JP2010515442A - 単球を増殖するための方法 - Google Patents
単球を増殖するための方法 Download PDFInfo
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Abstract
Description
i)MafBおよびc−Mafを発現しないマウスに由来する単球を単離すること、および
ii)M−CSFの存在下で前記単球を培養すること
からなるステップを含む方法をさらに提供する。
定義:
「コード配列」またはRNA、ポリペプチド、タンパク質、または酵素などの発現産物を「コードする」配列は、発現時に、そのRNA、ポリペプチド、タンパク質、または酵素の生成をもたらすヌクレオチド配列である、すなわちヌクレオチド配列は、そのポリペプチド、タンパク質、または酵素のアミノ酸配列をコードする。タンパク質のコード配列は、開始コドン(通常ATG)および停止コドンを含み得る。
本発明者は、単球を数カ月間の培養中に、前記細胞中のMafBおよびc−Mafの発現を不活性化することによって、生成、維持および増殖することができることを実証している。
単球を単離すること、
前記単球中のMafBおよびc−Mafの発現または活性を阻害すること、
マクロファージまたは樹状細胞への単球の分化を可能にする条件で、MafBおよびc−Mafの発現または活性が阻害されている単球を培養することを含む。
本発明の方法は、治療分野で大変興味深い、単球、マクロファージまたは樹状細胞の生成をもたらす。
本発明の他の目的は、マウス単球を生成するための方法に関するものであり、前記方法は
i)MafBおよびc−Maf因子に欠陥があるマウスに由来する単球を単離すること、および
ii)M−CSFの存在下で前記単球を培養すること
からなるステップを含む。
本発明によれば、単球、マクロファージおよび樹状細胞はin vitroで容易かつ効果的に生成することができる。多数のin vitro増殖単球、マクロファージおよび樹状細胞を得る能力は治療分野の新たな機会を開く。
本発明は医薬組成物を提供する。このような組成物は、本発明によって生成される治療有効量の単球および/またはマクロファージおよび/または樹状細胞、および薬剤として許容される担体または賦形剤を含む。前に記載した「治療有効量」の細胞とは、任意の医学的治療に適用可能な妥当なリスク対効果比で、疾患または障害を治療するのに十分な量の前記細胞を意味する。しかしながら、本発明の組成物の1日当たりの全使用量は、理にかなった医学的判断の範囲内で主治医によって決定され得ることは理解されよう。任意の特定の患者に関する具体的な治療有効用量のレベルは、治療する障害および障害の重度、利用する具体的な化合物の活性、利用する具体的な組成物、患者の年齢、体重、一般的な健康状態、性別および食生活、投与の時間、投与の経路、および利用する具体的な化合物の排出速度、治療の期間、利用する具体的な細胞と併用または同時に使用する薬剤、および医学分野でよく知られている同様の要因を含めた様々な要因に依存するはずである。
本発明の単球、マクロファージおよび樹状細胞を、前記細胞が対象のタンパク質をコードする対象の治療用核酸を発現するように、さらに遺伝子工学処理することができる。
ドナー器官の供給不足のために、同種移植片に対する代替が大いに必要とされている。細胞補充療法は、肝臓、膵臓、または膵島細胞移植に対する魅力的な代替を与えることができる。このような療法は、移植が不可能であるかまたは示されない器官系における治療の選択肢を与えることもできる。幹細胞または前駆細胞だけでなく、成熟単球、マクロファージを含めた骨髄単球性委任細胞も、特に肝臓および膵臓における器官再生を目的とするターゲティングおよび高耐性細胞療法に関する有意な可能性を与えることが近年示されている。マウス起源とヒト起源の両方のこのような成熟骨髄単球性細胞は、異なるマウスモデル中の肝臓および膵島β組織に有意に貢献することができ、これらの器官において組織特異的機能を果たすことができることは示されている(Camargo,F.D.,Green,R. et al,2003;Willenbring,Bailey et al.2004;Ruhnke,Ungefroren et al.2005)。この機構は完全には明らかでないが、これらの観察結果は、損傷器官へのマクロファージの直接投与またはそれらの増殖性前駆細胞の全身移植は、魅力的な低侵襲性の治療戦略となることを示す。しかしながら、この手法の臨床適用性の展望は、培養中に十分な数の単球を増幅することが困難であることによって妨げられる。
特定の疾患では、単球、マクロファージまたは樹状細胞を破壊する、またはその数を減らすこと、または感染単球、マクロファージまたは樹状細胞を標的とし、治療することのいずれかが望ましい可能性がある。このような場合、単球、マクロファージまたは樹状細胞を標的とする薬剤を開発することが望ましい。
