暨南大学 | 一种半成熟树突状细胞的体外制备方法 |
WO2013078059A1 (en) * | 2011-11-22 | 2013-05-30 | Trustees Of Tufts College | Small molecule enhancer for dendritic cell cancer vaccines |
SG11201406924UA (en) | 2012-04-26 | 2014-11-27 | Riken | New carbamate glycolipid and use thereof |
JP2014111631A (ja) * | 2014-01-31 | 2014-06-19 | Tella Inc | 樹状細胞の培養方法 |
WO2016185481A2 (en) | 2015-05-20 | 2016-11-24 | Yeda Research And Development Co. Ltd. | Method of targeting senescent cells |
JP7017008B2 (ja) * | 2015-10-15 | 2022-02-08 | 国立大学法人京都大学 | 多能性幹細胞からcd4陽性t細胞を製造する方法 |
JP6088633B2 (ja) * | 2015-12-24 | 2017-03-01 | 株式会社ガイアバイオメディシン | 樹状細胞の培養方法 |
JP6426767B2 (ja) * | 2017-02-01 | 2018-11-21 | 株式会社ガイアバイオメディシン | 樹状細胞の培養方法 |
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US5811297A (en) | 1996-03-07 | 1998-09-22 | Amba Biosciences, Llc | Immortalized hematopoietic cell lines, cell system thereof with stromal cells, in vitro, ex vivo and in vivo uses, & in vitro generation of dendritic cells and macrophages |
WO1998001538A1 (en) | 1996-07-10 | 1998-01-15 | Immunex Corporation | Method of activating dendritic cells |
CN1408850A (zh) * | 2001-09-18 | 2003-04-09 | 王虹 | 人血树突状细胞永生化技术 |
ATE446106T1 (de) | 2001-11-29 | 2009-11-15 | Dandrit Biotech As | Pharmazeutische zusammensetzung zur auslösung einer immunantwort bei einem menschen oder einem tier |
IL152904A0 (en) * | 2002-01-24 | 2003-06-24 | Gamida Cell Ltd | Utilization of retinoid and vitamin d receptor antagonists for expansion of renewable stem cell populations |
US20070269414A1 (en) * | 2003-11-04 | 2007-11-22 | Shinji Okano | Method for Producing Gene Transferred Denritic Cells |
AU2005257105A1 (en) | 2004-06-24 | 2006-01-05 | Dnavec Research Inc. | Anticancer agent containing minus-strand RNA virus |
CA3123228A1 (en) * | 2008-03-27 | 2009-10-01 | Asterias Biotherapeutics, Inc. | Differentiation of primate pluripotent stem cells to hematopoietic lineage cells |
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EP2154243B1 (en) | 2016-01-13 |
JP5227317B2 (ja) | 2013-07-03 |
KR101506751B1 (ko) | 2015-03-27 |
KR20100035634A (ko) | 2010-04-05 |
EP2154243A4 (en) | 2011-07-06 |
US8283163B2 (en) | 2012-10-09 |
CN101755045A (zh) | 2010-06-23 |
WO2008143047A1 (ja) | 2008-11-27 |
EP2154243A1 (en) | 2010-02-17 |
CA2687534A1 (en) | 2008-11-27 |
US20100184214A1 (en) | 2010-07-22 |
CN101755045B (zh) | 2014-02-12 |
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