マウス:本発明者らは、129Sv−C57BL/6バックグラウンドのMafB欠損マウスの生成、およびmafBおよびgfp用のプライマーを用いたPCRによるそれらの遺伝子型決定、ノックアウト対立遺伝子におけるmafBの置換(Bianchi et al.2003)を以前に記載した。c−Maf欠損マウスの生成も記載されている(Kim et al.1999)。MafB+/−とc−Maf+/−マウスを交配してMafB;c−Maf+/−;+/−マウスを得て、これらを異系交配してMafB;c−Maf−/−;−/−胚を得た。全ての実験は、特定病原体を含まない条件下に維持したマウスを使用して機関のガイドラインに従い実施した。
MafB、c−Maf二重欠損胎児肝細胞は単球コロニー形成能を増大させた:MafB欠損は新生児期に致死的であるので、本発明者らは、E14.5胎児肝臓中の造血に対するMafB/c−Maf二重欠損の影響を分析した。系統特異的表面マーカーのFACS染色によって、MafB/c−Maf欠損E14.5胎児肝臓における系統分布の異常が露呈することはなかった。特異的サイトカインに応答して増殖する可能性がある細胞数を定量化するために、E14.5胚由来のMafB/c−Maf欠損または野生型(WT)対照細胞を、サイトカイン混合物(II−3、II−6、GM−CSF、SCFおよびEpo;図1A)または個々の骨髄性サイトカイン(M−CSF、GM−CSF、G−CSFまたはII−3、図1B〜E)のいずれかを含むメチルセルロース培地中で培養した。単球コロニー(CFU−M)は、単球増殖を支持する全ての条件(M−CSF、GM−CSF、IL−3および混合条件)下で、野生型胎児肝細胞と比較してMafB/c−Maf欠損に関して有意に増大し、一方他の型のコロニーは依然として正常範囲内であった。さらに、単球コロニーのこのような増大は、個々のMafBまたはc−Maf欠損胎児肝細胞においては見られなかった(示さず)。これは、MafBとc−Mafの複合消失は、骨髄性サイトカインに応答して単球コロニーを生じる細胞数の増大をもたらしたことを示した。
Claims (17)
- 単球、マクロファージまたは樹状細胞を増殖するためのex vivoでの方法であって、単球、マクロファージまたは樹状細胞中のMafBおよびc−Mafの発現または活性を阻害すること、および少なくとも1つのサイトカインの存在下で前記細胞を増殖することを含む方法。
- MafBおよびc−Mafの発現を、siRNAオリゴヌクレオチド、アンチセンスオリゴヌクレオチドまたはリボザイムを使用することによって阻害する、請求項1に記載の方法。
- MafBおよびc−Mafの活性を、野生型MafBおよびc−Mafと競合する突然変異MafBおよびc−Mafポリペプチドを使用することによって阻害する、請求項1に記載の方法。
- サイトカインがM−CSFである、請求項1から3のいずれかに記載の方法。
- 請求項1から4のいずれかに記載の方法によって得ることができる単球、マクロファージまたは樹状細胞。
- MafBおよびc−Mafを発現しない、またはその中でMafBおよびc−Mafの発現または活性が無効化または阻害されている、単球、マクロファージまたは樹状細胞。
- MafBおよびc−Maf遺伝子を欠く、請求項6に記載の単球、マクロファージまたは樹状細胞。
- マウス起源である、請求項5から7のいずれかに記載の単球、マクロファージまたは樹状細胞。
- ヒト起源である、請求項5から7のいずれかに記載の単球、マクロファージまたは樹状細胞。
- ミクログリア、組織球、ホーフバウアー細胞、メサンギウム細胞、クッパー細胞、腹腔マクロファージ、肺胞マクロファージ、表皮または皮膚マクロファージ、辺縁帯マクロファージ、メタロフィリックマクロファージ、赤脾髄マクロファージ、白脾髄マクロファージおよび破骨細胞からなる群から選択される、請求項5から9のいずれかに記載のマクロファージ。
- 抗原分子をさらに添加した、請求項5から9のいずれかに記載の樹状細胞。
- 請求項5から9のいずれかに記載の単球、マクロファージまたは樹状細胞を薬剤として許容される担体と組み合わせて含む医薬組成物。
- ワクチンとして使用するための、抗原分子を添加した請求項11に記載の樹状細胞を含む医薬組成物。
- 癌、急性または後天性免疫不全症、慢性または急性損傷、創傷、変性疾患、自己免疫疾患、慢性炎症疾患、アテローム性動脈硬化症、多発性関節炎および骨関節炎、骨粗鬆症、感染性疾患、および代謝性疾患からなる群から選択される疾患の治療を目的とする医薬品を製造するための、請求項5から11のいずれかに記載の単球、マクロファージまたは樹状細胞の使用。
- 再生医療を目的とする医薬品を製造するための、請求項5から11のいずれかに記載の単球、マクロファージまたは樹状細胞の使用。
- 薬剤をスクリーニングするための、請求項5から11のいずれかに記載の単球、マクロファージまたは樹状細胞の使用。
- マウス単球を生成および増殖するための方法であって、
i)MafBおよびc−Mafを発現しないマウスに由来する単球を単離すること、および
ii)M−CSFの存在下で前記単球を培養すること
からなるステップを含む方法。
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